A mild and efficient cyanosilylation of ketones catalyzed by a Lewis acid-Lewis base bifunctional catalyst

Article abstract of DOI:10.1016/S0040-4020(03)00908-6

A new family of bifunctional catalysts (N-oxides-Ti(OⁱPr)₄ (2:1)) containing a Lewis acid and a Lewis base was developed and applied to the catalytic cyanosilylation of ketones. Utilizing rac((1R,2S) and (1S,2R))-1-(2′-pyridylmethyl)-2-diphenylhydroxymethylpyrrolidine N-oxide-titanium (2:1) complex and N-benzyl-diethanolamine N-oxide-titanium (2:1) complex as catalysts, the cyanosilylation products were obtained in 42-97% yield. Based on experimental phenomena and kinetic studies, a catalytic cycle was proposed to explain the remarkable activities of these catalysts. Investigations indicated that rac((1R,2S) and (1S,2R))-1-(2′-pyridylmethyl)-2-diphenylhydroxymethylpyrrolidine N-oxide-titanium (2:1) complex and N-benzyl-diethanolamine N-oxide-titanium (2:1) complex should promote the reaction via a dual activation of the ketone by the titanium and TMSCN by the N-oxide.

Full text of DOI:10.1016/S0040-4020(03)00908-6

Tetrahedron 59 (2003) 5667–5675
A mild and efficient cyanosilylation of ketones catalyzed by a
Lewis acid–Lewis base bifunctional catalyst
a
c
b
Yongcun Shen,b Xiaoming Feng,a Yan Li, Guolin Zhang and Yaozhong Jiang
,
*
aSichuan Key Laboratory of Green Chemistry and Technology, College of Chemistry, Sichuan University, Chengdu 610064,
People’s Republic of China
bChengdu Institute of Organic Chemistry, Chinese Academy of Sciences, Chengdu 610041, People’s Republic of China
cChengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, People’s Republic of China
Received 13 November 2002; revised 12 May 2003; accepted 5 June 2003
Abstract—A new family of bifunctional catalysts (N-oxides–Ti(OiPr)4 (2:1)) containing a Lewis acid and a Lewis base was developed and
applied to the catalytic cyanosilylation of ketones. Utilizing rac((1R,2S) and (1S,2R))-1-(20-pyridylmethyl)-2-diphenylhydroxymethylpyr-
rolidine N-oxide–titanium (2:1) complex and N-benzyl-diethanolamine N-oxide–titanium (2:1) complex as catalysts, the cyanosilylation
products were obtained in 42–97% yield. Based on experimental phenomena and kinetic studies, a catalytic cycle was proposed to explain
the remarkable activities of these catalysts. Investigations indicated that rac((1R,2S) and (1S,2R))-1-(20-pyridylmethyl)-2-diphenylhydroxy-
methylpyrrolidine N-oxide–titanium (2:1) complex and N-benzyl-diethanolamine N-oxide–titanium (2:1) complex should promote the
reaction via a dual activation of the ketone by the titanium and TMSCN by the N-oxide.
q 2003 Elsevier Ltd. All rights reserved.
1. Introduction
reaction by simultaneously enhancing the electrophilic
character of one portion and the nucleophilic character of
the other.5
Cyanohydrins are highly versatile synthetic intermediates,
which can easily be converted into a wide variety of
important synthetic intermediates including a-hydroxy
acids, a-amino acids, and b-amino alcohols.1 The import-
ance of the cyanosilylation for the synthesis of cyanohydrins
has stimulated considerable interest in the development of
catalysts. Despite numerous and significant advances in this
area,2 the overall scope of this reaction remains limited. A
conceptually direct and attractive approach is to transform
ketones to chiral or achiral building blocks containing a
quaternary carbon center by a catalytic C–C bond
formation. The reaction of this approach, however, has
proven to be a formidable task.3 In fact, before Shibasaki’s
bifunctional catalyst concept was put forward, relative few
studies on cyanosilylation of ketones, especially on
asymmetric cyanosilylation of ketones was reported due to
relatively low reactivity of ketones. A number of recent
studies have shown that multifunctional ligands possessed
useful characteristics for catalysis and asymmetric syn-
thesis.4 For example, ligands have been reported in which
one portion engaged a Lewis acid moiety that coordinated
an electrophilic substrate while another portion of the ligand
coordinated to the nucleophilic substrate partner. Dual
coordination by such catalyst assemblies further enables the
Examples of this motif can be found in the heterobimetallic
complexes4 and the phosphine oxide-derived catalysts
developed by Shibasaki and co-workers.6 Other bifunctional
ligands that operate along these lines have also been
discovered.7 Inspired by the pioneering work of Shibasaki
on asymmetric cyanosilylation using chiral titanium8 and
aluminum6 phosphane oxide-derived complexes as
bifunctional catalysts, we initiated a project to develop
N-oxide–titanium complexes as bifunctional catalysts for
the addition of cyanide to ketones. Early results of using the
oxygen atom of a N–O group to activate TMSCN
demonstrated the feasibility of our approach.9 In a recent
preliminary communication, we reported studies of the
cyanosilylation of ketones promoted by achiral N-oxide–
titanium complex.10 In this paper, full details of the
preparation and use of 1a-1d–titanium (2:1) complexes
are reported, along with further studies on the relationship of
catalyst structure, reactivity, substrate generality, dual activity
mechanism of catalyst, and limitations of the reaction.
2. Results and discussion
The goal of the present work was to construct scaffolds in
which the Lewis acid and base elements can be indepen-
dently manipulated. In particular, new compounds can be
Keywords: Lewis acid; Lewis base; catalyst; cyanosilylation; ketone.
*
Corresponding author. Tel.: þ86-28-85418249; fax: þ86-28-85412907;
e-mail: xmfeng@pridns.scu.edu.cn
0040–4020/$ - see front matter q 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0040-4020(03)00908-6

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Y. Shen et al. / Tetrahedron 59 (2003) 5667–5675
Table 1. Effects of ligands on the cyanosilylation of acetophenone with
TMSCN
Entry
Ligand
T (8C)
Time (h)
Isolated yield (%)
1
2
3
4
1a
1b
1c
1d
0
0
0
0
48
48
48
48
80
56
75
40
Figure 1. Structure of the designed ligands 1-2.
Reaction conditions: ligand–Ti(OiPr)4¼2:1; concentration of substrate is
envisioned with functional groups specifically tailored to
the nucleophile and electrophile of a given reaction and with
the optimal spacing and orientation between groups. The
structurally well-defined and rigid Corey reagent was
chosen as a starting point, leading to general structures
1-2 (Fig. 1). An apical coordination metal at the N-oxide
metal center could act as the docking site for a Lewis basic
substrate. In addition, the ease of preparation and derivation
on of the Corey backbone was ideal for the rapid
construction of many ligands.
