Asymmetric Cyanosilylation of Ketones Catalyzed by Bifunctional Chiral N-Oxide Titanium Complex Catalysts

Article abstract of DOI:10.1002/ejoc.200300415

A new bifunctional catalytic system based on chiral N-oxide titanium complexes has been used for the asymmetric cyanosilylation of ketones. Screening of a variety of chiral N-oxide metal complexes resulted in (1R,2S)-1-(2'-pyridylmethyl)-2-(diphenylhydroxymethyl)pyrrolidine N-oxide titanium complex, which gave O-TMS cyanohydrins in good yields with enantiometric excesses of up to 69 percent. A catalytic cycle based on experimental phenomena and studies was proposed to explain the origin of the asymmetric induction.

Full text of DOI:10.1002/ejoc.200300415

FULL PAPER
Asymmetric Cyanosilylation of Ketones Catalyzed by Bifunctional Chiral
N-Oxide Titanium Complex Catalysts
Yongcun Shen,[b] Xiaoming Feng,*[a] Yan Li,[a] Guolin Zhang,[c] and Yaozhong Jiang[b]
Keywords: Asymmetric catalysis / Asymmetric synthesis / Enantioselectivity / Ketones / N,O ligands
A new bifunctional catalytic system based on chiral N-oxide
titanium complexes has been used for the asymmetric cyano-
enantiomeric excesses of up to 69 %. A catalytic cycle based
on experimental phenomena and studies was proposed to
silylation of ketones. Screening of a variety of chiral N-oxide explain the origin of the asymmetric induction.
metal complexes resulted in (1R,2S)-1-(2Ј-pyridylmethyl)-2-
(diphenylhydroxymethyl)pyrrolidine N-oxide titanium com-
plex, which gave O-TMS cyanohydrins in good yields with
( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2004)
Introduction
to quinoline or isoquinoline derivatives (Reissert-type reac-
tion).[6] We have recently reported that chiral N-oxides can
effectively activate TMSCN to catalyze the asymmetric cy-
anosilylation of imines[7] and that achiral and chiral N-ox-
ide titanium complexes can effectively catalyze the cyanosi-
lylation of ketones.[8] This paper describes the studies of
relationships between catalyst structure and activity, sub-
strate generality, mechanism, and limitations of asymmetric
cyanosilylation of ketones catalyzed by chiral N-oxide ti-
tanium complexes.
A number of recent studies have shown that multifunc-
tional catalysts possess special characteristics for catalysis
and asymmetric synthesis.[1] These catalysts must contain a
Lewis acid moiety that activates an electrophilic substrate
and a Lewis base moiety that activates a nucleophilic sub-
strate. The positioning of the two reactive partners in close
proximity and with the correct relative geometry by such a
catalyst assembly facilitates a reaction in a manner similar
to that of Nature’s enzymatic processes. Dual coordination
by such catalyst assemblies further assists the reaction by
simultaneously enhancing the electrophilic character of one
partner and the nucleophilic character of the other.[2]
An example of this motif can be found in heterodimetal-
lic complexes in which the central metal atom, as a Lewis
acid, has been proposed to coordinate with the electrophile,
while an appropriate functionality, such as the hemilable
BINOLate oxygen atoms, functions as a Lewis base to co-
ordinate with the nucleophile. Very recently, Shibasaki et al.
have reported a series of bifunctional Lewis acid/Lewis base
(LALB) catalysts derived from BINOL and natural glucose
as the chiral scaffold. In particular, phosphane oxide de-
rived catalysts (Figure 1) were very efficient for the asym-
metric cyanosilylation of aldehydes,[3] imines (Strecker reac-
tion),[4] and ketones,[5] as well as for the addition of cyanide
Figure 1. Structure of bifunctional catalysts
Results and Discussion
We selected Corey’s reagent as a scaffold for arranging
the Lewis acid and Lewis base moieties as shown in Fig-
ure 2. While the Lewis acid metal atom was connected to
the hydroxy group of the hydroxymethyl function at the 2-
position and an available coordinating atom at the 1-posi-
tion, a Lewis base N-oxide moiety was located at the 1-
position to promote the reaction effectively by a dual acti-
vation pathway. The following two points were considered
in the design of the ligands. Ligands containing atoms with
different coordinate abilities on the aryl ring at the 1-posi-
tion were to be investigated for the effect of ligandϪmetal
[a]
Sichuan Key Laboratory of Green Chemistry and Technology,
College of Chemistry, Sichuan University,
Chengdu 610064, China
Fax: (internat.) ϩ 86-28-85418249
E-mail: xmfeng@pridns.scu.edu.cn
[b]
Chengdu Institute of Organic Chemistry, Chinese Academy of
Sciences,
Chengdu 610041, China
[c]
Chengdu Institute of Biology, Chinese Academy of Sciences,
Chengdu 610041, China
Eur. J. Org. Chem. 2004, 129Ϫ137
DOI: 10.1002/ejoc.200300415
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
129

Y. Shen, X. Feng, Y. Li, G. Zhang, Y. Jiang
FULL PAPER
complexes on reactivity and enantioselectivity. On the other
hand, the steric effects of the substituents on the hydroxy-
methyl group at the 2-position and the aryl ring at the 1-
position were also to be considered. The ligand structures
shown in Figure 2 were very flexible for optimization of the
structures of the ligands by changing of the metal, the coor-
dination abilities of coordinate atoms on the aryl ring at the
1-position and the steric effects of aryl ring and substituents
on the hydroxymethyl moiety at the 2-position.
Scheme 1. Synthesis of ligands
Table 1. Asymmetric cyanosilylation of acetophenone catalyzed by
N-oxide Ti(OiPr)4 complexes
Entry[a] Catalyst
Time [h] Yield [%] ee [%][b] Config.[c]
1
2
3
4
5
6
7
8
(1R,2S)-2a 30
32
48
5
27
29
36
35
11
0.8
51.0
10.0
9.0
43.0
7.5
(S)
(R)
(S)
(S)
(R)
(R)
(S)
(S)
Figure 2. The designed Lewis acid/Lewis base catalyst
(1R,2S)-2b 30
(1R,2S)-2c 30
(1R,2S)-2d 30
(1R,2S)-2e 30
(1R,2S)-2f 48
(1R,2S)-2g 96
(1R,2S)-2h 48
Optimization of the Catalyst
4.3
15.5
To optimize the catalytic activity of complexes 2aϪh, a
series of amino N-oxides 1aϪh were prepared as shown in
Scheme 1. Complexes of 1aϪh and titanium were tested for
their capability to catalyze the asymmetric addition of tri-
[a]
All reactions were carried out at 0 °C according to the exper-
imental procedure, ligand/Ti(OiPr)4 ϭ 1:1.2. [b] Determined by chi-
ral GC assay (Chirasil DEX CB). [c] Determined by comparison of
the elution order of chiral GC assay with that reported in the litera-
methylsilyl cyanide to acetophenone at 0 °C. The results, ture.[5,9]
shown in Table 1, illustrate that the structure of the ligand
strongly affects the reactivity and enantioselectivity. The
screening results indicate that the catalysts 2aϪh, with simi-
To optimize the reaction conditions, a series of metals
lar structures, have different enantioselective induction was screened in combination with ligand (1R,2S)-1b for ca-
abilities. Complex (1R,2S)-2a was ineffective in promoting talysis of the addition of TMSCN to acetophenone
the enantioselective cyanosilylation of acetophenone (Table 2). Although the Zr and Sm catalysts showed better
(Table 1, Entry 1). The best result, shown in Entry 2 of reactivities (Table 2, Entries 2 and 3), it was found that the
Table 1, gave the O-TMS cyanohydrin with 51 % ee on ap- Ti catalyst gave the best enantioselectivity (Table 2, Entry
plication of (1R,2S)-2b, introduced into catalytic asymmet- 4). We also examined the effects of solvent. Better results
ric reduction of ketones by O’Neil,[10] while chiral catalysts were obtained in halogenated solvents such as CH2Cl2 and
(1R,2S)-2c, (1R,2S)-2d, and (1R,2S)-2h gave no meaningful CHCl3 (Table 3, Entries 3 and 5). Although better enanti-
enantiomeric excess (Table 1, Entries 3, 4, and 8). We at- oselectivity was also obtained in THF, the reactivity in THF
tempted to improve the enantiomeric excess of the product was obviously inferior to that in CH2Cl2 (Table 3, Entry 4).
by increasing the bulk of the substituent on the hydroxy-
methyl moiety at the 2-position with β-naphthyl instead of
phenyl, but the catalytic activity of catalyst (1R,2S)-2e was
apparently inferior to that of catalyst (1R,2S)-2b (Table 1,
Entry 5). When Ar ϭ 2-pyridyl, we further explored the
effects on the enantioselectivity of the ortho substituent of
the 2-pyridyl ring. The results indicated that the ortho-posi-
tion substituent greatly affected the enantioselectivity. In-
creasing bulk of the ortho-position substituent resulted in
the ee value of the product being sharply decreased
(Table 1, Entries 6 and 7), probably due to spatial hindrance
by the substituent blocking the coordination between the
nitrogen and the titanium atoms.
