Asymmetric synthesis of a new salen type-titanium complex as the catalyst for asymmetric trimethylsilylcyanation of aldehydes

Article abstract of DOI:10.1002/jccs.201000101

This work describes the asymmetric synthesis of a new salen-type ligand via a Diels-Alder reaction and Curtius rearrangement. The ligand with a norbornane skeleton was used in the trimethylsilylcyanation of aldehydes, but the enantioselectivity was 55%ee. The norborane skeleton was cleaved to destroy this rigidity, and the eanatioselectivity was thereby increased to 85%ee.

Full text of DOI:10.1002/jccs.201000101

726
Journal of the Chinese Chemical Society, 2010, 57, 726-737
Asymmetric Synthesis of a New Salen Type-titanium Complex as the
Catalyst for Asymmetric Trimethylsilylcyanation of Aldehydes
Zheng-Chang Lin (
Department of Chemistry, National Dong Hwa University, Shoufeng, Hualien 974, Taiwan, R.O.C.
) and Chinpiao Chen* (
)
This work describes the asymmetric synthesis of a new salen-type ligand via a Diels-Alder reaction
and Curtius rearrangement. The ligand with a norbornane skeleton was used in the trimethylsilylcyanation
of aldehydes, but the enantioselectivity was 55%ee. The norborane skeleton was cleaved to destroy this ri-
gidity, and the eanatioselectivity was thereby increased to 85%ee.
Keywords: Asymmetric synthesis; Diels-Alder reaction; Curtius rearrangement;
Trimethylsilylcyanation.
1. INTRODUCTION
participation of various chiral diacids because of different
dihedral angles involved. The synthesis of 8 proceeds by
Scheme I, which involves the known Lewis acid-Et2AlCl
catalyzed Diels-Alder reaction between cyclopentadiene
and (-)-menthol-derived dimenthyl fumarate (1) at -78
°C.10 The cycloaddition proceeds with high diastereoselec-
tivity, and after hydrolysis, affords the bicycle[2.2.1]hep-
5-ene-2,3-dicarboxylic acid (3) with the (2S,3S) absolute
configuration. Hydrogenation of 3 produced bicyclo[2.2.1]-
heptane-2,3-dicarboxylic acid (4), which was converted to
diamine by Curtius rearrangement.11 Accordingly, com-
pound 4 was treated with thionyl chloride and sodium azide
and the acid azide 5 thus formed was refluxed in benzene,
before being treated with 8 M hydrochloric acid to yield
diamine 6. Salen ligand 8 was prepared following the
Jacobsen method12 by condensation with hydroxyl alde-
Optically active cyanohydrins are highly versatile in-
termediates in the organic synthesis of various classes of
chiral compounds, including a-hydroxy carboxylic acids,1
a-hydroxy aldehydes,2 a-hydroxy ketones3 and b-amino
alcohols.4 The catalytic enantioselective silylcyanation of
carbonyl compounds is a simple and convenient means of
forming such compounds using Lewis acids, such as Ti(O-
i-Pr)4,5 TiCl4,6 AlCl3,7 R2AlCl8 and others,9 in combination
with chiral ligands. Tri and tetra-coordinated chiral salen-
type ligands are by far the most attractive and widely used
ligand system employed in these reactions because of their
relatively simple synthesis and their ability to be structur-
ally tuned at numerous points. Chiral salen-type ligands
with various architectures have been found to differ at ei-
ther the diamine part or the aldehyde moieties, and have
been demonstrated to be excellent ligands in a variety of
asymmetric transformations. Accordingly the synthesis of
new chiral diamines with interesting structural features is
always desirable. Two novel tetradendate Jacobsen-type
chiral ligands (8 and 13), derived from C1 symmetric di-
amines (Fig. 1), were designed and synthesized, and em-
ployed as enantioselective catalysts of the asymmetric ad-
dition of TMSCN to aldehydes to for cyanohydrins in the
presence of Ti(OiPr)4.
2. RESULTS AND DISCUSSION
The synthesis of ligands depends on an asymmetric
Diels-Alder reaction with high diastereoselectivity as a key
step. This process avoids the need for any chiral resolving
agent otherwise, as the in case of diamines 6 and 12, the
Fig. 1. Structures of Jacobsen-type c1-symmetric chiral
ligands.

Salen Catalyst, Asymmetric Trimethylsilylcyanation
J. Chin. Chem. Soc., Vol. 57, No. 4A, 2010 727
Scheme II Synthesis of ligand 13
Scheme I Synthetic route to ligand 8
N-Boc groups and the cleavage of the double bond by
ozonolysis yieled the corresponding dialdehyde, which
was reduced to diol 12 by sodium borohydride. The re-
moval of Boc groups under acidic conditions and the cou-
pling of the resulting diamine with 7 produced salen ligand
13 in 97% yield.19 Attempts to open the ring by the ozono-
lysis of other intermedites 2 or 3 were unsuccessful and
formed several unidentified products.
hyde 7, in 95% yield. Chiral HPLC analysis revealed that
the enantiomeric purity of the diamines exceeded 99% in
both case by chiral HPLC analysis.