0.34 M.
Table 2. Effects of solvent on the cyanosilylation of acetophenone with
TMSCN
Entry
Solvent
T (8C)
Time (h)
Isolated yield (%)
1
2
3
4
5
CH2Cl2
THF
Et2O
Toluene
CH3CN
0
0
0
0
0
62
72
72
76
72
82
40
48
35
To optimize the catalytic activity of N-oxides 1–titanium
(2:1) complexes, the effect of varying each aspect of its
structure was investigated, starting with the substituents
attached to the nitrogen atom at the 1-position. Ligands
1a-1d were prepared in four steps11 as shown in Scheme 1 to
determine whether the effective coordinating atom on the
aryl ring at the 1-position is the key feature controlling the
catalytic activity. At first, combinations of Ti(OiPr)4 and
different N-oxides were optimized by the model reaction of
TMSCN with acetophenone. The catalyst was in situ
prepared by stirring a solution of ligand (20 mol%) and
Ti(OiPr)4 (10 mol%) in CH2Cl2. Without catalyst isolation,
acetophenone was added to a cooled catalyst solution at 08C,
followed by dropwise addition of TMSCN, to afford the
O-TMS cyanohydrin (Scheme 2). Each catalyst was
evaluated for its ability to catalyze the addition of
trimethylsilyl cyanide to acetophenone as shown in
Scheme 2. The results shown in Table 1 illustrate that
1a–titanium (2:1) was the best catalyst in terms of reactivity
and the product was obtained in 80% isolated yield. In terms
Trace
Reaction conditions: ligand 1a (20 mol%)–Ti(OiPr)4¼2:1; concentration
of substrate is 0.34 M.
of yield, 1b and 1d were the worst ligands (Table 1, entries 2
and 4).
The solvent effect was investigated by using the standard
procedure. The solvent survey revealed that CH2Cl2 was the
best solvent, providing the product of the cyanosilylation in
high isolated yield (Table 2). In solvents containing
coordinate oxygen or nitrogen atoms, such as THF, Et2O,
CH3CN, the reactions gave the product in lower yields. It
was noteworthy that the product was trace when the reaction
proceeded in CH3CN. This result was different from that
reported by Saravanan.2 Toluene afforded a similar result to
ether-type solvents.
In order to optimize the reaction conditions for a higher
isolated yield, the effect of the molar ratio of ligand 1a to
Ti(OiPr)4 was carefully examined. The molar ratio of ligand
1a to Ti(OiPr)4 dramatically influenced the isolated yield.
When the molar ratio of ligand 1a to Ti(OiPr)4 was 2:1, the
best isolated yield was obtained. The isolated yield
increased with the molar ratio of ligand 1a to Ti(OiPr)4
(Table 3, entries 3 and 4). The concentration of substrate
and catalyst was also an important factor to obtain a high
isolated yield. The optimized concentration of substrate was
0.34 M when 10 mol% amount of catalyst 1a–titanium
Table 3. Effects of ratio of ligand to metal ion on the cyanosilylation of
acetophenone with TMSCN
Scheme 1. Synthesis of ligands 1 and 2.
Entry
Catalyst (1a–Ti(OiPr)4)
Time (h)
Isolated yield (%)
1
2
3
4
2:1
62
72
72
72
82
69
56
40
1.25:1
1:1
1:1.25
Scheme 2. Cyanosilylation of ketones catalysed by N-oxides–titanium
(2:1) complexes.
Reaction conditions: concentration of substrate is 0.34 M; in CH2Cl2; at
08C.

Y. Shen et al. / Tetrahedron 59 (2003) 5667–5675
5669
Table 4. Effects of concentration of substrate and catalyst on the
cyanosilylation of acetophenone with TMSCN
Entry
Concentration
of substrate
(M)
Concentration
of catalyst
(M)
Isolated
yield
(%)
1
2
3
4
5
0.68
0.34
0.17
0.11
0.085
0.068
0.034
0.017
0.011
0.0085
68
80
72
53
37
Scheme 3. Synthesis of ligand 10.
Reaction conditions: 1a (20 mol%)–Ti(OiPr)4¼2:1; in CH2Cl2; at 08C;
Table 6. Cyanosilylation of ketones (R1COR2) catalyzed by N-oxide (10)–
reaction time: 48 h.
Ti(OiPr)4 (2:1) complex
Entry
R1
R2
Time (h)
Isolated yield (%)a
Table 5. Cyanosilylation of ketones (R1COR2) catalyzed by 1a–Ti(OiPr)4
(2:1) complex
1
2
3
4
5
Ph
4-FC6H4
C6H5
C6H5(CH2)2
4-NO2C6H4
CH3
CH3
C2H5
CH3
CH3
68
68
80
96
80
80
84
87
93
76
Entry
R1
R2
Time (h)
Isolated yield (%)a
1
2
3
4
5
6
7
8
C6H5
2-FC6H4
4-FC6H4
C6H5(CH2)2
C6H5
4-CH3C6H4
b-Naphthyl
4-NO2C6H4
C6H5CHvCH
n-C5H11
CH3
CH3
CH3
CH3
C2H5
CH3
CH3
CH3
CH3
CH3
CH3
CH3
62
68
68
96
72
92
98
80
96
51
98
76
82
85
84
93
87
79
79
86
80
97
54
42
All the reactions were carried out according to experimental procedure, but
1a was replaced by N-oxide (10).
a
The isolated yields were given on the isolated O-TMS cyanohydrins after
chromatographic purification, satisfactory spectral data (1H NMR, 13C
NMR, IR) and elemental analysis were obtained for the new compounds.
9
N-oxide instead of 1a. For this purpose, N-oxide (10) was
synthesized (Scheme 3) and employed for cyanosilylation
of ketones according to the procedure described above. The
results of representative substrates were shown in Table 6.
Gratifyingly, the results indicated that catalytic activity of
N-oxide (10)–Ti(OiPr)4 was similar to that of 1a–Ti(OiPr)4
for this reaction. So N-oxide (10), as an inexpensive ligand,
could be employed in the cyanosilylation of ketones, and
made this method more practical.
10
11
12
4-NH2C6H4
2-Thiophenyl
All the reactions were carried out according to the experimental procedure.
a
The isolated yields were given on the isolated O-TMS cyanohydrins after
chromatographic purification, satisfactory spectral data (1H NMR, 13C
NMR, IR) and elemental analysis were obtained for the new compounds.