Table 2. Effect of combination of different metals with (1R,2S)-1b
on the asymmetric addition of TMSCN to acetophenone
Entry[a]
M(OR)x
Yield [%]
ee [%][b]
Config.[c]
1
2
3
4
Al(OiPr)3
Sm(OiPr)3
Zr(OtBu)4
Ti(OiPr)4
19
64
67
48
0.8
0.2
1.0
(S)
(R)
(S)
(R)
51.0
[a]
All reactions were carried out at 0 °C for 30 h according to the
experimental procedure. [b] Determined by chiral GC assay (Chira-
sil DEX CB). [c] Determined by comparison of the elution order of
chiral GC assay with that reported in the literature.[5,9]
130
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Eur. J. Org. Chem. 2004, 129Ϫ137

Asymmetric Cyanosilylation of Ketones
FULL PAPER
The effect of the molar ratio of ligand (1R,2S)-1b to TiIV
was then examined (Table 4), and it was found that the ratio
of ligand to TiIV had a large effect on the enantioselectivity
of the reaction. Increasing the ratio of ligand to TiIV pro-
duced decreases in enantioselectivity and increases in yields.
The best result was obtained when the molar ratio of ligand
to TiIV was 1:1.2 (Table 4, Entry 2). Further studies indi-
cated that the concentration of acetophenone had a slight
effect on the enantioselectivity, but a larger effect on the
yield of the addition of TMSCN to acetophenone. The op-
timum concentration of acetophenone was 0.34  (Table 5,
Table 3. Effects of solvent on the asymmetric addition of TMSCN
to acetophenone
Entry[a]
Solvent
Yield [%]
ee [%][b]
1
2
3
4
5
Et2O
51
56
48
43
66
3.5 (R)
14 (R)
51 (R)
53 (R)
47 (R)
toluene
CH2Cl2
THF
CHCl3
[a]
All reactions were carried out at 0 °C for 30 h according to the
experimental procedure. [b] Determined by chiral GC assay (Chira-
sil DEX CB) and by comparison of the elution order of chiral GC Entry 3).
assay with that reported in the literature.[5,9]
The proportion of the catalyst was an important factor
for the asymmetric cyanosilylation of acetophenone. When
the proportion of catalyst was 20 mol %, the reaction pro-
ceeded more efficiently at 0 °C to give the product in 48 %
yield with 51 % ee after 30 h (Table 5, Entry 2). When the
proportion of the catalyst was increased further, the yield
was greatly decreased. When the catalyst was used in stoi-
chiometric amounts, the product was obtained only in
traces (Table 6, Entry 6). This was probably due to an ag-
gregation of catalyst molecules reducing the effective quan-
tity of the catalyst.
Only a small temperature effect was observed for the re-
action in the presence of catalyst (1R,2S)-2b, as shown in
Table 7. The reaction gave O-TMS cyanohydrin with 51 %
ee in 48 % yield at 0 °C for 30 h, but the reaction carried
out at Ϫ27 °C gave only trace amounts of product with
57 % ee after 38 h. Consequently, the best reaction con-
ditions were found to involve 20 mol % of (1R,2S)-1b
Ti(OiPr)4 (1:1.2) and 0.34  acetophenone in CH2Cl2 at
0 °C.
Table 4. Effects of the ratio of (1R,2S)-1b to TiIV on the asymmetric
addition of TMSCN to acetophenone
Entry[a]
(1R,2S)-1b/TiIV
(molar ratio)
Yield [%]
ee [%][b]
1
2
3
4
5
0.5:1
0.83:1
1:1
1.25:1
2:1
16
48
64
59
80
50 (R)
51 (R)
46 (R)
23 (R)
0
[a]
All reactions were carried out at 0 °C for 30 h according to the
experimental procedure. [b] Determined by chiral GC assay (Chira-
sil DEX CB) and by comparison of the elution order of chiral GC
assay with that reported in the literature.[5,9]
Table 5. Effects of the concentration of acetophenone on the asym-
metric addition of TMSCN to acetophenone catalyzed by (1R,2S)-
1b Ti(OiPr)4 complex
Table 7. Effects of temperature on the asymmetric addition of
TMSCN to acetophenone
Entry[a] Concentration [mol/L] Time [h] Yield [%] ee [%][b]
Entry[a]
Temp. [°C]
Time [h]
Yield [%]
ee [%][b]
1
2
3
4
0.085
0.170
0.340
0.680
30
30
30
30
27
48
61
48
53 (R)
51 (R)
53 (R)
50 (R)
1
2
3
0
Ϫ27
Ϫ78
30
38
72
48
6
trace
51 (R)
57 (R)
Ϫ
[a]
[a] All the reactions were carried out at 0 °C according to the exper-
All the reactions were carried out according to the experimental
[b]
[b]
procedure.
Determined by chiral GC assay (Chirasil DEX CB)
imental procedure.
Determined by chiral GC assay (Chirasil
and by comparison of the elution order of chiral GC assay with
DEX CB) and by comparison of the elution order of chiral GC
that reported in the literature.[5,9]
assay with that reported in the literature.[5,9]
Table 6. Effects of the proportion of catalyst (1R,2S)-2b on the asymmetric addition of TMSCN to acetophenone
Entry[a]
Proportion of catalyst [mol %]
Temp. [°C]
Time [h]
Yield [%]
ee [%][b]
1
2
3
4
5
6
10
20
20
30
50
100
Ϫ27
Ϫ27
0
0
0
0
34
38
30
30
30
30
trace
trace
48
48
37
29 (R)
57 (R)
51 (R)
53 (R)
46 (R)
Ϫ
trace
[a]
All reactions were carried out according to the experimental procedure. [b] Determined by chiral GC assay (Chirasil DEX CB) and by
comparison of the elution order of chiral GC assay with that reported in the literature.[5,9]
Eur. J. Org. Chem. 2004, 129Ϫ137
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 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
131

Y. Shen, X. Feng, Y. Li, G. Zhang, Y. Jiang
FULL PAPER
In order to improve the enantioselectivity of the asym-
metric cyanosilylation of acetophenone, we investigated the
use of chiral or achiral additives such as R-BINOL and
Ph3PO etc. (Figure 3). Unfortunately, no effective additive
was found. In addition, it was surprising that the reaction
Table 8. The effects of different chiral and achiral additives on the
asymmetric addition of TMSCN to acetophenone catalyzed by
(1R,2S)-2b complex
Entry[a] Additive [mol %]
Time [h] Yield [%] ee [%][b]
˚
did not proceed when molecular sieves (4 A), an effective
˚
1
2
3
4
5
6
7
8
molecular sieves (4 A)
salen 11 [20]
(S)-10 [20]
Ph3PϭO [20]
(R)-10 [20]
30
30
30
36
41
Ϫ
Ϫ
additive in some asymmetric reactions, were used as an ad-
ditive in the reaction. One possible explanation for this was
the existence of a hydrogen bond between the NϪO group
of the N-oxide and the surface of the molecular sieves
65
69
64
64
51
64
93
57
40
53
48
49 (R)
0 (R)
7 (R)
1 (R)
1 (R)
0 (R)
0 (R)
2 (R)
11 (R)
2 (R)
12 (R)
isoquinoline N-oxide [109 41
˚
(4 A), hindering the NϪO group of the N-oxide from
calix[4]arene [10]
ortho-ethoxyphenol [10]
(R)-9 [20]
30
30
41
30
44
44
activating TMSCN.
9
10
11
12
(S)-9 [20]
CH3Ph2PϭO [20]
CH3Ph2PϭO [40]
[a] All the reactions were carried out at 0 °C according to the experi-
[b]
ment procedure. Determined by chiral GC assay (Chirasil DEX
CB) and by comparison of the elution order of chiral GC assay
with that reported in the literature.[5,9]
The experimental results indicated that the ee values ob-
tained were strongly dependent on the ketones used (i.e.,
the nature of the substrates strongly influenced the reactiv-
ity and enantioselectivity). Ketones with substituents in or-
tho positions were most notable; 2Ј-fluoroacetophenone, for
example, gave the product in 47 % yield with 55 % ee. This
was the first example of asymmetric cyanosilylation of 2Ј-
fluoroacetophenone. Interestingly, benzylacetone and trans-
4-phenyl-3-buten-2-one as substrate gave the products in
68 % ee and 25 % ee, respectively. These results are different
from those of Shibasaki.[5]
Figure 3. Additives used
Substrate Generality
Encouraged by the results from acetophenone with
(1R,2S)-2b complex as a catalyst, we investigated the scope
of the asymmetric cyanosilylation of ketones under the op-
timized conditions (Table 8). A summary of the results ob-
tained is presented in Table 9. The data show that aromatic,
conjugated, and aliphatic ketones afforded the correspond-
ing products in moderate to good yields with moderate
% ees.