Following the synthesis of the designed ligand 13
with such structural features as a small dihedral angle
(close to Jacobsen ligand), and additional binding primary
alcoholic groups, the asymmetric addition of TMSCN to al-
dehydes was screened. The reaction was optimized using
two Lewis acids Et2AlCl and Ti(O-i-Pr)4 in various sol-
vents and at various reaction temperatures. Table 1 presents
the results. Under identical reaction conditions, Et2AlCl
gave higher yields of cyanohydrin than Ti(O-i-Pr)4, al-
though Ti(O-i-Pr)4 gave higher enantioselectivities. THF
as a reaction solvent afforded the most favorable enantio-
selectivities among the solvents screened. Similarly, reac-
tions conducted at lower temperatures (-78 °C) afforded
the best enantioselectivity (71%ee), but with low yield
(8%).
The efficiency of the chiral salen ligand 8 in the
asymmetric trimethylsilylcyanation of benzaldehyde was
investigated using trimethylsilylcyanide in the presence of
Ti(O-i-Pr)4 in acetonitrile at -40 °C. The reaction afforded
cyanohydrin in 43%ee in 63% isolated yield. Optimization
of the ligand system using Et2AlCl in hexane at -20 °C gave
the same result (45%ee). Increasing the reaction tempera-
ture to the reflux temperature of acetonitrile slightly im-
proved the enantioselectivity (55%ee in both cases). The
lower selectivity associated with 8 was related to the larger
dihedral angle of the diimine groups caused by the bicyclic
ring system. Therefore, further ligand optimization was
conducted by modifying the system to a monocyclic sys-
tem. Hence, compound 13 was designed to reveal the nec-
essary of monocyclic system.
Isopropyl alcohol and molecular sieves (4 Å) were
used as additives (Table 2) to improve the enantiomeric ex-
cess of the trimethylsilylcyanation of benzaldehyde. Iso-
propyl alcohol (2 equivalents) and molecular sieves (60
mg) exhibited the best enantioselectivities (85%ee), but
Scheme II represents the synthesis of 13. Compound
3 underwent Curtius rearrangement, as described above, to
yield diamine 10. The amino groups were protected by

728 J. Chin. Chem. Soc., Vol. 57, No. 4A, 2010
Lin and Chen
Table 1. Enantiomeric excess (ee%) of the trimethylsilylcyana-
tion of benzaldehyde in the various conditions in the
presence of ligand 13
Table 4. Enantiomeric excess (ee%) of the trimethylsilylcyana-
tion of benzaldehyde in the various time in the presence
of ligand 13
1. 5 mol% ligand 13
Entry
Time (h)
Yield (%)
ee (%)
OAc
*
O
OH
*
Ac2O, py
DCM, 2 h
5 mol% Lewis acid
TMSCN, solvent, 24 h
2. 2N HCl, 1 h
1
2
3
4
5
024
048
072
096
168
08
23
33
45
83
63
85
69
63
61
Ph
CN
Ph
H
Ph
CN
Entry Lewis acid Solvent Temp. (°C) Yield (%) ee (%)a
1
2
3
4
5
6
7
8
Et2AlCla
Et2AlCla
Et2AlCla
Et2AlCla
Et2AlCla
Et2AlCla
Toluene
Hexane
THF
-20
-20
-20
-20
-20
-40
-40
-40
-40
-40
-40
-78
86
86
90
95
91
65
26
71
51
08
25
08
03
13
15
28
29
23
21
33
17
29
59
71
a The ee% of product was determined by HPLC on chiral OD
column.
CH3CN
CH2Cl2
CH2Cl2
Ti(OiPr)4 Toluene
Table 5. Enantiomeric excess (ee%) of the trimethylsilylcyana-
Ti(OiPr)4
Ti(OiPr)4
Ti(OiPr)4
Ti(OiPr)4
Ti(OiPr)4
Hexane
CH2Cl2
CH3CN
THF
tion of various benzaldehydes in the presence of ligand
13
9
10
11
12
O
1. 5 mol% ligand 13
O
*
R1
OH
*
O
THF
R1COX, py,
DCM, 2 h
5 mol% Ti(OiPr)4
a The ee% of product was determined by HPLC on chiral OD
column.
R
CN
R
CN
R
H
TMSCN, 48 h
2. 2N HCl, 1 h
14a-14o
R
1 =Me, t-Bu, Ph
X = OAc or Cl
15a-15o
Yield
ee (%)c
b
Entry
Aldehyde
[a]D (c) CHCl3
(%)a
(config.)e
Table 2. Enantiomeric excess (ee%) of the trimethylsilylcyana-
tion of benzaldehyde in the various additives in the
presence of ligand 13
1
2
3
4
5
6
7
8
benzaldehyde
o-anisaldehyde
m-anisaldehyde
p-anisaldehyde
o-tolualdehyde
m-tolualdehyde
p-tolualdehyde
23
12
08
10
23
20
21
+20.3 (1.28) 85 (R)16
+4.2 (1.19) 23 (R)17
+12.7 (1.02) 47 (R)13
+8.0 (1.19) 27 (R)13
+18.1 (1.12) 45 (R)18
Entry
Additive
Yield (%)
ee (%)a
1
2
3
4
5
6
7
8
-
30 mg 4 Å MS
60 mg 4 Å MS
120 mg 4 Å MS
1eq. IPA
08
10
23
25
11
10
05
25
71
73
85
79
79
85
79
79
+1.4 (1.05)
+13.8 (0.05) 30 (R)19
5 (R)19
o-chlorobenzaldehyde 32
m-chlorobenzaldehyde 28
p-chlorobenzaldehyde 37
m-cyanobenzaldehyde 15
-1.09 (1.37)
25 (S)14
9
+13.9 (1.57) 47 (R)19
+6.4 (1.09) 21 (R)19
2eq. IPA
4eq. IPA
60 mg 4 Å MS + 2eq. IPA
10
11
12
13
14
15
+2.7 (0.91)
+2.3 (1.01)
17 (-)d
3 (R)13
p-cyanobenzaldehyde
(E)-cinnamaldehyde
11
10
a The ee% of product was determined by HPLC on chiral OD
column.