(2:1) was used. If the concentrations of substrate and
catalyst decreased to 2 and 4-fold lower than the optimal
concentration, the reaction catalyzed by 1a–Ti(IV) com-
plex proceeded slowly and afforded the product in lower
isolated yields (Table 4, entries 4 and 5). At a higher
concentration, the formation of titanium multinuclear
aggregates might compress the catalytic activity, and the
isolated yield was decreased to 68% (Table 4, entry 1).
To confirm that 1a–titanium (2:1) complex was a bifunc-
tional catalyst, we performed the following studies. First,
the activation ability of N-oxide toward TMSCN was
evaluated. The reaction of acetophenone with TMSCN in
the presence or absence of 20 mol% N,N-dimethylphenyl-
amine N-oxide was carried out, employing 20 mol%
Ti(OiPr)4 as Lewis acid at 08C in CH2Cl2. In the case
without N,N-dimethylphenylamine N-oxide, 20 mol%
Ti(OiPr)4 was used as a catalyst for this reaction, but no
product could be detected after 48 h. However, in the
presence of 20 mol% N,N-dimethylphenylamine N-oxide,
the product was obtained in 9% yield under the same
conditions. Lewis acidity of Ti(OiPr)4 and N,N-dimethyl-
phenylamine N-oxide complex was lower than that of
Ti(OiPr)4. If the complex, as a catalyst, derived from the
oxygen atom of the N–O group of N,N-dimethylphenyl-
amine N-oxide coordinated with Ti(OiPr)4 would promote
cyanosilylation of ketones, Ti(OiPr)4, as a catalyst, would
also catalyze the cyanosilylation of ketones. However, the
cyanosilylation product of the ketone was not obtained. So
from these results we reckoned that the N–O group of N,N-
dimethylphenylamine N-oxide was not coordinated with
Ti(OiPr)4 and activated trimethylsilyl cyanide as a Lewis
base. Further evidence that the N–O moiety of the N-oxide
was increasing nucleophilicity of trimethylsilyl cyanide was
obtained by employing a complex of 20 mol% Ti(OiPr)4 and
20 mol% triethanolamine N-oxide as a catalyst in the
reaction, and the yield of the reaction was raised to 37%.
With the optimized catalyst structure and reaction con-
ditions, the addition of trimethylsilyl cyanide to a range of
aromatic and aliphatic ketones catalyzed by 10 mol%
1a–titaniun (2:1) catalyst was investigated. The results
shown in Table 5 indicated that the aromatic, conjugated
and aliphatic ketones afforded the corresponding products in
good to excellent isolated yields (Table 5, entries 1–10) and
substituents on the aromatic ring had a slight influence on
the conversions. Especially, less reactive ketones such as
2-acetylthiophen gave the product in moderate isolated
yield (Table 5, entry 12) by our procedure. To the best of our
knowledge, this was the first example of cyanosilylation of
2-acetylthiophen. As a matter of fact, the low conversion of
2-acetylthiophen (Table 5, entry 12) was probably due to the
coordination between the sulfur atom on the thiophen ring
and titanium, which restricted coordination between the
carbonyl group and the titanium.
Although 1a was easily synthesized, Grignard reaction
conditions are severe in the process of preparation. We
attempted to employ more easily prepared and inexpensive

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Y. Shen et al. / Tetrahedron 59 (2003) 5667–5675
Because the oxygen atom of the N–O group of triethanol-
amine N-oxide was at the top of molecular tetrahedron
configuration and ‘naked’, it activated TMSCN as a Lewis
base. This also suggests that the internal Lewis basic oxygen
donor of 1a would activate TMSCN if the N-oxide was at
the defined position close to the activated ketones.
A preliminary evidence of the bifunctional catalysis by the
complex of 1a and Ti(OiPr)4 was obtained by the following
experiment. When 20 mol% 2a–Ti(OiPr)4 (2:1) complex
was used to catalyze the cyanosilylation of acetophenone at
08C in CH2Cl2, no product was obtained after 76 h. This
showed that, although the center metal of the catalyst could
activate the ketone, the reaction proceeded with difficulty.
This revealed that the N-oxide moiety played a crucial role
in the reaction. On the other hand, Lewis bases can catalyze
the addition of TMSCN to a carbonyl compound.12
However, in the absence of Ti(OiPr)4, when 20 mol% 1a
was used as a catalyst, the reaction did not proceed even
after 70 h. This result indicated that Ti(OiPr)4 was also
necessary for this reaction. To further explore the bifunc-
tional catalysis of 1a–Ti(OiPr)4 complex, the reaction of a
Lewis acid ligating ketone and N–O group as Lewis base
activating TMSCN was carried out, but the Lewis acid and
Lewis base center was not the same molecule. Employing
20 mol% 2a–Ti(OiPr)4 (1:1) complex as Lewis acid
activating acetophenone and 20 mol% N,N-dimethylphenyl-
amineN-oxide as a Lewis base activating TMSCN, the
reaction proceeded by mixing the two portions at 08C in
CH2Cl2, the product was obtained in 51% yield after 48 h.
From this result, it could be postulated that TMSCN
activated by N,N-dimethylphenylamine N-oxide should
attack the activated ketone.
Figure 2. Initial reaction rate in the absence of catalysts 1a–Ti(OiPr)4 (2:1)
(20 mol%) (X) and 1a–Ti(OiPr)4 (1:1) (20 mol%) (A).
N–O moiety of N-oxide and trimethylsilyl cyanide, a simple
spectroscopic study of 1a–titanium complex was carried
out. First, a solution of trimethylsilyl cyanide in CH2Cl2 was
prepared, and the infrared spectrum was recorded, with the
infrared absorption associated with CuN bond observed at
2190 and 2306 cm21; then a solution of TMSCN and N,N-
dimethylphenylamine N-oxide in CH2Cl2 was prepared for
the IR spectrum. It was found that the infrared absorption at
2190 cm21 disappeared. The same phenomenon was
observed during the process of cyanosilylation of aceto-
phenone catalyzed by 1a–Ti(OiPr)4 (2:1). The spectral
changes strongly revealed that interaction between the
oxygen atom of the N–O moiety of N-oxide and TMSCN
really existed and the N–O group was likely coordinated to
Si with respect to the cyanide to increase its nucleophilicity.
To elucidate the origin of the excellent isolated yield with
wide generality as a bifunctional catalysis of 1a–Ti(OiPr)4
(2:1) complex, we designed kinetic studies to compare the
reaction rate using 1a–Ti(OiPr)4 (1:1) and 1a–Ti(OiPr)4
(2:1) catalysts containing more N–O groups (Fig. 2). The
initial reaction rate using 1a–Ti(OiPr)4 (2:1) (20 mol%) as a
catalyst was faster than that using 1a–Ti(OiPr)4 (1:1)
(20 mol%) as a catalyst, reflecting the higher basicity or
with more Lewis basic oxygen donor of N-oxide activating
trimethylsilyl cyanide in the reaction. The increased
reaction rate by 1a–Ti(OiPr)4 (2:1) complex was consistent
with the dual activation mechanism of this catalyst. Much
more Lewis basic oxygen donor of N-oxide should activate
TMSCN more efficiently, thus facilitating the desired dual
activation pathway.