Preliminary Mechanistic Studies
Mechanistic studies provided a proposed mechanism
(Scheme 2) and a proposed transition state accounting for
Table 9. Asymmetric cyanosilylation of ketones catalyzed by (1R,2S)-2b complex
Entry[a]
Ketone
Time [h]
Yield [%][b]
ee [%]
Config.[c]
1
2
3
4
5
6
7
8
acetophenone
96
96
96
78
73
77
87
61
63
76
47
67
74
35
54[d]
69[e]
25[e]
68[d]
37[d]
41[d]
33[d]
55[d]
33[d]
26[d]
20[d]
(R)
(R)
(R)
(R)
(R)
(R)
(R)
(R)
(R)
(R)
(R)
β-acetonaphthanone
trans-4-phenyl-3-buten-2-one
benzylacetone
120
120
96
120
96
120
120
120
α-tetralone
4Ј-methylacetophenone
3Ј-chloroacetophenone
2Ј-fluoroacetophenone
4Ј-fluoroacetophenone
β-tetralone
9
10
11
2-acetylthiophene
[a]
[b]
All reactions were carried out at 0 °C according to the experimental procedure, (1R,2S)-1b/Ti(OiPr)4 ϭ 1:1.2. The yields given are
for the isolated O-TMS cyanohydrins after chromatographic purification; satisfactory spectroscopic (1H NMR,13C NMR, IR) and elemen-
[c]
tal analysis data were obtained for new compounds.
Determined by comparison of the elution order of chiral GC and HPLC (see
refs.[5,9]). Determined by chiral GC assay (Chirasil DEX CB). Determined by chiral HPLC assay (Chiralcel OJ).
[d]
[e]
132  2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim www.eurjoc.org
Eur. J. Org. Chem. 2004, 129Ϫ137

Asymmetric Cyanosilylation of Ketones
FULL PAPER
the origin of the asymmetric induction in cyanosilylation of combination of complex 13 with TMSCN would generate
ketones catalyzed by chiral (1R,2S)-2b (ligand/titanium ϭ the key intermediate 14.
1:1.2 ratio) complex.
Intermediate 14 is made up of both an activated ketone
and activated TMSCN. Intramolecular transfer of cyanide
within 14 would generate a complex 15 containing a ti-
tanium ion bound to cyanohydrin. Subsequent intramol-
ecular trimethylsilylation would give product O-TMS cy-
anohydrin and complex 12. Ketone coordinated to complex
12 would regenerate complex 13. This catalytic cycle also
correctly predicted the sense of asymmetric induction, coor-
dination of the acetophenone so as to minimize interactions
between the acetophenone and the phenyl group of the li-
gand (Figure 4) resulting in an orientation in which the si
face of the acetophenone would be exposed to intramolecu-
lar attack by the cyanide of activated TMSCN, producing
the (R) enantiomer of the O-TMS cyanohydrin.
Figure 4. Representation of the transition state for reaction
between a ketone and trimethylsilyl cyanide catalyzed by intermedi-
ate 14
Scheme 2. Proposed catalytic cycle
Conclusions
To investigate whether the NϪO moiety of the catalyst
N-oxide was coordinated to the central titanium ion, a com-
parison of different procedures for the preparation of cata-
lyst for asymmetric cyanosilylation of acetophenone was
undertaken. Were the NϪO group of ligand N-oxide coor-
dinated to the titanium ion in the preparation of the cata-
lyst, the coordination of the titanium ion would be satu-
rated and other coordinating groups would not change its
coordination. Hence, the enantioselectivity of the cyanide
addition to ketones would be similar in cases in which the
solvent was evaporated in vacuo and in which the solvent
was not removed after the preparation of the catalyst. In
fact, the observed enantiomeric excesses (49 and 0 %,
respectively) were surprisingly different. This suggested that
the small amount of 2-propanol produced by the prep-
aration of the catalyst had a large effect on the enantioselec-
tivity of the reaction and that the presence of 2-propanol
changed the coordination of the catalyst. On the other
hand, when additives with coordinated atoms were em-
In summary, we have synthesized a new chiral N-oxide
titanium complex to promote the asymmetric cyanosilyl-
ation of ketones. The reaction is mechanistically interesting
as the first asymmetric cyanosilylation of ketones achieved
by an N-oxide titanium approach. The experiments suggest
that the (1R,2S)-2b [ligand/Ti(OiPr)4 ϭ 1:1.2] complex
should promote the reaction through dual activation of ke-
tones by the titanium ion and TMSCN by the NϪO group
of the N-oxide. Importantly, the ligand of (1R,2S)-2b was
readily prepared from an inexpensive and readily available
chiral amino acid. Additional notable features of the reac-
tion included the simplicity and practical aspects of the
method. These features should provide potential for devel-
opment of this kind of fine-tuning catalyst. Future efforts
will be devoted to further searching for effective catalysts
for the asymmetric cyanosilylation of ketones.
ployed, we found that they produced deleterious enantiose- Experimental Section
lectivities (Table 8). This also indicated that the N-oxide
General: NMR spectra were recorded with Bruker 200, 300, and
NϪO group was not coordinated to the titanium ion of
the catalyst. Another feature also supports this conclusion.
When the proportion of the catalyst was increased, the yield
was decreased to trace amounts (Table 6). This indicated
that aggregation among catalyst molecules should be pre-
sent; otherwise a positive effect of loading of a catalyst
would have been expected for the reaction.
1
400 spectrometers, at 300 and 400 MHz for H NMR and 75 and
100 MHz for 13C NMR spectroscopy, respectively. Chemical shifts
1
in CDCl3 are reported downfield from TMS (δ ϭ 0) for H NMR
spectroscopy. For 13C NMR, chemical shifts are reported relative
to CDCl3 (δ ϭ77.00 ppm for 13C NMR as an internal reference).
IR spectra were recorded with a PerkinϪElmer 1600 series FT-IR
spectrometer. Column chromatography was performed on silica gel
H 60. In general, reactions were carried out in dry solvents under
A mechanistic hypothesis consistent with all of the obser-
vations discussed above is shown in Scheme 2. Thus, the nitrogen, unless otherwise noted. The enantiomeric excesses (ees)
Eur. J. Org. Chem. 2004, 129Ϫ137
www.eurjoc.org  2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 133

Y. Shen, X. Feng, Y. Li, G. Zhang, Y. Jiang
were determined by HPLC and GC analysis. HPLC was performed H) ppm. 13C NMR (100 MHz, CDCl3): δ ϭ 24.16, 29.79, 55.52,
FULL PAPER
with Waters HPLC systems consisting of the following: pump 880-
PU; detector 875-UV, measured at 254 nm; column Daicel Chiral-
60.57, 70.59, 77.94, 125.54, 125.58, 126.23, 126.37, 126.83, 128.07,
128.09, 128.17, 128.58, 139.65, 146.63, 147.99 ppm. IR (film): ν˜ ϭ
pak AS, AD, or Daicel Chiralcel OJ, OD; mobile phase hexane/2- 703, 766, 1100, 1128, 1447, 1492, 2967, 3436 cmϪ1. C24H25NO
propanol; flow rate, 0.5Ϫ1.0 mL/min. Chiral GC was performed (343.4): calcd. C 83.93, H 7.34, N 4.08; found C 83.79, H 7.16,
with a Varian GC system: column Chirasil Dex CB. Optical ro-
tations were recorded with a PerkinϪElmer 341 polarimeter, and
are reported together with the solvent and the concentration in g/
100 mL. Melting points are uncorrected. Elemental analyses were
performed with a Carlo-1106 analyzer. Tetrahydrofuran (THF) and
diethyl ether (Et2O) were distilled from sodium benzophenone ke-
tyl. Dichloromethane (CH2Cl2) was distilled from calcium hydride.
Other reagents were purified by conventional methods.
N 4.07.
(S)-2-(Hydroxydiphenylmethyl)-1-(2Ј-pyridylmethyl)pyrrolidine (6b):
Purification of the residue by silica gel column chromatography
(50 % EtOAc/petroleum ether) afforded a solid, which was recrys-
tallized from diethyl ether to give the title compound 6b (255.9 mg,
74 %) as colorless crystals; m.p. 120Ϫ123 °C. [α]2D9 ϭ ϩ39.6 (c ϭ
1
0.7 in CHCl3). H NMR (400 MHz, CDCl3): δ ϭ 1.63Ϫ1.68 (m, 2
H), 1.74Ϫ1.79 (m, 1 H), 1.93Ϫ2.01 (m, 1 H), 2.48Ϫ2.55 (m, 1 H),
2.97 (m, 1 H), 3.35 (m, 1 H), 4.06 (d, J ϭ 4.8 Hz, 1 H), 4.09 (d,
J ϭ 4.8 Hz, 1 H), 4.98 (br. s, 1 H), 7.05Ϫ7.10 (m, 3 H), 7.14Ϫ7.31
(m, 5 H), 7.57 (d, J ϭ 7.2 Hz, 3 H), 7.68 (d, J ϭ 7.2 Hz, 2 H), 8.42
(d, J ϭ 4 Hz, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ ϭ 24.38,
29.61, 55.71, 62.23, 70.89, 78.01, 121.79, 122.44, 125.55, 125.59,
126.24, 126.37, 128.01, 128.11, 136.31, 146.36, 147.71, 148.58,
159.69 ppm. IR (film): ν˜ ϭ 704, 750, 1100, 1186, 1478, 1590, 1620,
2954, 3332 cmϪ1. C23H24N2O (344.5): calcd. C 80.20, H 7.02, N
8.13; found C 80.02, H 6.91, N 8.08.