+6.25 (0.64) 65 (R)15
-2.4 (1.55) 55 (R)15
+9.5 (1.37) 75 (R)15
hydrocinnamaldehyde 18
isobutyraldehyde 55
a Isolated yield of 14a-14o; b The specific rotation of 14a-14o;
c The ee% of 15a-15o determined by HPLC on chiral OD
column; d The configuration could not be determined; e The
absolute configurations were assigned based on comparison with
the literature data.
Table 3. Enantiomeric excess (ee%) of the trimethylsilylcyana-
tion of benzaldehyde in the various amount of catalyst
Entry
Ligand 13/Ti(OiPr)4
Yield (%)
ee (%)
1
2
3
4
5
1 mol%
5 mol%
10 mol%
15 mol%
20 mol%
10
23
32
39
45
48
85
75
45
39
An optimal catalyst loading of 5 mol% of 13:Ti(Oi-
Pr)4 (1:1) gave the product with high stereoselection while
higher loadings reduced the enantiomeric excess, despite
the expected higher yields (Table 3). The same catalyst sys-
tem with longer reaction times (48 h) gave favorable re-
sults; however, extending the reaction time reduced the
enantioselectivity (Table 4).
a The ee% of product was determined by HPLC on chiral OD
column.
molecular sieves without added isopropyl alcohol were as-
sociated with a higher yield (23%).

Salen Catalyst, Asymmetric Trimethylsilylcyanation
J. Chin. Chem. Soc., Vol. 57, No. 4A, 2010 729
The optimal conditions were THF solvent, -78 °C,
molecular sieves as additive, 5 mol% of catalyst (Ti(OiPr)4
and ligand 13) and a reaction time of 48 h. This optimal re-
action conditions were utilized for the reaction of substi-
tuted benzaldehydes and TMSCN (Table 5); the best en-
antioselective substrate was benzaldehyde (85%ee) with R
configuration (exception o-chlorobenzaldehyde). The non-
aromatic aldehydes (entry 13-15) were also used in the tri-
methysilylcyanation, giving good enantioselectivity (55-
75%ee).
Macherey-Nagel.
4.2. Preparation of ligand 8
Synthesis of bis((1R,2S,5R)-2-isopropyl-5-methylcyclo-
hexyl) fumarate 1
A solution of fumaric acid (4.89 g, 42.18 mmol),
(–)-menthol (37.52 g, 240.52 mmol) and concentrated sul-
furic acid (2 mL) in benzene (50 mL) was refluxed for 15 h.
The reaction was traced by TLC until the fumaric acid was
completely consumed. The reaction solution was cooled to
room temperature and washed with water (twice), saturated
sodium bicarbonate solution (twice), and brine (once). The
organic phase then was dried over anhydrous magnesium
sulfate, and after filtration and concentration the residue
was purified by flash column chromatography using silica
gel as a stationary phase and using ethyl acetate-hexane
(1:99, 1:9) as the mobile phase. After concentration, com-
pound 1 (16.53 g, 42.16 mmol) yield 99% was produced,
and (–)-menthol (18.77 g, 120.32 mmol) recycled yield
50% was obtained. [a] 2D6. 9 = -93.6° (c 1.70, CHCl3). IR
(KBr): 2955, 2869, 1719, 1455, 1294, 1257, 1148, 990
cm-1. 1H NMR (400 MHz, CDCl3, d): 6.82 (s, 2H), 4.82-
4.75 (dt, J1 = 10.8 Hz, J2 = 4.3 Hz, 2H), 2.04-2.00 (m, 2H),
1.90-1.82 (m, 2H), 1.70-1.67 (m, 4H), 1.55-1.39 (m, 4H),
1.12-0.97 (m, 4H), 0.93-0.87 (m, 14H), 0.76-0.74 (d, J =
6.9 Hz, 6H). 13C NMR (100.6 MHz, CDCl3, d): 164.5,
133.8, 75.2, 47.0, 40.7, 34.1, 31.3, 26.1, 23.3, 22.0, 20.7,
16.2. MS m/z: 393 (M++1, 11), 255 (29), 154 (36), 139
(97), 95 (49), 83 (100), 55 (71). HRMS-FAB (m/z): [M+1]+
calcd for C24H41O4, 393.3005; found, 393.3013.
3. CONCLUSION
In summary, a new class of chiral salen-type ligands
were synthesized by the simple procedures of a Lewis
acid-catalyzed asymmetric Diels-Alder reaction between
cyclopentadiene and (–)-menthol-derived dimenthyl fuma-
rate and Curtius rearrangement. Preliminary results indi-
cate that the norbornane ring may fix the diimine groups in
the excessively rigid trans configuration, affecting en-
antioselectivity. Comparing ligand 8 and 13 suggests that
the norbornane ring is essential to the enantioselectivity.