From these mechanistic studies, the cyanosilylation of
ketones promoted by 1a–Ti(OiPr)4 (2:1) may be explained
by the working model depicted as 13 in Figure 3.
Significantly, the center titanium metal in complex 11 was
already six coordinate similar to that of Salen-titanium, so
the formation of a complex between titanium and
acetophenone would presumably only be possible if an
existing bond in the complex was broken first.13 Thus,
combination of complex 12 (obtained from complex 11 and
ketone) with TMSCN generated the key intermediate
complex 13, which comprised both an activated ketone
and an activated TMSCN. Intramolecular transfer of
cyanide within complex 13 generated a complex 14
containing a titanium bound cyanohydrin. Subsequent
intramolecular trimethylsilylation would give the product
and catalyst 11. Ketone coordinated to catalyst 11 would
regenerate complex 12.
These studies described above led to several key obser-
vations. (1) The presence of the N–O moiety of N-oxide
was critical to reactivity (compare 2a with 1a); (2) the
presence of a more Lewis basic N–O moiety influenced the
rate of cyanide addition. For instance, the initial rate of
reaction (within 10 h) with the 1a–Ti(OiPr)4 (2:1) catalyst
was almost two (1.8) times faster than that for 1a–Ti(OiPr)4
(1:1). The importance of the presence of the N–O moiety
and the significant influence on the reaction rate suggest that
the N–O moiety of 1a might participate actively in the
cyanosilylation of ketones.
3. Conclusion
A new strategy was devised to catalyze the addition of
trimethylsilyl cyanide to ketones using 1a and N-oxide
(10)–titanium (2:1) as catalysts. It was demonstrated that,
1a–titanium (2:1) and N-oxide (10)–titanium (2:1) com-
plexes can serve as bifunctional catalysts to deliver
appreciable reactivity. A possible mechanistic cycle and
To further prove interaction between the oxygen atom of the

Y. Shen et al. / Tetrahedron 59 (2003) 5667–5675
5671
Figure 3. Proposed catalytic cycle.
transition state structure for the addition of trimethylsilyl
cyanide to ketones promoted by catalyst 1a–titanium (2:1)
was presented. It must be noted that, although the above
catalytic cycle offered a plausible and consistent rationale
that accounted for numerous features of the titanium-
catalyzed cyanide addition, it failed to explain the more
subtle attributes of this class of transformation. The
remarkable activity of 1a–titanium (2:1) catalyst was also
explained by its ability to simultaneously activate both the
ketone and cyanide components of the reaction. Ongoing
work is aimed at the development of new catalysts for
asymmetric cyanosilylation of ketones and other asym-
metric C–C bond forming reactions.
distilled from sodium benzophenone ketyl. Dichloro-
methane (CH2Cl2) was distilled from calcium hydride.
Other reagents were purified by usual methods.
4.1.1. rac-N-Arylmethyl proline methyl ester (5). To a
solution of D,L-proline methyl ester hydrochloride 4 (1.66 g,
10 mmol) in dry DMF (10 mL) was added triethylamine
(2.0 mL, 15.3 mmol) at room temperature and the mixture
was stirred at room temperature for a few minutes. The
mixture was then filtrated to give a solution of D,L-proline
methyl ester in dry DMF.
The solution of D,L-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 508C, and monitored by TLC after 2 h until
halomethyl aromatic compound disappeared. Then the
mixture was poured into water and extracted with CH2Cl2
(3£20 mL). Organic layer was washed with water (100 mL)
and dried over anhydrous sodium sulfate. Evaporation of the
solvent under the reduced pressure and purification of the
residue by a silica gel column chromatography (50%
AcOEt–petroleum ether) afforded the title compounds
5a-5d, which were used for next reaction without further
purification.
4. Experimental
4.1. General
NMR spectra were recorded on a Bruker-200, 300 and 400
spectrometer, at 300, 400 MHz for 1H NMR, 75 MHz,
100 MHz for 13C NMR. Chemical shifts in CDCl3 were
reported downfield from TMS (d¼0) for 1H NMR. For 13
C
NMR, chemical shifts were reported in the scale relative to
CDCl3 (77.00 ppm for 13C NMR as an internal reference).
Infrared spectra were recorded on a Perkin–Elmer 1600
series FT-IR spectrometer. Column chromatography was
performed with silica gel H 60. In general, reactions were
carried out in dry solvents under a nitrogen atmosphere,
unless noted otherwise. Melting points are uncorrected.
Elemental analyses were performed on a Carlo-1106
analyzer. Tetrahydrofurn (THF) and diethyl ether were
4.2. General procedure for the preparation of rac-1-
arylmethyl-2-diphenylhydroxymethyl pyrrolidine
(2a-2d)
A dry, three-necked, round-bottomed flask was equipped

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Y. Shen et al. / Tetrahedron 59 (2003) 5667–5675
with a pressure-equalizing dropping funnel, a condenser, a
rubber septum and a magnetic stirrer. The contents of the
flask were placed under nitrogen, and 40 mL (8 mmol) of
phenylmagnesium bromide in THF solution (0.2 M) was
added. A solution of rac-N-arylmethyl proline methyl ester
5 (1 mmol) in dry THF (20 mL) was added to the
phenylmagnesium bromide solution over 1 h at 0 to
2108C with ice–salt bath cooling. After the addition, the
cooling bath was removed and the reaction mixture was
allowed to warm to room temperature and stirred for 1 day.