Methyl (S)-1-Arylpyrrolidine-2-carboxylates 5: Triethylamine
(2.0 mL, 15.3 mmol) was added at room temperature to a solution
of -proline methyl ester hydrochloride (4) (1.66 g, 10 mmol) in dry
DMF (10 mL) and the mixture was stirred at room temperature for
5 min. The mixture was then filtered to give a solution of -proline
methyl ester in dry DMF. The syntheses of methyl (S)-1-arylpyrrol-
idine-2-carboxylates proceeded according to ref.[12] A solution of -
proline methyl ester was added dropwise to a mixture of halomethyl
aromatic compound (6.67 mmol), anhydrous K2CO3 (0.78 g,
5.65 mmol), and NaI (44 mg, 0.29 mmol) in dry DMF (50 mL).
The mixture was kept at 50 °C, and the reaction monitored by TLC
until the halomethyl aromatic compound had disappeared. The
mixture was then poured into water (100 mL), the resulting mixture
was extracted with CH2Cl2 (3 ϫ 20 mL), and the organic layer
was washed with water (50 mL) and dried with anhydrous sodium
sulfate. Evaporation of the solvent under reduced pressure and
purification of the residue by silica gel column chromatography
(50 % EtOAc/petroleum ether) afforded the title compounds
5aϪ5g, which were used for the next reaction without further puri-
fication.
(S)-2-(Hydroxydiphenylmethyl)-1-(2Ј-methoxyphenylmethyl)-
pyrrolidine (6c): Purification of the residue by silica gel column
chromatography (petroleum ether/EtOAc ϭ 10:1) afforded a solid,
which was recrystallized from diethyl ether to give the title com-
pound 6c (283.9 mg, 76 %) as colorless crystals; m.p. 112Ϫ113 °C.
[α]2D3 ϭ ϩ103.6 (c ϭ 1.0 in CHCl3). H NMR (400 MHz, CDCl3):
1
δ ϭ 1.62 (m, 2 H), 1.74 (m, 1 H), 1.95 (m, 1 H), 2.34 (m, 1 H),
2.90 (m, 1 H), 2.96 (d, J ϭ 12.4 Hz, 1 H), 3.13 (d, J ϭ 12.4 Hz, 1
H), 3.76 (s, 3 H), 3.95 (m, 1 H), 4.94 (br. s, 1 H), 6.77 (d, J ϭ
8.8 Hz, 2 H), 6.95 (d, J ϭ 8.4 Hz, 2 H), 7.13 (m, 2 H,), 7.25Ϫ7.31
(m, 4 H), 7.57 (d, J ϭ 8.4 Hz, 2 H), 7.72 (d, J ϭ 8 Hz, 2 H) ppm.
13C NMR (100 MHz, CDCl3): δ ϭ 24.14, 29.82, 55.18, 55.40,
59.82, 70.44, 77.93, 113.40, 125.53, 125.59, 126.19, 126.35, 128.06,
128.14, 129.70, 131.77, 146.63, 148.05, 158.43 ppm. IR (film): ν˜ ϭ
3260, 2956, 1514, 1445, 1252, 1178, 750, 704 cmϪ1. C25H27NO2
(373.5): calcd. C 80.40, H 7.29, N 3.75; found C 80.27, H 7.27,
N 3.78.
(S)-1-Arylmethyl-2-(hydroxydiphenylmethyl)pyrrolidines
6a؊6h:
The syntheses of (S)-1-arylmethyl-2-(hydroxydiphenylmethyl)pyr-
rolidines 6aϪ6h were carried out according to ref.[11] A dry, three-
necked, round-bottomed flask was fitted with a pressure-equalizing
dropping funnel, a condenser, a rubber septum, and a magnetic
stirrer bar. The contents of the flask were placed under nitrogen,
and phenylmagnesium bromide (40 mL, 8 mmol) (or β-naphthyl-
magnesium bromide) in THF solution was added. A solution of
methyl (S)-1-arylpyrrolidine-2-carboxylate (5) (1 mmol) in THF
(10 mL) was added to the phenylmagnesium bromide solution at 0
to Ϫ10 °C with ice-salt bath cooling over 1 h. After the addition,
the cooling bath was removed and the reaction mixture was allowed
to warm to room temperature and stirred for 1 d. Satd. NH4Cl was
added to the reaction mixture. The resulting mixture was concen-
trated under reduced pressure to remove THF and the resulting
aqueous mixture was extracted with diethyl ether (3 ϫ 10 mL). The
ethereal extract was washed with brine (20 mL) and dried with an-
hydrous sodium sulfate, and the solvents were evaporated under
reduced pressure to give a solid, which was recrystallized to give
the corresponding title compounds 6aϪ6h.
(S)-2-(Hydroxydiphenylmethyl)-1-(3Ј-pyridylmethyl)pyrrolidine (6d):
Purification of the residue by silica gel column chromatography
(50 % EtOAc/petroleum ether) afforded a solid, which was recrys-
tallized from diethyl ether to give the title compound 6d (251.8 mg,
73 %) as colorless crystals; m.p. 125Ϫ127 °C. [α]2D2 ϭ ϩ90.0 (c ϭ
1
1.2 in CHCl3). H NMR (400 MHz, CDCl3): δ ϭ 1.62Ϫ1.70 (m, 2
H), 1.76Ϫ1.83 (m, 1 H), 1.95Ϫ2.03 (m, 1 H), 2.36 (m, 1 H), 2.90
(m, 1 H), 3.07 (d, J ϭ 12.8 Hz, 1 H), 3.16 (d, J ϭ 12.8 Hz, 1 H),
4.00 (m, 1 H), 4.66 (br. s, 1 H), 7.09Ϫ7.20 (m, 3 H), 7.26Ϫ7.35 (m,
5 H), 7.58 (m, 2 H), 7.71 (m, 2 H), 8.25 (d, J ϭ 1.6 Hz, 1 H), 8.43
(dd, J ϭ 1.6, 4.8 Hz, 1 H) ppm. 13C NMR (100 MHz, CDCl3):
δ ϭ 24.30, 29.67, 55.63, 57.95, 70.75, 78.12, 123.20, 125.52, 125.55,
126.36, 125.52, 128.13, 128.26, 134.89, 136.11, 146.22, 147.72,
148.36, 149.87 ppm. IR (film): ν˜ ϭ 709, 749, 1166, 1480, 1578,
1683, 2976, 3255 cmϪ1. C23H24N2O (344.5): calcd. C 80.20, H 7.02,
N 8.13; found C 80.21, H 6.88, N 7.85.
(S)-1-Benzyl-2-(hydroxydiphenylmethyl)pyrrolidine (6a): Purifi-
cation of the residue by silica gel column chromatography (5 %
EtOAc/petroleum ether) afforded a solid, which was recrystallized
from diethyl ether to give the title compound 6a (246.6 mg, 72 %)
as colorless crystals; m.p. 120Ϫ122 °C. [α]2D9 ϭ ϩ73.7 (c ϭ 1.0 in
(S)-2-[Hydroxybis(β-naphthyl)methyl]-1-(2Ј-pyridylmethyl)-
pyrrolidine (6e): Purification of the residue by silica gel column
CHCl3). 1H NMR (300 MHz, CDCl3): δ ϭ 1.62Ϫ1.80 (m, 3 H), chromatography (50 % EtOAc/petroleum ether) afforded the title
1.97Ϫ2.01 (m, 1 H), 2.37Ϫ2.40 (m, 1 H), 2.93Ϫ2.96 (m, 1 H), 3.06 compound 6e (281.5 mg, 63 %) as white crystals; m.p. 78Ϫ80 °C.
(d, J ϭ 12.6 Hz, 1 H), 3.26 (d, J ϭ 12.6 Hz, 1 H), 4.01 (m, 1 H),
4.98 (br. s, 1 H), 7.06Ϫ7.36 (m, 11 H), 7.63 (m, 2 H), 7.75 (m, 2 δ ϭ 1.73 (m, 2 H), 1.95 (m, 1 H), 2.11 (m, 1 H), 2.43 (m, 1 H),
[α]2D4 ϭ ϩ170.9 (c ϭ 1.13 in CHCl3). 1H NMR (300 MHz, CDCl3):
134
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Eur. J. Org. Chem. 2004, 129Ϫ137

Asymmetric Cyanosilylation of Ketones
FULL PAPER
2.97 (m, 1 H), 3.12 (d, J ϭ 13.2 Hz, 1 H), 3.26 (d, J ϭ 12.9 Hz, 1 perature for 5 h, the mixture was then allowed to warm slowly to
H), 4.27 (m, 1 H), 5.30 (br. s, 1 H), 7.10 (m, 1 H), 7.28 (m, 1 H), room temperature and filtered, and the solvents were evaporated
7.39Ϫ7.48 (m, 4 H), 7.70Ϫ7.90 (m, 8 H), 8.14 (m, 2 H), 8.37 (m, 2 under reduced pressure. The residue was purified by silica gel col-
H) ppm. 13C NMR (75 MHz, CDCl3): δ ϭ 24.22, 29.70, 55.59,
57.85, 70.23, 78.41, 123.07, 124.10, 124.26, 124.31, 125.89, 126.17,
127.34, 127.38, 127.79, 127.95, 128.07, 128.13, 132.00, 132.05,
133.10, 133.15, 143.38, 149.70 ppm. IR (film): ν˜ ϭ 758, 789, 858,
895, 1121, 1594, 1629, 2368, 2915, 3415 cmϪ1. C31H28N2O (444.6):
calcd. C 83.75, H 6.35, N 6.30; found C 83.73, H 6.46, N 6.30.
umn chromatography.