4. EXPERIMENTAL
4.1. General Chemical Procedures
All reactions were carried out in anhydrous solvents.
Tetrhydrofuran and diethyl ether were distilled from so-
dium-benzophenone under argon. Toluene, acetonitrile, di-
chloromethane, and hexane were distilled from calcium hy-
dride. 1H NMR spectra were acquired at 400 (indicated in
each case), and 13C NMR were acquired at 100.6 MHz on a
Bruker NMR spectrometer. Chemical shifts (d) are re-
ported in ppm relative to CDCl3 (7.26 and 77.0 ppm). Mass
spectra (MS) were determined on a Micromass Platform II
mass spectrometer at a 70 eV. High resolution mass spectra
(HRMS) were determined on a Finnigan/Thermo Quest
MAT 95XL mass spectrometer. Infrared spectra were re-
corded on a JASCO FT/IR 410 spectrometer. All asymmet-
ric reactions were carried out in dry glassware under nitro-
gen using a standard glovebox. Enantiomeric excesses
were determined on a Lab Alliance Series III high perfor-
mance liquid chromatography (HPLC) with Chiracel OD-
H chiral column (Daicel Chemical Industries, LTD). Opti-
cal rotations were measured on a JASCO P-1010 polari-
meter at the indicated temperature with a sodium lamp (D
line, 589 nm). Flash column chromatography was performed
using MN silica gel 60 (70-230 mesh) purchased from
Synthesis of (1R,2S,3S,4S)-bis((1R,2S,5R)-2-isopropyl-
5-methylcyclohexyl)bicyclo[2.2.1]hept-5-ene-2,3-dicar-
boxylate 2
To a solution of 1 (16.53 g, 42.16 mmol) in anhydrous
toluene (100 mL) was added Et2AlCl (46 mL, 1M in hex-
anes) dropwisely at -78 °C under argon and stirred for 20
min. Cyclopentadiene (4.9 mL, 59.02 mmol) was then
added slowly and stirred for 4 h. The reaction solution was
cooled in ice-bath, and was added water (10 mL) to quench
the reaction and stirred for 1 h. The organic phase was
washed with 1M HCl (twice), saturated sodium bicarbon-
ate solution (twice) and brine (once). The organic phase
then was dried over anhydrous magnesium sulfate, and af-
ter filtration and concentration the residue was purified by
flash column chromatography using silica gel as a station-
ary phase and using ethyl acetate-hexane (1:49) as the mo-
bile phase. After concentration, compound 2 (18.77 g, 40.98

730 J. Chin. Chem. Soc., Vol. 57, No. 4A, 2010
Lin and Chen
mmol) yield 97% was produced. mp: 80-82 °C. [a] D27.8
=
Synthesis of (1R,2S,3S,4S)-bicyclo[2.2.1]heptane-2,3-
dicarboxylic acid 4
-0.51° (c 5.20, CHCl3). IR (KBr): 2951, 2866, 1724, 1455,
1
1265, 1174, cm-1. H NMR (400 MHz, CDCl3, d): 6.30-
A solution of 3 (5.79 g, 31.81 mmol) in methanol (50
mL) was added 10% Pd/C (0.58 g), and under hydrogen at-
mosphere (1 atm) stirred for 1 h. The reaction was traced by
TLC until 3 was completely consumed. The reaction mix-
ture was filtered through a cake of celite, and the filtrate
was concentrated to produce 4 (5.82 g, 31.63 mmol) in 99%
yield. mp: 162-165 °C. [a] 2D0.1 = +25.7° (c 1.35, MeOH). IR
(KBr): 3225, 2977, 2958, 1682, 1389 cm-1. 1H NMR (400
MHz, CD3OD, d): 3.14-3.12 (m, 1H), 2.71-2.69 (d, J = 4.9
Hz, 1H), 2.60 (s, 1H), 2.55-2.54 (d, J = 3.9 Hz, 1H), 1.67-
1.58 (m, 1H), 1.54-1.52 (m, 1H), 1.50-1.41 (m, 1H), 1.37-
1.28 (m, 3H). 13C NMR (100.6 MHz, CD3OD, d): 176.7,
175.5, 49.4, 48.6, 41.7, 40.0, 37.6, 28.4, 23.7. MS m/z: 185
(M++1, 22), 167 (39), 154 (100), 136 (92), 120 (18), 107
(41), 89 (44), 77 (52), 67 (33). HRMS-FAB (m/z): [M+1]+
calcd for C9H13O4, 185.0814; found, 185.0825.
6.28 (dd, J1 = 5.6 Hz, J2 = 3.1 Hz, 1H), 6.03-6.01 (dd, J1 =
5.6 Hz, J2 = 2.7 Hz, 1H), 4.72-4.65 (dt, J1 = 21.7 Hz, J2 =
4.3 Hz, 1H), 4.60-4.54 (dt, J1 = 21.7 Hz, J2 = 4.3 Hz, 1H),
3.36-3.34 (t, J = 4.2 Hz, 1H), 3.26 (s, 1H), 3.10 (s, 1H),
2.67-2.66 (dd, J1 = 4.5 Hz, J2 = 1.4 Hz, 1H), 2.00-1.87 (m,
4H), 1.69-1.65 (m, 4H), 1.62-1.59 (d, J = 8.6 Hz, 1H),
1.50-1.35 (m, 5H), 1.09-0.93 (m, 4H), 0.91-0.88 (m, 14H),
0.76-0.73 (t, J = 6.8 Hz, 6H). 13C NMR (100.6 MHz,
CDCl3, d): 174.0, 172.8, 137.6, 134.8, 74.5, 74.4, 48.0,
47.7, 47.3, 47.2, 46.9, 46.9, 45.8, 40.8, 40.8, 34.2, 31.3,
31.3, 26.2, 26.0, 23.2, 23.1, 22.0, 20.8, 16.0. MS m/z: 458
(M+, 0.4), 320 (4), 182 (43), 138 (100), 94 (4), 83 (75), 66
(33), 55 (27). HRMS-EI (m/z): [M]+ calcd for C29H46O4,
458.3396; found, 458.3392.