Sat. NH4Cl solution (20 mL) was added to the reaction
mixture. The resulted mixture was concentrated under
reduced pressure to remove THF and the resultant aqueous
mixture was extracted with ethyl ether (3£10 mL). The
ethereal extract was washed with brine (20 mL), dried over
anhydrous sodium sulfate and evaporated under reduced
pressure to give a solid, which was purified by silica gel
column chromatography and recrystallized to give the title
compounds 2a-2d.
silica gel column chromatography (50% AcOEt–petroleum
ether) afforded a solid, which was recrystallized from ethyl
ether to give the title compound 2c (218.4 mg, 64%) as
colorless crystals, mp 125–1278C. [Found: C, 80.21; H,
6.88; N, 7.85. C23H24N2O requires C, 80.23; H, 6.98; N,
8.14%]; Rf (50% AcOEt–petroleum ether) 0.54; nmax (KBr)
3255, 2967, 1683, 1578, 1480, 1166, 749, 709 cm21; dH
(400 MHz, CDCl3) 8.43 (1H, dd,J¼1.6, 4.8 Hz, C5H4N),
8.25 (1H, d, J¼1.6 Hz, C5H4N), 7.71 (2H, m, C5H4N),
7.56–7.59 (2H, m, Ph), 7.26–7.35 (5H, m, Ph), 7.09–7.19
(3H, m, Ph), 4.66 (1H, s, OH), 4.00 (1H, dd, J¼4.4, 9.6 Hz,
C4H7N), 3.16 (1H, d, J¼12.8 Hz, NCH2C5H4N), 3.07 (1H,
d, J¼12.8 Hz, NCH2C5H4N), 2.88–2.92 (1H, m, C4H7N),
2.32–2.38 (1H, m, C4H7N), 1.95–2.03 (1H, m, C4H7N),
1.80–1.83 (1H, m, C4H7N), 1.63–1.69 (2H, m, C4H7N); dC
(100 MHz, CDCl3) 149.86, 148.36, 147.72, 146.21, 136.11,
134.89, 128.26, 128.13, 126.52, 126.35, 125.55, 125.52,
123.20, 78.12, 70.75, 57.95, 55.63, 29.67, 24.30.
4.2.4. rac-1-Benzyl-2-diphenylhydroxymethylpyrroli-
dine (2d). Purification of the residue by silica gel column
chromatography (5% AcOEt–petroleum ether) afforded
solid, which was recrystallized from ethyl ether to give the
title compound 2d (299.1 mg, 87%) as colorless crystals,
mp 120–1228C. [Found: C, 83.79; H, 7.16; N, 4.07.
C24H25NO requires C, 83.96; H, 7.29; N, 4.08%]; Rf (5%
AcOEt–petroleum ether) 0.57; nmax (KBr) 3436, 2967,
1492, 1447, 1128, 1100, 766, 703 cm21; dH (300 MHz,
CDCl3) 7.75 (2H, m, Ph), 7.63 (2H, m, Ph), 7.06–7.36
(11H, m, Ph), 4.98 (1H, s, OH), 3.98–4.04 (1H, m, C4H7N),
3.26 (1H, d, J¼12.6 Hz, NCH2Ph), 3.08 (1H, d, J¼12.6 Hz,
NCH2Ph), 2.93–2.96 (1H, m, C4H7N), 2.37–2.40 (1H, m,
C4H7N), 1.97–2.01 (1H, m, C4H7N), 1.62–1.80 (3H, m,
C4H7N); dC (100 MHz, CDCl3) 147.99, 146.63, 139.65,
128.58, 128.17, 128.09, 128.07, 126.83, 126.37, 126.23,
125.58, 125.54, 77.94, 70.59, 60.57, 55.52, 29.79, 24.15.
4.2.1. rac-1-(20-Pyridylmethyl)-2-diphenylhydroxy-
methylpyrrolidine (2a). Purification of the residue by
silica gel column chromatography (50% AcOEt–petroleum
ether) afforded a solid, which was recrystallized from ethyl
ether to give the title compound 2a (137.9 mg, 40%) as
colorless crystals, mp 120–1238C. [Found: C, 80.02; H,
6.91; N, 8.08. C23H24N2O requires C, 80.23; H, 6.98; N,
8.14%]; Rf (50% AcOEt–petroleum ether) 0.47; nmax (KBr)
3332, 2954, 1620, 1590, 1478, 1186, 1100, 750, 704 cm21
;
dH (400 MHz, CDCl3) 8.42 (1H, d, J¼4 Hz, C5H4N), 7.84
(2H, d, J¼1.2 Hz, C5H4N), 7.57 (3H, m, C5H4N, Ph), 7.16–
7.31 (5H, m, Ph), 7.05–7.14 (3H, m, Ph), 4.98 (1H, s, OH),
4.09 (1H, d, J¼4.8 Hz, NCH2C5H4N), 4.06 (1H, d,
J¼4.8 Hz, NCH2C5H4N), 3.35 (1H, m, C4H7N), 2.97 (1H,
m, C4H7N), 2.48–2.55 (1H, m, C4H7N), 1.93–2.01 (1H, m,
C4H7N), 1.74–1.79 (1H, m, C4H7N), 1.63–1.68 (2H, m,
C4H7N); dC (100 MHz, CDCl3) 159.69, 148.58, 147.71,
146.36, 136.31, 128.11, 128.01, 126.37, 126.24, 125.59,
125.55, 122.44, 121.79, 78.01, 70.89, 62.23, 55.71, 29.61,
24.38.
4.2.5. N-Benzyl-diethanolamine (9). To a solution of
diethanolamine (8.40 g, 80.0 mmol) and TEA (13.4 mL,
96 mmol) in dry DMF (20 mL) was added benzyl bromide
(10.5 mL, 88.0 mmol) at room temperature and at same
temperature stirred for 1 h, then the resulting mixture was
poured into water. The resulting mixture was extracted with
CH2Cl2 (3£20 mL), organic layer was washed with water
(50 mL), dried over anhydrous sodium sulfate and concen-
trated under reduced pressure to give the title compound 9,
which was used in next step without further purification.
4.2.2. rac-1-(20-Methoxyphenylmethyl)-2-diphenyl-
hydroxymethylpyrrolidine (2b). Purification of the residue
by silica gel column chromatography (9% AcOEt–
petroleum ether) afforded a solid, which was recrystallized
from ethyl ether to give thetitle compound 2b (176.1 mg,
47%) as colorless crystals, mp 112–1138C. [Found: C,
80.27; H, 7.27; N, 3.78. C25H27NO2 requires C, 80.43; H,
7.24; N, 3.75%]; Rf (9% AcOEt–petroleum ether) 0.43;
nmax (KBr) 3260, 2956, 1514, 1445, 1252, 1178, 750,
704 cm21; dH (400 MHz, CDCl3) 7.72 (2H, d, J¼8 Hz, Ph),
7.57 (2H, d, J¼8.4 Hz, Ph), 7.28 (4H, m, Ph), 7.13 (2H, m,
Ph), 6.86 (4H, m, Ph) 4.94 (1H, s, OH), 3.95 (1H, m,
C4H7N), 3.76 (3H, s, OCH3), 3.13 (1H, d,J¼12.8 Hz,
NCH2Ph), 2.96 (1H, d,J¼12.8 Hz, NCH2Ph), 2.90 (1H, m,
C4H7N), 2.34 (1H, dd,J¼9.2, 15.6 Hz, C4H7N), 1.95 (1H,
m, C4H7N), 1.74 (1H, m, C4H7N), 1.62 (2H, m, C4H7N); dC
(100 MHz, CDCl3) 158.43, 148.05, 146.63, 131.77, 129.70,
128.14, 128.06, 126.35, 126.19, 125.59, 125.53, 113.40,
77.93, 70.43, 59.81, 55.39, 55.18, 29.82, 24.13.