(1R,2S)-1-Benzyl-2-(hydroxydiphenylmethyl)pyrrolidine
N-Oxide
(1a): The residue was purified by silica gel column chromatography
(5 % CH3OH/EtOAc) to give the title compound 1a (983.3 mg,
91 %) as a white solid; m.p. 185Ϫ187 °C. [α]2D9 ϭ ϩ60.4 (c ϭ 0.55
in CHCl3). 1H NMR (300 MHz, CDCl3): δ ϭ 1.67Ϫ1.72 (m, 1 H),
1.84Ϫ1.90 (m, 2 H), 2.05Ϫ2.11 (m, 1 H), 2.45 (m, 2 H), 3.35 (d,
J ϭ 7.6 Hz, 1 H), 3.41 (d, J ϭ 7.6 Hz, 1 H), 3.94 (m, 1 H),
7.11Ϫ7.16 (m, 2 H), 7.24Ϫ7.34 (m, 9 H), 7.60 (d, J ϭ 7.6 Hz, 2
H), 7.88 (d, J ϭ 7.6 Hz, 2 H), 12.37 (br. s, 1 H) ppm. 13C NMR
(100 MHz, CDCl3): δ ϭ 19.33, 26.03, 67.54, 70.43, 75.12, 77.63,
79.22, 124.63, 126.21, 126.52, 127.77, 128.00, 128.69, 131.88,
(S)-2-(Hydroxydiphenylmethyl)-1-(3Ј-methyl-2Ј-pyridylmethyl)-
pyrrolidine (6f): Purification of the residue by silica gel column
chromatography (50 % EtOAc/petroleum ether) afforded a solid,
which was recrystallized from diethyl ether to give the title com-
pound 6f (271.4 mg, 76 %) as colorless crystals; m.p. 136Ϫ139 °C.
1
[α]2D4 ϭ ϩ54.9 (c ϭ 0.39 in CHCl3). H NMR (300 MHz, CDCl3):
δ ϭ 1.62Ϫ1.81 (m, 3 H), 1.92Ϫ2.02 (m, 1 H), 2.49Ϫ2.56 (m, 4 H), 132.14, 148.05, 148.68 ppm. IR (film): ν˜ ϭ 700, 751, 806, 1375,
3.01 (m, 1 H), 3.38 (m, 2 H), 4.09 (s, 1 H), 5.13 (br. s, 1 H), 6.95 1490, 2957, 3426 cmϪ1. C24H25NO2 (359.5): calcd. C 80.19, H 7.01,
(m, 2 H), 7.17Ϫ7.30 (m, 6 H), 7.49 (m, 1 H), 7.61 (dd, J ϭ 7.2,
28.5 Hz, 4 H) ppm. 13C NMR (75 MHz, CDCl3): δ ϭ 24.28, 24.31,
29.61, 55.62, 62.12, 71.01, 77.99, 119.17, 121.24, 125.59, 125.62,
126.17, 126.30, 127.91, 128.02, 136.50, 146.39, 147.55, 157.10 ppm.
IR (film): ν˜ ϭ 710, 766, 870, 1108, 1158, 1450, 1578, 2946, 3274
cmϪ1. C24H26N2O (358.5): calcd. C 80.41, H 7.31, N 7.81; found
C 80.22, H 7.66, N 7.37.
N 3.90; found C 80.06, H 6.90, N 4.04.
(1R,2S)-2-(Hydroxydiphenylmethyl)-1-(2Ј-pyridylmethyl)pyrrolidine
N-Oxide (1b): The residue was purified by silica gel column chro-
matography (9 % CH3OH/EtOAc) to give the title compound 1b
(888.5 mg, 82 %) as a white solid; m.p. 172Ϫ175 °C. [α]2D9 ϭ ϩ34.0
1
(c ϭ 0.6 in CHCl3). H NMR (400 MHz, CDCl3): δ ϭ 1.75Ϫ1.82
(m, 1 H), 1.99Ϫ2.09 (m, 1 H), 2.22Ϫ2.31 (m, 1 H), 2.47Ϫ2.55 (m,
1 H), 2.85Ϫ2.90 (m, 1 H), 3.53Ϫ3.60 (m, 1 H), 3.78 (d, J ϭ
12.4 Hz, 1 H), 3.86 (d, J ϭ 12.4 Hz, 1 H), 4.68 (t, J ϭ 8.8 Hz, 1
H), 7.14Ϫ7.41 (m, 8 H), 7.58Ϫ7.64 (m, 3 H), 7.86 (d, J ϭ 7.2 Hz,
2 H), 8.51 (d, J ϭ 4 Hz, 1 H), 11.81 (br. s, 1 H) ppm. 13C NMR
(100 MHz, CDCl3): δ ϭ 20.16, 26.32, 69.41, 73.08, 77.21, 78.02,
123.68, 124.77, 126.40, 126.57, 126.84, 127.69, 128.20, 136.36,
146.74, 147.48, 148.68, 151.96 ppm. IR (film): ν˜ ϭ 704, 750, 845,
(S)-2-(Hydroxydiphenylmethyl)-1-(2Ј-quinolinylmethyl)pyrrolidine
(6g): Purification of the residue by silica gel column chromatogra-
phy (25 % EtOAc/petroleum ether) afforded a solid, which was
recrystallized from diethyl ether to give the title compound 6g
(135.9 mg, 35 %) as colorless crystals; m.p. 148Ϫ149 °C. [α]2D3
ϭ
ϩ108.3 (c ϭ 0.60 in CHCl3). 1H NMR (300 MHz, CDCl3): δ ϭ
1.62Ϫ1.83 (m, 3 H), 2.01 (m, 1 H), 2.60 (m, 1 H), 2.95 (m, 1 H),
3.53 (m, 2 H), 4.16 (m, 1 H), 5.02 (br. s, 1 H), 7.05 (m, 1 H), 1050, 1177, 1488, 1592, 2963, 3423 cmϪ1. C23H24N2O2 (360.5):
7.19Ϫ1.35 (m, 7 H), 7.76 (m, 6 H), 8.07 (m, 2 H) ppm. 13C NMR calcd. C 76.64, H 6.71, N 7.77; found C 76.44, H 6.66, N 7.82.
(75 MHz, CDCl3): δ ϭ 24.36, 29.60, 55.77, 62.84, 71.10, 78.04,
(1R,2S)-2-(Hydroxydiphenylmethyl)-1-[(2Ј-methoxyphenyl)-
methyl]pyrrolidine N-Oxide (1c): The residue was purified by silica
gel column chromatography (10 % CH3OH/EtOAc) to give the title
120.45, 125.53, 125.56, 126.03, 126.03, 126.24, 126.40, 127.20,
127.40, 128.00, 128.12, 128.43, 128.83, 129.09, 129.29, 129.55,
129.97, 136.27, 146.31, 147.19, 147.62, 160.12 ppm. IR (film): ν˜ ϭ
compound 1c (1.09 g, 94 %) as a white solid; m.p. 188Ϫ190 °C.
707, 769, 823, 871, 962, 1034, 1110, 1310, 1499, 1598, 2813, 2961,
[α]D24 ϭ ϩ73.0 (c ϭ 0.40 in CHCl3). H NMR (400 MHz, CDCl3):
δ ϭ 1.76 (m, 1 H), 2.05 (m, 1 H), 2.28 (m, 1 H), 2.51 (m, 1 H),
2.87 (m, 1 H), 3.20 (m, 1 H), 3.55 (d, J ϭ 12.4 Hz, 1 H), 3.63 (d,
J ϭ 12.4 Hz, 1 H), 3.77 (s, 3 H), 4.47 (t, J ϭ 8.8 Hz, 1 H), 6.81 (d,
J ϭ 8.4 Hz, 4 H), 7.14Ϫ7.36 (m, 8 H), 7.57 (d, J ϭ 8 Hz, 2 H),
7.86 (d, J ϭ 7.8 Hz, 2 H), 11.95 (br. s, 1 H) ppm. 13C NMR
(100 MHz, CDCl3): δ ϭ 20.07, 26.88, 55.25, 68.50, 71.55, 76.68,
78.16, 113.50, 123.59, 124.83, 126.50, 126.56, 126.87, 128.20,
133.10, 146.84, 147.58, 160.14 ppm. IR (film): ν˜ ϭ 706, 746, 1178,
1
3357 cmϪ1. C27H26N2O (394.5): calcd. C 82.20, H 6.64, N 7.10;
found C 81.95, H 6.66, N 7.23.
(S)-1-[(3Ј,5Ј-Di-tert-butylphenyl)methyl]-2-(hydroxydiphenylmethyl)-
pyrrolidine (6h): Purification of the residue by silica gel column
chromatography (17 % EtOAc/petroleum ether) afforded a solid,
which was recrystallized from diethyl ether to give the title com-
pound 6h (329.7 mg, 70 %) as colorless crystals; m.p. 170Ϫ171 °C.
[α]2D2 ϭ ϩ20.0 (c ϭ 1.3 in CHCl3). 1H NMR (300 MHz, CDCl3):
δ ϭ 1.23 (s, 9 H), 1.38 (s, 9 H), 1.69 (m, 2 H), 1.89 (m, 1 H), 2.07 1264, 1516, 2930, 3424 cmϪ1. C25H27NO3 (389.5): calcd. C 77.09,
(m, 1 H), 2.42 (m, 1 H), 2.88 (m, 1 H), 3.27 (d, J ϭ 12.8 Hz, 1 H), H 6.99, N 3.60; found C 76.91, H 6.83, N 3.59.