Synthesis of (1S,2S,3S,4R)-bicyclo[2.2.1]hept-5-ene-
2,3-dicarboxylic acid 3
Synthesis of (1R,2S,3S,4S)-bicyclo[2.2.1]heptane-2,3-
dicarbonyl diazide 5
A suspenion of 2 (18.77 g, 40.98 mmol) and 2 M
NaOH (195 mL) in ethanol (390 mL) was refluxed at 120
°C for 24 h. The reaction was traced by TLC until the com-
pound 2 was completely consumed. The reaction solution
was cooled to room temperature and concentrated until one
third of the solution remained. The remained solution was
extracted with hexane (twice), and the organic solution was
washed with brine. The organic phase then was dried over
anhydrous magnesium sulfate, and after filtration and con-
centration gave (–)-menthol (11.50 g, 73.71 mmol) recy-
cled yield 90%. The aqueous phase was cooled in ice-bath
and acidified by adding concentrated hydrochloric acid to
pH 2 and some solid precipitated. The aqueous solution
was extracted with ethyl acetate (twice), and the extracts
were washed with brine. The organic phase then was dried
over anhydrous magnesium sulfate and after filtration and
concentration gave 3 (6.90 g, 37.91 mmol) yield 92%. mp:
170-173 °C. [a] 2D0.1 = +127.4° (c 1.29, MeOH). IR (KBr):
3420, 2983, 2923, 1700, 1422, 1279, 948 cm-1. 1H NMR
(400 MHz, DMSO-d6, d): 6.28-6.25 (dd, J1 = 5.6 Hz, J2 =
3.1 Hz, 1H), 6.04-6.02 (dd, J1 = 5.6 Hz, J2 = 2.3 Hz, 1H),
3.16-3.13 (m, 2H), 3.01 (s, 1H), 2.40-2.39 (m, 1H), 1.48-
1.46 (d, J = 8.4 Hz, 1H), 1.33-1.30 (dd, J1 = 8.4 Hz, J2 = 1.3
Hz, 1H). 13C NMR (100.6 MHz, DMSO-d6, d): 175.8,
174.6, 137.9, 135.4, 47.9, 47.5, 47.3, 47.2, 45.3. MS m/z:
182 (M+, 0.1), 137 (4), 120 (1), 91 (16), 66 (100). HRMS-
EI (m/z): [M]+ calcd for C9H10O4, 182.0579; found,
182.0588.
A solution of 4 (6.22 g, 33.82 mmol) in thionyl chlo-
ride (15 mL, 207.2 mmol) was refluxed at 100 °C for 1.5 h.
The refluxing condenser was changed to distillation con-
denser to remove the excess of thionyl chloride. The re-
mained residue was dried under vacuum for 2 h to give a
brown liquid. To the brown liquid was added acetone (10
mL) and a solution of NaN3 (6.59 g, 101.46 mmol) in water
(10 mL), and stirred for 1 h. The reaction was quenched by
adding a little water, and extracted with chloroform (twice).
The organic phase was washed with saturated sodium bi-
carbonate solution (once) and brine (once). The organic
phase then was dried over anhydrous magnesium sulfate,
and after filtration and concentration (do not heat) under
vacuum gave crude product without further purification for
the next step reaction. IR (KBr): 2969, 2881, 2140, 1635,
1172 cm-1. 1H NMR (400 MHz, CDCl3, d): 3.23-3.20 (m,
1H), 2.82-2.80 (dd, J1 = 5.3 Hz, J2 = 1.0 Hz, 1H), 2.66-2.64
(m, 1H), 2.61-2.60 (d, J = 3.9 Hz, 1H), 1.66-1.60 (m, 1H),
1.55-1.44 (m, 2H), 1.39-1.25 (m, 3H). 13C NMR (100.6
MHz, CDCl3, d): 181.0, 180.0, 51.4, 50.4, 42.0, 40.6, 38.0,
28.7, 23.9.