4.2.6. rac((1R,2S) and (1S,2R))1-Arylmethyl-2-diphenyl-
hydroxymethylpyrrolidine N-oxide (1a-1d). Synthesis of
aminoalcohol N-oxide proceeded according to Ref. 7. To a
solution of aminoalcohol (3.0 mmol) and anhydrous K2CO3
(621 mg, 4.5 mmol) in CH2Cl2 (25 mL) was added 70–74%
mCPBA (718.8 mg, 3.0 mmol) under nitrogen atmosphere
at 2788C. The resulting mixture was stirred for 5 h at same
temperature, then the mixture was warmed slowly to room
temperature, filtrated and evaporated under reduced
pressure. The residue was purified by silica gel column
chromatography.
4.2.7. rac((1R,2S) and (1S,2R))-1-(20-Pyridylmethyl)-2-
diphenylhydroxymethylpyrrolidine N-oxide (1a). The
residue was purified by silica gel column chromatography
4.2.3. rac-1-(30-Pyridylmethyl)-2-diphenylhydroxy-
methylpyrrolidine (2c). Purification of the residue by

Y. Shen et al. / Tetrahedron 59 (2003) 5667–5675
5673
(17% CH3OH–AcOEt) to give the title compound 1a
(922.0 mg, 85%) as white solid, mp 167–1688C. [Found: C,
76.44; H, 6.66; N, 7.82. C23H24N2O2 requires C, 76.67; H,
6.67; N, 7.78%]; Rf (17% CH3OH–AcOEt) 0.45; nmax
(KBr) 3423, 2963, 1592, 1488, 1177, 1050, 845, 750,
704 cm21; dH (400 MHz, CDCl3) 11.81 (1H, s, OH), 8.51
(1H, d, J¼4 Hz, C5H4N), 7.86 (2H, d, J¼7.2 Hz, C5H4N),
7.58–7.64 (3H, m, Ph, C5H4N), 7.14–7.41 (8H, m, Ph),
4.68 (1H, t,J¼8.8 Hz, C4H7N), 3.86 (1H, d, J¼12.4 Hz,
NCH2C5H4N), 3.78 (1H, d, J¼12.4 Hz, NCH2C5H4N),
3.53–3.60 (1H, m, C4H7N), 2.85–2.90 (1H, m, C4H7N),
2.47–2.55 (1H, m, C4H7N), 2.22–2.31 (1H, m, C4H7N),
1.99–2.09 (1H, m, C4H7N), 1.75–1.82 (1H, m, C4H7N); dC
(100 MHz, CDCl3) 151.96, 148.68, 147.48, 146.74, 136.35,
128.20, 127.69, 126.84, 126.56, 126.40, 124.76, 123.67,
78.01, 77.21, 73.07, 69.40, 26.32, 20.16.
CDCl3) 12.37 (1H, s, OH), 7.88 (2H, d, J¼7.6 Hz, Ph), 7.60
(2H, d, J¼7.6 Hz, Ph), 7.24–7.34 (11H, m, Ph), 5.05 (1H,
m, C4H7N), 3.41 (1H, d, J¼7.6 Hz, NCH2Ph), 3.35 (1H, d,
J¼8 Hz, NCH2Ph), 3.35 (1H, m, C4H7N), 2.45 (1H, m,
C4H7N), 2.05–2.11 (1H, m, C4H7N), 1.84–1.90 (2H, m,
C4H7N), 1.67–1.72 (1H, m, C4H7N); dC (100 MHz, CDCl3)
148.68, 148.05, 132.14, 131.88, 128.69, 128.00, 127.77,
126.52, 126.21, 124.63, 79.22, 77.63, 75.12, 70.43, 67.54,
26.03, 19.33.
4.2.11. N-Benzyl-diethanolamine N-oxide (10). The resi-
due was purified by silica gel column chromatography (33%
CH3OH–AcOEt) to give the title compound 10 (225.4 mg,
36%) as white solid, mp 135–1378C; Rf (33% CH3OH–
AcOEt) 0.41; dH (200 MHz, CDCl3) 7.37–7.46 (5H, m, Ph),
5.15 (2H, br, OH), 4.61 (2H, s, NCH2Ph), 4.12 (4H, m,
CH2OH), 3.46–3.47 (4H, t, J¼1.6 Hz, CH2); m/z 212
(MþþH, 81%).
4.2.8. rac((1R,2S) and (1S,2R))-1-(20-Methoxyphenyl-
methyl)-2-diphenylhydroxymethylpyrrolidine N-oxide
(1b). The residue was purified by silica gel column
chromatography (9% CH3OH–AcOEt) to give the title
compound1b (1.03 g, 89%) as white solid, mp 182–1848C.
[Found: C, 76.91; H, 6.83; N, 3.59. C25H27NO3 requires C,
77.12; H, 6.94; N, 3.60%]; Rf (9% CH3OH–AcOEt) 0.45;
4.3. A general procedure for the cyanosilylation
reactions of ketones
To a solution of 1a (12.2 mg, 0.034 mmol) in CH2Cl2
(1 mL) was added Ti(OiPr)4 (1 M in toluene, 17 mL,
0.017 mmol) at room temperature, and the mixture was
stirred for 1 h, CH2Cl2 was evaporated under reduced
pressure. The resulting residue was further dried in vacuum
for 30 min. The residue was dissolved in CH2Cl2 (0.5 mL).
To this solution, the ketone (0.17 mmol) was added under
ice–water bath, followed by the addition of TMSCN
(45 mL, 0.34 mmol) as shown in Table 5. The reaction
was monitored by TLC, and after the reaction period
described in Table 5, the solution was concentrated, usual
workup and purification by silica gel chromatography (1.6%
ether–petroleum ether) gave the title compounds 7a-7n.
nmax (KBr) 3424, 2930, 1516, 1264, 1178, 746, 706 cm21
;
dH (400 MHz, CDCl3) 7.86 (2H, d, J¼7.8 Hz, Ph), 7.15–
7.36 (8H, m, Ph), 6.82 (4H, d, J¼8.4 Hz, Ph), 4.47 (1H, t,
J¼8.8 Hz, C4H7N), 3.77 (3H, s, OCH3), 3.59 (2H, dd,
J¼12.4, 32 Hz, NCH2Ph), 3.20 (1H, m, C4H7N), 2.87 (1H,
m, C4H7N), 2.51 (1H, m, C4H7N), 2.28 (1H, m, C4H7N),
2.05 (1H, m, C4H7N), 1.76 (1H, m, C4H7N); dC (100 MHz,
CDCl3) 160.14, 147.58, 146.84, 133.10, 128.20, 126.87,
126.56, 126.50, 124.83, 123.59, 113.50, 78.16, 76.68, 71.55,
68.50, 55.25, 26.88, 20.07.