3.51 (d, J ϭ 12.8 Hz, 1 H), 3.98 (m, 1 H), 6.69 (s, 1 H), 7.09Ϫ7.34
(1R,2S)-2-(Hydroxydiphenylmethyl)-1-(3Ј-pyridylmethyl)pyrrolidine
N-Oxide (1d): The residue was purified by silica gel column chro-
matography (17 % CH3OH/EtOAc) to give the title compound 1d
(1.07 g, 99 %) as white crystals; m.p. 138Ϫ139 °C. [α]2D3 ϭ ϩ107.1
(m, 8 H), 7.59 (m, 4 H) ppm. 13C NMR (100 MHz, CDCl3): δ ϭ
24.37, 29.36, 29.44, 31.62, 34.02, 34.78, 55.17, 61.82, 72.65, 79.71,
122.11, 122.68, 123.21, 125.71, 125.87, 126.69, 126.93, 128.19,
128.41, 134.83, 140.07, 145.71, 153.34 ppm. IR (film): ν˜ ϭ 704, 748,
1242, 1448, 2958, 3424 cmϪ1. C32H41NO2 (471.7): calcd. C 81.48,
H 8.76, N 2.97; found C 81.46, H 8.75, N, 3.14.
1
(c ϭ 1.0 in CHCl3). H NMR (400 MHz, CDCl3): δ ϭ 1.80Ϫ1.85
(m, 1 H), 2.05Ϫ2.16 (m, 1 H), 2.25Ϫ2.32 (m, 1 H), 2.55 (m, 1 H),
2.85 (m, 1 H), 3.22 (d, J ϭ 9.6 HZ, 1 H), 3.27 (d, J ϭ 9.6 Hz, 1
H), 3.62 (s, 1 H), 4.53 (t, J ϭ 8.4 Hz, 1 H), 7.17Ϫ7.37 (m, 7 H),
(1R,2S)-1-Arylmethyl-2-(hydroxydiphenylmethyl)pyrrolidine N-Ox-
ides 1a؊h: The syntheses of amino alcohol N-oxides were carried 7.57Ϫ7.59 (d, J ϭ 7.6 Hz, 2 H), 7.81Ϫ7.88 (m, 3 H), 8.43 (s, 1 H),
out according to ref.[12] mCPBA (70Ϫ74 %, 718.8 mg, 3.0 mmol) 8.56 (s, 1 H), 11.68 (br. s, 1 H) ppm. 13C NMR (100 MHz, CDCl3):
was added at Ϫ78 °C under nitrogen to a solution of amino alcohol
6 (3.0 mmol) and anhydrous K2CO3 (621.0 mg, 4.5 mmol) in
CH2Cl2 (25 mL), the resulting mixture was stirred at the same tem-
δ ϭ 20.07, 26.67, 69.09, 69.11, 77.81, 78.07, 123.22, 124.76, 126.40,
126.71, 127.07, 127.52, 128.29, 128.35, 140.10, 146.65, 147.32,
150.41, 151.49 ppm. IR (film): ν˜ ϭ 704, 750, 845, 1050, 1177, 1488,
Eur. J. Org. Chem. 2004, 129Ϫ137
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 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
135

Y. Shen, X. Feng, Y. Li, G. Zhang, Y. Jiang
FULL PAPER
1592, 2963, 3423 cmϪ1. C23H24N2O2 (360.5): calcd. C 76.64, H (film): ν˜ ϭ 704, 746, 876, 1048, 1242, 1448, 1602, 2366, 2958, 3424
6.61, N 7.77; found C 76.44, H 6.66, N 7.82.
cmϪ1. C32H41NO3 (487.7): calcd. C 78.81, H 8.47, N 2.87; found
C 78.63, H 8.38, N 2.94.
(1R,2S)-2-[Hydroxybis(β-naphthyl)methyl]-1-(2Ј-pyridylmethyl)-
pyrrolidine N-Oxide (1e): The residue was purified by silica gel col-
umn chromatography (10 % CH3OH/EtOAc) to give the title com-
pound 1e (1.270 g, 92 %) as white crystals; m.p. 155Ϫ157 °C.
General Procedure for Asymmetric Cyanosilylation of Ketones:
Ti(OiPr)4 (1  in toluene, 41 µL, 0.041 mmol) was added at room
temperature to a solution of (1R,2S)-1b (12.2 mg, 0.034 mmol) in
CH2Cl2 (1 mL), and the mixture was stirred for 1 h. CH2Cl2 was
evaporated under reduced pressure and the resulting residue was
further dried in vacuo for 30 min. The residue was dissolved in
CH2Cl2 (0.5 mL). The ketone (0.17 mmol) was then added to this
solution, in an ice/water bath, followed by the addition of TMSCN
(45 µL, 0.34 mmol) as shown in Table 9. The reaction was moni-
tored by TLC and, after the reaction time given in Table 9, the
solution was concentrated, worked up as usual, and purified by
silica gel chromatography (1.6 % diethyl ether/petroleum ether) to
give the product.
1
[α]D23 ϭ ϩ176.4 (c ϭ 0.33 in CHCl3). H NMR (300 MHz, CDCl3):
δ ϭ 1.87 (m, 1 H), 2.19Ϫ2.37 (m, 2 H), 2.62Ϫ2.70 (m, 1 H), 2.91
(m, 1 H), 3.29Ϫ3.39 (m, 1 H), 3.77 (m, 2 H), 4.87 (t, J ϭ 9 Hz, 1
H), 7.28 (m, 1 H), 7.42Ϫ7.48 (m, 4 H), 7.76Ϫ7.93 (m, 9 H), 8.12
(s, 1 H), 8.40 (s, 1 H), 8.55 (m, 2 H) ppm. 13C NMR (75 MHz,
CDCl3): δ ϭ 20.14, 26.39, 69.37, 73.09, 76.60, 78.45, 123.37,
123.43, 123.72, 124.61, 125.26, 125.84, 125.96, 126.03, 126.15,
127.37, 127.40, 127.69, 127.89, 128.05, 128.30, 128.48, 132.13,
132.23, 133.09, 133.21, 136.41, 143.98, 144.69, 148.68, 151.79 ppm.
IR (film): ν˜ ϭ 704, 750, 838, 1490, 1598, 3438 cmϪ1. C31H28N2O2
(460.6): calcd. C 80.84, H 6.13, N 6.08; found C 80.69, H 6.28,
N 6.26.
2-Phenyl-2-(trimethylsilyloxy)propionitrile (8a): The title compound
8a (29.0 mg, 78 %) was obtained as a colorless oil. [α]2D4 ϭ ϩ12.0
(c ϭ 0.10 in CHCl3, 53.8 % ee) {ref.[5] [α]2D4 ϭ ϩ21.9 (c ϭ 1.18 in
(1R,2S)-2-(Hydroxydiphenylmethyl)-1-[(3Ј-methyl-2Ј-pyridyl)-
methyl]pyrrolidine N-Oxide (1f): The residue was purified by silica
gel column chromatography (17 % EtOAc/CH3OH) to give the title
compound 1f (846.3 mg, 79 %) as white crystals; m.p. 169Ϫ171 °C.
1
CHCl3, 93 % ee)}. H NMR (300 MHz, CDCl3): δ ϭ 0.19 (s, 9 H,
SiMe3), 1.87 (s, 3 H), 7.27Ϫ7.57 (m, 5 H) ppm. GC [Varian, CP-
Chirasil Dex CB (0.25 ϫ 25 m), column temperature ϭ 100 °C
(isothermal), injector temperature ϭ 200 °C, detector tempera-
ture ϭ 250 °C, inlet pressure ϭ 5.516 ϫ 104 Pa]: tr[minor, (S)] ϭ
24.87 min, tr[major, (R)] ϭ 25.87 min.
[α]2D6 ϭ ϩ21.0 (c ϭ 0.37 in CHCl3). H NMR (300 MHz, CDCl3):
1
δ ϭ 1.78 (m, 1 H), 2.03 (m, 1 H), 2.29 (m, 1 H), 2.51 (m, 1 H),
2.54 (s, 3 H), 2.89 (m, 1 H), 3.59 (m, 1 H), 3.80 (m, 2 H), 4.75 (t,
J ϭ 9.0 Hz, 1 H), 7.18Ϫ7.34 (m, 8 H), 7.52Ϫ7.61 (m, 3 H), 7.88
(d, J ϭ 7.5 Hz, 2 H) ppm. 13C NMR (75 MHz, CDCl3): δ ϭ 20.11,
24.27, 26.32, 69.26, 73.21, 77.35, 77.96, 123.13, 124.41, 124.73,
2-Naphthyl-2-(trimethylsilyloxy)propionitrile (8b): The title com-
pound 8b (33.4 mg, 73 %) was obtained as white crystals. [α]2D4
ϭ
126.40, 126.47, 126.73, 128.11, 128.13, 136.58, 146.74, 147.55, ϩ7.5 (c ϭ 0.59 in CHCl3, 69 % ee).[5] 1H NMR (300 MHz, CDCl3):
151.22, 157.40 ppm. IR (film): ν˜ ϭ 706, 750, 838, 1052, 1176, 1490,
1598, 3438 cmϪ1. C24H26N2O2 (374.5): calcd. C 76.98, H 7.00, N
7.48; found C 76.78, H 6.88, N 7.30.