Synthesis of (1R,2S,3S,4S)-bicyclo[2.2.1]heptane-2,3-
diamine; hydrochloride 6
The crude product 5 solution in benzene (48 mL) was
refluxed for 2 h, and then cooled to room temperature. To
this cooling solution was added 8 M HCl (90 mL) and
refluxed for 4 h. The reaction solution was cooled to room

Salen Catalyst, Asymmetric Trimethylsilylcyanation
J. Chin. Chem. Soc., Vol. 57, No. 4A, 2010 731
temperature and extracted with diethyl ether. The aqueous
phase was concentrated to give a white solid, which was
washed with anhydrous tetrahydrofuran. The solid was
dried under vacuum to produce 6 (5.46 g, 27.57 mmol) in
81% yield. mp: 270 °C (decomposed). [a] 2D3 = +17.7° (c
1.23, H2O). IR (KBr): 3432, 2985, 2884, 1558, 1488, 1056
= +364.7° (c 1.26, CHCl3). IR (KBr): 2957, 2869, 1624,
1593, 1440, 1249, 1173 cm-1. 1H NMR (400 MHz, CDCl3,
d): 13.68 (s,1H), 13.63 (s, 1H), 8.34 (s, 1H), 8.26 (s, 1H),
7.38 (d, J = 1.5 Hz, 1H), 7.06-7.04 (t, J = 2.4 Hz, 1H),
3.58-3.56 (m, 1H), 3.18-3.16 (m, 1H), 2.45-2.43 (m, 1H),
2.33-2.32 (d, J = 4.5 Hz, 1H), 2.15-2.13 (d, J = 10.1 Hz,
1H), 2.04-1.98 (m,1H), 1.73-1.80 (m, 1H), 1.57-1.51 (m,
3H), 1.47 (s, 9H), 1.46 (s, 9H), 1.28 (s, 18H). 13C NMR
(100.6 MHz, CDCl3, d): 166.1, 164.2, 158.0, 157.9, 140.2,
136.6, 127.0, 126.9, 126.2, 118.0, 117.8, 80.5, 79.9, 45.3,
43.4, 36.4, 35.1, 34.2, 31.7, 31.6, 29.8, 29.7, 29.5, 27.3,
22.1. MS m/z: 558 (M+, 40), 325 (100), 296 (13), 264 (7),
244 (11), 219 (5). HRMS-EI (m/z): [M]+ calcd for
C37H54N2O2, 558.4185; found, 558.4177.
1
cm-1. H NMR (400 MHz, D2O, d): 3.45-3.43 (m, 1H),
3.04-3.03 (m, 1H), 2.52-2.50 (m, 1H), 2.33-2.32 (m, 1H),
1.69-1.61 (m, 2H), 1.54-1.41 (m, 2H), 1.35-1.28 (m, 1H),
1.25-1.18 (m, 1H). 13C NMR (100.6 MHz, D2O, d): 57.2,
57.2, 40.9, 39.7, 34.4, 25.9, 19.3. MS m/z: 126 (M+, 23),
108 (14), 97 (16), 92 (12), 85 (23), 70 (51), 56 (100).
HRMS-EI (m/z): [M]+ calcd for C9H14N2, 126.1157; found,
126.1149.
Synthesis of 3,5-di-tert-butyl-2-hydroxybenzaldehyde 7
A solution of 2,4-di-tert-butylphenol (12.82 g, 62.23
mmol) and HMTA (17.42 g, 124.46 mmol) in glacial acetic
acid (30 mL) was refluxed for 2 h. The cooled reaction so-
lution was added 33% sulfuric acid (30 mL) and refluxed
for 1 h. When the reaction solution was cooled to 80 °C, the
solution was transferred to a separatory funnel. The organic
phase was concentrated, and the residue was purified by
flash column chromatography using silica gel as a station-
ary phase and using ethyl acetate-hexane (5:95) as the mo-
bile phase to give a yellow powder 7 (6.55 g, 27.99 mmol)
in 45% yield. mp: 53-55 °C. 1H NMR (400 MHz, CDCl3,
d): 11.64 (s, 1H), 9.87 (s, 1H), 7.59-7.58 (d, J = 2.4 Hz,
1H), 7.35-7.34 (d, J = 2.4 Hz, 1H), 1.43 (s, 1H), 1.33 (s,
1H). 13C NMR (100.6 MHz, CDCl3, d): 197.3, 159.1,
141.6, 137.5, 131.9, 127.8, 120.0, 35.0, 34.2, 31.3, 29.3. IR
(KBr): 2959, 2871, 1648, 1439, 1248 cm-1.
4.3. Preparation of ligand 13
Synthesis of (1R,2S,3S,4S)-bicyclo[2.2.1]hept-5-ene-
2,3-dicarbonyl diazide 9
A solution of 3 (0.82 g, 4.5 mmol) in thionyl chloride
(2 mL, 27.6 mmol) was refluxed at 100 °C for 1.5 h. The
refluxing condenser was changed to distillation condenser
to remove the excess of thionyl chloride. The remained res-
idue was dried under vacuum for 2 h to give a brown liquid.
To the brown liquid was added acetone (2 mL) and a solu-
tion of NaN3 (0.88 g, 13.5 mmol) in water (2 mL), and
stirred for 1 h. The reaction was quenched by adding a little
water, and extracted with chloroform (twice). The organic
phase was washed with saturated sodium bicarbonate solu-
tion (once) and brine (once). The organic phase then was
dried over anhydrous magnesium sulfate, and after filtra-
tion and concentration (do not heat) under vacuum gave
crude product 9 without further purification for the next
step reaction. IR (KBr): 2975, 2877, 2140, 1702, 1641,
1170, 1085 cm-1. 1H NMR (400 MHz, CDCl3, d): 6.22-6.19
(dd, J1 = 5.5 Hz, J2 = 3.2 Hz, 1H), 6.05-6.03 (dd, J1 = 5.6
Hz, J2 = 2.8 Hz, 1H), 3.34-3.32 (m, 1H), 3.20-3.18 (m, 1H),
3.09-3.07 (m, 1H), 2.61-2.60 (dd, J1 = 4.4 Hz, J2 = 1.4 Hz,
1H), 1.51-1.49 (m, 1H), 1.41-1.38 (m, 1H). 13C NMR (100.6
MHz, CDCl3, d): 180.6, 179.4, 137.5, 135.0, 50.2, 49.4,
48.0, 47.0, 46.0.