4.2.9. rac((1R,2S) and (1S,2R))-1-(30-Pyridylmethyl)-2-
diphenylhydroxymethylpyrrolidine N-oxide (1c). The
residue was purified by silica gel column chromatography
(17% CH3OH–AcOEt) to give the title compound 1c
(726.8 g, 67%) as white solid, mp 171–1728C. [Found: C,
76.44; H, 6.66; N, 7.82. C23H24N2O2 requires C, 76.67; H,
6.67; N, 7.78%]; Rf (17% CH3OH–AcOEt) 0.51; nmax(KBr)
4.3.1. 2-Trimethylsilyloxy-2-phenylpropanenitrile (7a).
The title compound 7a (30.5 mg, 82%) as a colorless oil; Rf
(1.6% ether–petroleum ether) 0.43; dH (300 MHz, CDCl3)
7.27–7.57 (5H, m, Ph). 1.87 (3H, s, CH3), 0.19 (9H, s,
(CH3)3Si).
3423, 2963, 1592, 1488, 1177, 1050, 845, 750, 704 cm21
;
4.3.2. 2-Trimethylsilyloxy-2-(20-fluorophenyl)propane-
nitrile (7b). The title compound 7b (34.2 mg, 85%) as a
colorless oil; Rf (1.6% ether–petroleum ether) 0.50; dH
(300 MHz, CDCl3) 7.60 (1H, m, Ph), 7.36 (1H, m, Ph),
7.11–7.22 (2H, m, Ph), 1.96 (3H, s, CH3), 0.27 (9H, s,
(CH3)3Si).
dH (400 MHz, CDCl3) 11.68 (1H, s, OH), 8.56 (1H, s,
C5H4N), 8.43 (1H, s, C5H4N), 7.81–7.88 (3H, m, C5H4N,
Ph), 7.57–7.59 (2H, d, J¼7.6 Hz, Ph), 7.17–7.37 (7H, m,
Ph), 4.53 (1H, t, J¼8.4 Hz, C4H7N), 3.62 (1H, s, C4H7N),
3.38 (1H, d, J¼9.6 Hz, NCH2C5H4N), 3.22 (1H, d,
J¼9.6 Hz, NCH2C5H4N), 2.85 (1H, m, C4H7N), 2.54 (1H,
m, C4H7N), 2.32–2.25 (1H, m, C4H7N), 2.13–2.05 (1H, m,
C4H7N), 1.85–1.80 (1H, m, C4H7N); dC (100 MHz, CDCl3)
151.48, 150.41, 147.32, 146.65, 140.10, 128.35, 128.29,
127.52, 127.07, 126.71, 126.40, 124.76, 123.22, 78.07,
77.81, 69.11, 69.06, 26.67, 20.07.
4.3.3. 2-Trimethylsilyloxy-2-(40-fluorophenyl)propane-
nitrile (7c). The title compound 7c (33.8 mg, 84%) as
colorless oil; Rf (1.6% ether–petroleum ether) 0.54; dH
(300 MHz, CDCl3) 7.54 (2H, m, Ph), 7.09 (2H, m, Ph), 1.86
(3H, s, CH3), 0.20 (9H, s, (CH3)3Si).
4.2.10. rac((1R,2S) and (1S,2R))-1-Benzyl-2-diphenyl-
hydroxymethylpyrrolidine N-oxide (1d). The residue
was purified by silica gel column chromatography (5%
CH3OH–AcOEt) to give the title compound 1d (829.3 mg,
77%) as white solid, mp 187–1888C. [Found: C, 80.06; H,
6.90; N, 4.04. C24H25NO2 requires C, 80.22; H, 6.96; N,
3.90%]; Rf (5% CH3OH–AcOEt) 0.46; nmax (KBr) 3426,
2957, 1490, 1375, 806, 751, 700 cm21; dH (300 MHz,
4.3.4. 2-Trimethylsilyloxy-2-methyl-4-phenylbutane-
nitrile (7d). The title compound 7d (39.2 mg, 93%) as
colorless oil; Rf (1.6% ether–petroleum ether) 0.50; dH
(300 MHz, CDCl3) 7.22–7.33 (5H, m, Ph) 2.85 (2H, m, CH2),
2.06 (2H, m, CH2), 1.65 (3H, s, CH3), 0.28 (9H, s, (CH3)3Si).
4.3.5. 2-Trimethylsilyloxy-2-phenylbutanenitrile (7e).
The title compound 7e (34.6 mg, 87%) as colorless oil; Rf

5674
Y. Shen et al. / Tetrahedron 59 (2003) 5667–5675
(1.6% ether–petroleum ether) 0.42; dH (300 MHz, CDCl3)
7.50 (2H, m, Ph), 7.40 (3H, m, Ph), 1.92–2.23 (2H, m,
CH2), 0.99 (3H, t, J¼7.2 Hz, CH3), 0.15 (9H, s, (CH3)3Si).
4.3.6. 2-Trimethylsilyloxy-2-(40-methylphenyl)propane-
nitrile (7f). The title compound 7f (31.3 mg, 79%) as
colorless oil; Rf (1.6% ether–petroleum ether) 0.44; dH
(300 MHz, CDCl3) 7.44 (2H, m, Ph), 7.20–7.28 (2H, m,
Ph), 2.38 (3H, s, PhCH3), 1.86 (3H, s, CH3), 0.18 (9H, s,
(CH3)3Si).
References
1. (a) Gregory, R. J. H. Chem. Rev. 1999, 99, 3649–3682.
(b) Matthews, B. R.; Gountzos, H.; Jackson, W. R.; Watson,
K. G. Tetrahedron Lett. 1989, 30, 5157–5160. (c) Jackson,
W. R.; Jacobs, H. A.; Jayatilake, G. S.; Matthews, B. R.;
Watson, K. G. Aust. J. Chem. 1990, 43, 2045–2048.
(d) Jackson, W. R.; Jacobs, H. A.; Matthews, B. R.; Jayatilake,
G. S.; Watson, K. G. Tetrahedron Lett. 1990, 31, 1447–1451.
(e) Ziegler, T.; Horsch, B.; Effenberger, F. Synthesis 1990,
575–578. (f) Effenberger, F.; Stelzer, U. Angew. Chem. Int.