δ ϭ 0.22 (s, 9 H, SiMe3), 1.97 (s, 3 H), 7.20Ϫ7.67 (s, 3 H), 7.92 (m,
3 H), 8.07 (s, 1 H) ppm. HPLC (Chiralcel OJ, iPrOH/hexane ϭ
1:99, flow ϭ 1.0 mL/min): tr[major, (R)] ϭ 5.40 min, tr[minor,
(S)] ϭ 6.52 min.
(1R,2S)-2-(Hydroxydiphenylmethyl)-1-(2Ј-quinolinylmethyl)-
pyrrolidine N-Oxide (1g): The residue was purified by silica gel col-
umn chromatography (17 % CH3OH/EtOAc) to give the title com-
2-Methyl-4-phenyl-2-(trimethylsilyloxy)but-3-enenitrile (8c): The
title compound 8c (32.1 mg, 77 %) was obtained as a colorless oil.
[α]2D6 ϭ ϩ12.5 (c ϭ 0.54 in CHCl3, 25 % ee).[9] 1H NMR (300 MHz,
CDCl3): δ ϭ 0.27 (s, 9 H, SiMe3), 1.77 (s, 3 H), 6.15 (d, J ϭ
15.9 Hz, 1 H), 6.91 (d, J ϭ 15.9 Hz, 1 H), 7.28Ϫ7.45 (m, 5 H)
ppm. 13C NMR (100 MHz, CDCl3): δ ϭ 1.71, 30.83, 69.92, 120.63,
126.84, 128.54, 128.71, 129.47, 130.90, 135.06 ppm. HPLC
pound 1g (1.08 g, 92 %) as white crystals; m.p. 155Ϫ157 °C. [α]2D4
ϭ
ϩ8.1 (c ϭ 0.12 in CHCl3). 1H NMR (300 MHz, CDCl3): δ ϭ 1.82
(m, 1 H), 2.07 (m, 1 H), 2.29 (m, 1 H), 2.58 (m, 1 H), 2.92 (m, 1
H), 3.74 (m, 1 H), 4.05 (m, 2 H), 4.85 (t, J ϭ 9 Hz, 1 H), 7.17 (m,
2 H), 7.28Ϫ7.35 (m, 5 H), 7.58Ϫ7.64 (m, 4 H), 7.90 (m, 3 H), 8.08
(m, 2 H) ppm. 13C NMR (75 MHz, CDCl3): δ ϭ 20.07, 26.23,
69.70, 73.40, 76.53, 78.18, 117.30, 119.28, 124.21, 124.73, 126.23,
126.36, 126.52, 126.81, 127.03, 127.61, 127.66, 127.94, 128.19,
129.00, 129.57, 136.00, 146.75, 147.13, 147.51, 153.04 ppm. IR
(film): ν˜ ϭ 704, 750, 838, 1490, 1598, 3438 cmϪ1. C27H26N2O2
(410.5): calcd. C 79.00, H 6.38, N 6.82; found C 78.88, H 6.57,
N 7.08.
(Chiralcel OD, iPrOH/hexane
ϭ 1:99, flow ϭ 1.0 mL/min):
tr[minor, (S)] ϭ 8.79 min, tr[major, (R)] ϭ 9.99 min.
2-Methyl-4-phenyl-2-(trimethylsilyloxy)butanenitrile (8d): The title
compound 8d (36.7 mg, 87 %) was obtained as a colorless oil.
[α]2D4 ϭ ϩ7.7 (c ϭ 0.39 in CHCl3, 68 % ee).[9] 1H NMR (300 MHz,
CDCl3): δ ϭ 0.28 (s, 9 H, SiMe3), 1.65 (s, 3 H), 2.06 (m, 2 H), 2.85
(m, 2 H), 7.22Ϫ7.33 (m, 5 H) ppm. HPLC (Chiralcel OD, iPrOH/
hexane ϭ 1:99, flow ϭ 1.0 mL/min): tr[minor, (S)] ϭ 5.49 min,
tr[major, (R)] ϭ 6.65 min.
(1R,2S)-1-[(3Ј,5Ј-Di-tert-butylphenyl)methyl]-2-(hydroxydiphenyl-
methyl)pyrrolidine N-Oxide (1h): The residue was purified by silica
gel column chromatography (33 % diethyl ether/petroleum ether)
to give the title compound 1h (1.40 g, 99 %) as white crystals; m.p. 2-(Trimethylsilyloxy)-1,2,3,4-tetrahydronaphthalene-1-carbonitrile
154Ϫ155 °C. [α]2D9 ϭ ϩ10.0 (c ϭ 0.60 in CHCl3). 1H NMR
(8e): The title compound 8e (25.4 mg, 61 %) was obtained as a
(400 MHz, CDCl3): δ ϭ 1.24 (s, 9 H), 1.37 (s, 9 H), 1.83Ϫ1.87 (m, colorless oil. [α]2D6 ϭ ϩ4.6 (c ϭ 0.51 in CHCl3, 30 % ee). 1H NMR
1 H), 2.12Ϫ2.19 (m, 1 H), 2.24Ϫ2.33 (m, 1 H), 2.59 (m, 1 H), (300 MHz, CDCl3): δ ϭ 0.24 (s, 9 H, SiMe3), 2.06 (m, 2 H), 2.23
3.14Ϫ3.19 (m, 1 H), 3.25Ϫ3.33 (m, 1 H), 3.54 (d, J ϭ 13.2 Hz, 1 (m, 1 H), 2.35 (m, 1 H), 2.85 (m, 2 H), 7.13 (m, 1 H), 7.29 (m, 2
H), 4.01 (d, J ϭ 12.8 Hz, 1 H), 4.61 (t, J ϭ 8.8 Hz, 1 H), 7.14Ϫ7.35 H), 7.67 (m, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ ϭ 1.27,
(m, 8 H), 7.57 (d, J ϭ 7.2 Hz, 2 H), 7.83 (d, J ϭ 7.6 Hz, 2 H), 9.75 18.62, 28.25, 67.64, 69.79, 122.03, 126.55, 127.94, 128.98, 129.19,
(br. s, 1 H), 12.68 (br. s, 1 H) ppm. 13C NMR (100 MHz, CDCl3):
135.59, 136.03 ppm. C14H19NOSi (245.4): calcd. C 68.52, H 7.80,
δ ϭ 19.65, 26.57, 29.56, 31.58, 33.99, 35.02, 69.24, 72.42, 77.81, N 5.71; found C 68.30, H 7.70, N 6.11.GC [Varian, CP-Chirasil
78.98, 118.72, 124.71, 125.65, 126.07, 126.30, 126.81, 127.32, Dex CB (0.25 ϫ 25 m), column temperature ϭ 124 °C (isothermal),
128.35, 128.55, 137.95, 140.12, 145.81, 146.74, 155.24 ppm. IR injector temperature ϭ 200 °C, detector temperature ϭ 250 °C,
136
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2004, 129Ϫ137

Asymmetric Cyanosilylation of Ketones
inlet pressure ϭ 5.516 ϫ 104 Pa]: tr[major, (R)] ϭ 31.47 min, 2.00 (s, 3 H), 7.00 (m, 1 H), 7.21Ϫ7.34 (m, 2 H) ppm. 13C NMR
FULL PAPER
tr[minor, (S)] ϭ 33.53 min.
(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): calcd. 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 ϫ 25 m), column temperature ϭ 80 °C (isothermal),
injector temperature ϭ 200 °C, detector temperature ϭ 250 °C,
inlet pressure ϭ 5.516 ϫ 104 Pa]: tr[minor, (S)] ϭ 27.33 min,
tr[major, (R)] ϭ 29.27 min.
2-(4Ј-Methylphenyl)-2-(trimethylsilyloxy)propanenitrile (8f): The
title compound 8f (25.0 mg, 63 %) was obtained as a colorless oil.
[α]2D4 ϭ ϩ16.7 (c ϭ 0.11 in CHCl3, 41 % ee).[5] 1H NMR (300 MHz,
CDCl3): δ ϭ 0.18 (s, 9 H, SiMe3), 1.86 (s, 3 H), 2.38 (s, 3 H),
7.20Ϫ7.28 (m, 2 H), 7.44 (m, 2 H) ppm. GC [Varian, CP-Chirasil
Dex CB (0.25 ϫ 25 m), column temperature ϭ 105 °C (isothermal),
injector temperature ϭ 200 °C, detector temperature ϭ 250 °C,
inlet pressure ϭ 5.516 ϫ 104 Pa]: tr[minor, (S)] ϭ 38.67 min,
tr[major, (R)] ϭ 39.53 min.
Acknowledgments
The authors are grateful to the National Science Foundation of
China (nos. 20390050 and 20225206) and the Ministry of Edu-
cation, P. R. China for the financial support.
2-(3Ј-Chlorophenyl)-2-(trimethylsilyloxy)propanenitrile (8g): The
title compound 8g (32.8 mg, 76 %) was obtained as a colorless oil.