Synthesis of (1R,2S,3S,4S)-N,N¢-Bis-(3,5-di-tert-butyl-
2-hydroxy-benzylidene)-bicyclo[2.2.1]heptane-2,3-di-
amine 8
To a solution of 6 (0.72 g, 3.65 mmol) and 7 (1.71 g,
7.30 mmol) in methanol (30 mL) was added Et3N (3.05 mL,
21.90 mmol), and stirred at room temperature for 16 h. The
reaction was monitored by TLC until the starting materials
were consumed completely. The reaction solution was con-
centrated to give a yellow solid, which was dissolved in di-
chloromethane and washed with water (once) and brine
(once). The organic phase was dried over anhydrous mag-
nesium sulfate. After filtration and concentration the resi-
due was purified by flash column chromatography using
silica gel as a stationary phase and using ethyl acetate-hex-
ane (1:49) as the mobile phase to produce a yellow powder
8 (1.84 g, 3.29 mmol) in 90% yield. mp: 202-204 °C.[a]D27.8
Synthesis of (1R,2S,3S,4S)-bicyclo[2.2.1]hept-5-ene-
2,3-diamine; hydrochloride 10
The crude product 9 solution in benzene (10 mL) was
refluxed for 2 h, and then cooled to room temperature. To
this cooling solution was added 8 M HCl (15 mL) and
refluxed for 4 h. The reaction solution was cooled to room
temperature and extracted with diethyl ether (twice). The
aqueous phase was concentrated to give a white solid,

732 J. Chin. Chem. Soc., Vol. 57, No. 4A, 2010
Lin and Chen
which was washed with anhydrous tetrahydrofuran. The
solid was dried under vacuum to produce a purple powder
10 (0.81 g, 4.15 mmol) in 92% yield. mp: 250 °C (decom-
posed). [a] 2D4 = +51.2° (c 1.12, H2O). IR (KBr): 3444,
3073, 2989, 2923, 1562, 1488, 1052 cm-1. 1H NMR (400
MHz, D2O, d): 6.36-6.34 (dd, J1 = 5.6 Hz, J2 = 3.5 Hz, 1H),
6.17-6.15 (dd, J1 = 5.8 Hz, J2 = 2.7 Hz, 1H), 3.71-3.69 (m,
1H), 3.12-3.10 (m, 1H), 3.03-3.02 (m, 1H), 2.99-2.97 (m,
1H), 1.76-1.68 (m, 2H). 13C NMR (100.6 MHz, D2O, d):
138.4, 133.9, 55.8, 55.5, 46.5, 44.9, 44.8. MS m/z: 125
(M++1, 19), 107 (21), 89 (13), 77 (18), 63 (9). HRMS-FAB
(m/z): [M+1]+ calcd for C7H13N2, 125.1079; found,
125.1076.
the starting material was consumed completely. An argon
gas was bubbled through the reaction solution for 10 min,
and DMS (1.5 mL) was added. The reaction solution was
kept stirring, and the temperature was raised from -78 °C to
0 °C in 4 h. Subsequently NaBH4 (0.22 g, 5.8 mmol) was
added, and stirred at 0 °C for 1 h. The reaction was quenched
by adding a small amount of water, and the solvent was re-
moved to give a white solid product. The crude product was
dissolved in chloroform, and washed with water (once) and
brine (once). The organic phase was dried over anhydrous
magnesium sulfate, after filtration and concentration and
recrystallized from chloroform to produce a white powder
A (0.82 g, 2.3 mmol) in 79% yield. mp: 178-180 °C. [a] D24. 4
= -12.8° (c 1.10, MeOH). IR (KBr): 3359, 2981, 2935,
1677, 1527, 1176 cm-1. 1H NMR (400 MHz, CD3OD, d):
3.72-3.67 (t, J = 8.6 Hz, 1H), 3.51-3.47 (m, 1H), 3.43-3.32
(m, 4H), 2.18-2.13 (m, 1H), 1.91-1.84 (m, 1H), 1.79-1.70
(m, 1H), 1.37-1.34 (m, 1H), 1.32 (s, 1H). 13C NMR (100.6
MHz, CD3OD, d): 157.3, 157.1, 78.8, 78.7, 62.8, 61.8,
57.9, 57.6, 44.5, 39.6, 28.1, 27.3. MS m/z: 361 ([M+1]+,
84), 305 (25), 289 (14), 249 (52), 231 (37), 205 (100), 187
(41), 161 (49), 144 (29), 126 (25). HRMS-FAB (m/z):
[M+1]+ calcd for C17H33N2O6, 361.2339; found, 361.2346.