Ed. Engl. 1991, 30, 873–874. (g) Zandbergen, P.; Brussee, J.;
Van der Gen, A.; Kruse, C. G. Tetrahedron: Asymmetry 1992,
3, 769–773, and references therein cited. (h) Griengl, H.;
Hickel, A.; Johnson, D. V.; Kratky, C.; Schmidt, M.; Schwab,
H. Chem. Commun. 1997, 1933–1940, and references therein
cited.
4.3.7. 2-Trimethylsilyloxy-2-(20-naphthyl)propanenitrile
(7g). The title compound 7h (36.1 mg, 79%) as white solid;
Rf (1.6% ether–petroleum ether) 0.60; dH (300 MHz,
CDCl3) 8.07 (1H, s, C10H7) 7.92 (3H, m, C10H7), 7.20–
7.67 (3H, s, C10H7), 1.97 (3H, s, CH3), 0.22 (9H, s,
(CH3)3Si).
2. (a) Evans, D. A.; Truesdale, L. K.; Carroll, G. L. J. Chem. Soc.,
Chem. Commun. 1973, 55–58. (b) Gassman, P. G.; Talley, J. J.
Tetrahedron Lett. 1978, 19, 3773–3776. (c) Noyori, R.;
Murato, S.; Suzuki, M. Tetrahedron 1981, 37, 3899–3910.
(d) Reetz, M. T.; Drewes, M. W.; Harms, K.; Reif, W.
Tetrahedron Lett. 1988, 29, 3295–3298. (e) Singh, V. K.;
Saravanan, P.; Anand, R. V. Tetrahedron Lett. 1998, 39,
3823–3824. (f) Wilkinson, H. S.; Grover, P. T.;
Vandenbossche, C. P.; Bakale, R. P.; Bhongle, N. N.; Wald,
S. A.; Senanayake, C. H. Org. Lett. 2001, 3, 553–556.
(g) Bandini, M.; Cozzi, P. G.; Melchiorre, P.; Umani-Ronchi,
A. Tetrahedron Lett. 2001, 42, 3041–3043, and references
therein cited. (h) North, M. Synlett 1993, 807–820, and
references therein cited.
4.3.8. 2-Trimethylsilyloxy-2-(40-nitrophenyl)propane-
nitrile (7h). The title compound 7h (38.6 mg, 86%) as
colorless oil; dH (300 MHz, CDCl3) 8.30 (2H, d, J¼9.0 Hz,
Ph), 7.75 (2H, d, J¼9.0 Hz, Ph), 1.89 (3H, s, CH3), 0.26
(9H, s, (CH3)3Si).
4.3.9. 2-Trimethylsilyloxy-2-methyl-4-phenyl-3-butene-
nitrile (7j). The title compound 7j (33.3 mg, 80%) as
colorless oil; Rf (1.6% ether–petroleum ether) 0.58; dH
(300 MHz, CDCl3) 7.28–7.45 (5H, m, Ph), 6.91 (1H, d,
J¼15.9 Hz, CHv), 6.15 (1H, d, J¼15.9 Hz, CHv), 1.77
(3H, s, CH3), 0.27 (9H, s, (CH3)3Si); dC (CDCl3, 100 MHz)
135.06, 130.90, 129.47, 128.71, 128.54, 126.84, 120.63,
69.92, 30.83, 1.71.
3. (a) Corey, E. J.; Guzman-Perez, A. Angew. Chem. Int. Ed.
1998, 37, 380–401. (b) Fuji, K. Chem. Rev. 1993, 93,
2037–2066. (c) Dosa, P. I.; Fu, G. C. J. Am. Chem. Soc. 1998,
120, 445–446.
4.3.10. 2-Trimethylsilyloxy-2-methylheptanenitrile (7k).
The title compound 7k (35.1 mg, 97%) as colorless oil; Rf
(1.6% ether–petroleum ether) 0.60; dH (300 MHz, CDCl3)
1.70 (2H, m, CH2), 1.58 (3H, s, CH3), 1.50 (2H, m, CH2),
1.42 (1H, m, CH2), 1.34 (4H, m, CH2), 0.92 (3H, t,
J¼6.9 Hz, CH3), 0.25 (9H, s, (CH3)3Si).
4.3.11. 2-Trimethylsilyloxy-2-(40-aminophenyl)propane-
nitrile (7m). The title compound 7m (21.3 mg, 54%) as
colorless oil; Rf (1.6% ether–petroleum ether) 0.35; dH
(300 MHz, CDCl3) 7.28–7.34 (2H, m, Ph), 6.64–6.71 (2H,
m, Ph), 3.78 (2H, br, NH2), 1.85 (3H, s, CH3), 0.15 (9H, s,
(CH3)3Si).
4. (a) Corey, E. J.; Shibata, S. J. Am. Chem. Soc. 1987, 109,
5551–5553. (b) Kitamura, M.; Suga, S.; Niwa, M.; Noyori, R.
J. Am. Chem. Soc. 1995, 117, 4832–4842. (c) Shibasaki, M.;
Sasai, H.; Arai, T. Angew. Chem. Int. Ed. Engl. 1997, 36,
1236–1256. (d) Kim, Y. S.; Matsunaga, S.; Das, J.; Sekine, A.;
Oshima, T.; Shibasaki, M. J. Am. Chem. Soc. 2000, 122,
6506–6507, and references therein. (e) Gample, M. P.; Smith,
A. R. C.; Wills, M. J. Org. Chem. 1998, 63, 6068–6071.
(f) Yamakawa, M.; Ito, H.; Noyori, R. J. Am. Chem. Soc. 2000,
122, 1466–1478, and references therein. (g) Trost, B. M.; Ito,
H. J. Am. Chem. Soc. 2004, 122, 12003–12004. (h) List, B.;
Pojarliev, P.; Castello, C. Org. Lett. 2001, 3, 573–575, and
references therein.
4.3.12. 2-Trimethylsilyloxy-2-thiophenylpropanenitrile
(7n). The title compound 7n (12.9 mg, 42%) as colorless
oil. [Found: C, 53.48; H, 6.94; N, 6.43. C10H15NOSiS
requires C, 53.33; H, 6.66; N, 6.22%]; Rf (1.6% ether–
petroleum ether) 0.55; dH (300 MHz, CDCl3) 7.21–7.34
(2H, m, Ph), 7.00 (1H, m, Ph), 2.00 (3H, s, CH3), 0.20 (9H,
s, (CH3)3Si); dC (75 MHz, CDCl3) 146.27, 126.61, 125.97,
124.70, 120.82, 68.24, 33.40, 0.78.
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