[α]2D6 ϭ ϩ7.1 (c ϭ 0.34 in CHCl3, 33 % ee). H NMR (300 MHz,
1
[1] [1a]
CDCl3): δ ϭ 0.22 (s, 9 H, SiMe3), 1.86 (s, 3 H), 7.34Ϫ7.55 (m, 4
H) ppm. 13C NMR (100 MHz, CDCl3): δ ϭ 0.97, 33.41, 70.90,
121.03, 122.73, 124.84, 128.76, 129.83, 134.60, 144.05 ppm.
C12ClH16NOSi (421.0): calcd. C 56.79, H 6.35, N 5.52; found C
56.61, H 6.39, N 5.90. GC [Varian, CP-Chirasil Dex CB (0.25 ϫ
25 m), column temperature ϭ 120 °C (isothermal), injector tem-
perature ϭ 200 °C, detector temperature ϭ 250 °C, inlet pressure ϭ
5.516 ϫ 104 Pa]: tr[minor, (S)] ϭ 38.07 min, tr[major, (R)] ϭ
39.00 min.
E. J. Corey, S. Shibata, J. Am. Chem. Soc. 1987, 109,
[1b]
5551Ϫ5553.
M. Kitamura, S. Suga, M. Niwa, R. Noyori,
J. Am. Chem. Soc. 1995, 117, 4832Ϫ4842. [1c] M. Shibasaki, H.
Sasai, T. Arai, Angew. Chem. Int. Ed. Engl. 1997, 36,
1236Ϫ1256. [1d] Y. S. Kim, S. Matsumaga, J. Das, A. Sekine, T.
Oshima, M. Shibasaki, J. Am. Chem. Soc. 2000, 122,
6506Ϫ6507 and references therein.
Smith, M. Wills, J. Org. Chem. 1998, 63, 6068Ϫ6071.
Yamakawa, H. Ito, R. Noyori, J. Am. Chem. Soc. 2000, 122,
[1e]
M. P. Gample, A. R. C.
[1f]
M.
[1g]
1466Ϫ1478 and references therein.
Am. Chem. Soc. 2000, 122, 12003Ϫ12004.
B. M. Trost, H. Ito, J.
[1h]
B. List, P. Pojar-
2-(2Ј-Fluorophenyl)-2-(trimethylsilyloxy)propanenitrile (8h): The
title compound 8h (18.9 mg, 47 %) was obtained as a colorless oil.
liev, C. Castello, Org. Lett. 2001, 3, 573Ϫ575 and references
therein.
[α]2D4 ϭ ϩ9.1 (c ϭ 0.10 in CHCl3, 55 % ee). H NMR (300 MHz,
1
[2] [2a]
[2b]
M. Sawamura, Y. Ito, Chem. Rev. 1992, 92, 857Ϫ871.
CDCl3): δ ϭ 0.27 (s, 9 H, SiMe3), 1.96 (s, 3 H), 7.11Ϫ7.22 (m, 2
H), 7.36 (m, 1 H), 7.60 (m, 1 H) ppm. 13C NMR (100 MHz,
CDCl3): δ ϭ 1.0, 30.8, 68.4, 116.5, 120.6, 124.2, 126.7, 130.6,
159.4 ppm. GC [Varian, CP-Chirasil Dex CB (0.25 ϫ 25 m), col-
umn temperature ϭ 100 °C (isothermal), injector temperature ϭ
200 °C, detector temperature ϭ 250 °C, inlet pressure ϭ 5.516 ϫ
104 Pa]: tr[minor, (S)] ϭ 31.47 min, tr[major, (R)] ϭ 32.53 min.
E. K. Van den Beuken, B. L. Feringa, Tetrahedron 1998, 54,
12985Ϫ13011.
1865Ϫ1882.
[2c]
G. J. Rowlands, Tetrahedron 2001, 57,
[2d]
T. Nemoto, T. Ohshima, K. Yamaguchi, M.
[2e]
Shibasaki, J. Am. Chem. Soc. 2001, 123, 2725Ϫ2732.
H.
Steinhagen, G. Helmchen, Angew. Chem. Int. Ed. Engl. 1996,
35, 2339Ϫ2342.
[3] [3a]
Y. Hamashima, D. Sawada, M. Kanai, M. Shibasaki, J.
[3b]
Am. Chem. Soc. 1999, 121, 2641Ϫ2642.
Y. Hamashima, D.
Sawada, H. Nogami, M. Kanai, M. Shibasaki, Tetrahedron
2001, 57, 805Ϫ814.
M. Takamura, Y. Hamashima, H. Usuda, M. Kanai, M. Shiba-
saki, Angew. Chem. Int. Ed. 2000, 39, 1650Ϫ1652.
[5a] Y. Hamashima, M. Kanai, M. Shibasaki, J. Am. Chem. Soc.
2000, 122, 7412Ϫ7413. [5b] Y. Hamashima, M. Kanai, M. Shib-
asaki, Tetrahedron Lett. 2001, 42, 691Ϫ693.
2-(4Ј-Fluorophenyl)-2-(trimethylsilyloxy)propanenitrile (8i): The title
compound 8i (27.0 mg, 67 %) was obtained as a colorless oil (33 %
ee). H NMR (300 MHz, CDCl3): δ ϭ 0.20 (s, 9 H, SiMe3), 1.86
[4]
[5]
1
(s, 3 H), 7.09 (m, 2 H), 7.54 (m, 2 H) ppm. 13C NMR (100 MHz,
CDCl3): δ ϭ 1.0, 33.5, 71.0, 115.6, 121.4, 126.5, 138.0, 162.2 ppm.
GC [Varian, CP-Chirasil Dex CB (0.25 ϫ 25 m), column tempera-
ture ϭ 100 °C (isothermal), injector temperature ϭ 200 °C, detec-
tor temperature ϭ 250 °C, inlet pressure ϭ 5.516 ϫ 104 Pa]:
tr[minor, (S)] ϭ 28.67 min, tr[major, (R)] ϭ 31.00 min.
[6]
M. Takamura, K. Funabashi, M. Kanai, M. Shibasaki, J. Am.
Chem. Soc. 2000, 122, 6327Ϫ6328.
[7] [7a]
B. Liu, X.-M. Feng, F.-X. Chen, G.-L. Zhang, X. Cui, Y.-
Z. Jiang, Synlett 2001, 1551Ϫ1554. [7b] Z.-G. Jiao, X.-M. Feng,
B. Liu, F.-X. Chen, G.-L. Zhang, Y.-Z. Jiang, Eur. J. Org.
Chem. 2003, 3818Ϫ3826.
2-(Trimethylsilyloxy)-1,2,3,4-tetrahydronaphthane-2-carbonitrile
(8j): The title compound 8j (31.0 mg, 74 %) was obtained as a col-
orless oil (26 % ee). 1H NMR (300 MHz, CDCl3): δ ϭ 0.28 (s, 9
H, SiMe3), 2.00Ϫ2.30 (m, 2 H), 3.02Ϫ3.15 (m, 3 H), 3.34 (d, J ϭ
16.5 Hz, 1 H), 7.05Ϫ7.28 (m, 4 H) ppm. 13C NMR (100 MHz,
CDCl3): δ ϭ 1.26, 26.05, 35.58, 42.85, 68.39, 121.50, 126.20,
126.65, 128.53, 129.05, 131.19, 133.80, 131.19 ppm. GC [Varian,
CP-Chirasil Dex CB (0.25 ϫ 25 m), column temperature ϭ 124 °C
(isothermal), injector temperature ϭ 200 °C, detector tempera-
ture ϭ 250 °C, inlet pressure ϭ 5.516 ϫ 104 Pa]: tr[major, (R)] ϭ
27.87 min, tr[minor, (S)] ϭ 29.93 min.
[8] [8a]
Y.-C. Shen, X.-M. Feng, Y. Li, G.-L. Zhang, Y.-Z. Jiang,
[8b]
Synlett 2002, 793Ϫ795.
Zhang, Y.-Z. Jiang, Synlett 2002, 1353Ϫ1355.
X.-M. Feng, Y. Li, G.-L. Zhang, Y.-Z. Jiang, Tetrahedron 2003,
59, 5667Ϫ5675.
Y.-C. Shen, X.-M. Feng, G.-L.
[8c]
Y.-C. Shen,
[9]
H.-B. Deng, P. M. Isler, M. L. Snapper, A. H. Hoveyda, Angew.
Chem. Int. Ed. 2002, 41, 1009Ϫ1012.
I. A. O’Neil, C. D. Turner, S. B. Kalindjian, Synlett 1997,
777Ϫ779.
G. Chelucci, M. Falorni, G. Giacomelli, Tetrahedron: Asym-
metry 1990, 1, 843Ϫ849.
[10]
[11]
[12]
2-(Thien-2-yl)-2-(trimethylsilyloxy)propanenitrile (8k): The title
compound 8k (10.6 mg, 34.6 %) was obtained as a colorless oil
I. A. O’Neil, N. D. Miller, J. V. Barkley, M. R. Low, S. B.
Kalindjian, Synlett 1995, 619Ϫ621.
1
(20 % ee). H NMR (300 MHz, CDCl3): δ ϭ 0.20 (s, 9 H, SiMe3),
Received July 4, 2003
Eur. J. Org. Chem. 2004, 129Ϫ137
www.eurjoc.org
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
137