Synthesis of (1R,2S,3S,4S)-(2,3-diamino-4-hydroxy-
methyl-cyclopentyl)-methanol; hydrochloride 12
Synthesis of (1R,2S,3S,4S)-(3-tert-butoxycarbonyl-
aminobicyclo[2.2.1]hept-5-en-2-yl)-carbamic acid
tert-butyl ester 11
To a solution of 10 (0.78 g, 4 mmol) in methanol (10
mL) was added Et3N (1.7 mL, 12.2 mmol) and Boc2O (2
mL, 8.8 mmol) subsequently, and stirred at room tempera-
ture for 12 h. The reaction was monitored by TLC until the
starting materials were consumed completely. The solvent
was removed to give a white crude product, which was dis-
solved in ethyl acetate and washed with water (once) and
brine (once). The organic phase then was dried over anhy-
drous magnesium sulfate, and after filtration and concen-
tration the residue was purified by flash column chroma-
tography using silica gel as a stationary phase and using
ethyl acetate-hexane (3:7) as the mobile phase to give a
white powder compound 11 (0.99 g, 3.05 mmol) in 76%
yield. mp: 200-202 °C. [a] 2D8 = +51.9° (c 1.13, CHCl3). IR
(KBr): 3336, 3313, 2977, 2931, 1677, 1535, 1172 cm-1. 1H
NMR (400 MHz, CDCl3, d): 6.33-6.31 (dd, J1 = 4.8 Hz, J2 =
2.8 Hz, 1H), 6.16-6.14 (dd, J1 = 5.6 Hz, J2 = 2.6 Hz, 1H),
4.89 (br, 1H), 4.40 (br, 1H), 3.71 (s, 1H), 3.05 (s, 1H), 2.92
(s, 1H), 2.83 (s, 1H), 1.67-1.64 (m, 1H), 1.60-1.57 (m, 1H),
1.44 (s, 9H), 1.43 (s, 9H). 13C NMR (100.6 MHz, CDCl3,
d): 155.5, 155.4, 138.1, 134.2, 79.3, 60.0, 58.8, 48.7, 45.4,
45.3, 28.4. MS m/z: 325 (M++1, 61), 269 (45), 258 (34),
213 (61), 202 (19), 169 (37), 152 (8), 57 (100). HRMS-
FAB (m/z): [M+1]+ calcd for C17H29N2O4, 325.2127;
found, 325.2139.
To a solution of A (0.30 g, 0.84 mmol) in EtOH (10
mL) was added 6 M HCl (1 mL), and refluxed for 3 h. The
reaction was monitored by TLC until the starting material
was consumed completely. The reaction solution was cooled
to room temperature, and the solvent was removed. The
residue was dissolved in water, and the aqueous phase was
extracted with diethyl ether (twice). The aqueous phase
was concentrated and dried under vacuum to give a yellow
solid 12 (0.19 g, 0.84 mmol) in 99% yield. [a] 2D3. 7 = -13.6°
(c 1.36, MeOH). IR (KBr): 3421, 3390, 1592, 1488, 1060,
1014 cm-1. 1H NMR (400 MHz, D2O, d): 3.84-3.80 (dd, J1 =
8.0 Hz, J2 = 5.3 Hz, 1H), 3.68-3.59 (m, 2H), 3.56-3.48 (m,
3H), 2.58-2.48 (m, 1H), 2.27-2.17 (m, 1H), 1.97-1.90 (m,
1H), 1.42-1.33 (m, 1H). 13C NMR (100.6 MHz, D2O, d):
61.6, 59.4, 57.9, 56.2, 43.8, 40.1, 27.5.
Synthesis of (1R,2S,3S,4S)-(–)-{2,3-bis-[(3,5-di-tert-
butyl-2-hydroxy-benzylidene)-amino]-4-hydroxymeth-
yl-cyclopentyl}-methanol 13
Synthesis of (1R,2S,3S,5S)-(2-tert-butoxycarbonyl-
amino-3,5-bis-hydroxymethyl-cyclopentyl)-carbamic
acid tert-butyl ester
To a solution of 7 (0.39 g, 1.68 mmol) and 12 (0.19 g,
0.84 mmol) in methanol (10 mL) was added Et3N (0.35 mL,
2.52 mmol), and stirred at room temperature for 16 h. The
reaction was monitored by TLC until the starting materials
To a solution of 11 (0.94 g, 2.9 mmol) in methanol (20
mL) at -78 °C was passed an ozone through the reaction so-
lution for 5 min. The reaction was monitored by TLC until

Salen Catalyst, Asymmetric Trimethylsilylcyanation
J. Chin. Chem. Soc., Vol. 57, No. 4A, 2010 733
were consumed completely. The reaction solution was con-
centrated to give a yellow solid, which was dissolved in di-
chloromethane and washed with water (once) and brine
(once). The organic phase was dried over anhydrous mag-
nesium sulfate. After filtration and concentration the resi-
due was purified by flash column chromatography using
silica gel as a stationary phase and using ethyl acetate-hex-
ane (1:19, 1:2) as the mobile phase to produce a yellow
powder 13 (0.48 g, 0.81 mmol) in 97% yield. mp: 98-100
°C. [a] 2D6. 9 = +260.0° (c 1.15, CHCl3). IR (KBr): 3363,
2981, 2931, 2854, 1681, 1523, 1164 cm-1. 1H NMR (400
MHz, CDCl3, d): 13.49 (br, 1H), 13.35 (br, 1H), 8.33 (s,
1H), 8.30 (s, 1H), 7.37-7.35 (dd, J1 = 4.6 Hz, J2 = 2.4 Hz,
2H), 7.04-7.01 (dd, J1 = 7.0 Hz, J2 = 5.3 Hz, 2H), 3.99-3.95
(m,1H), 3.85-3.74 (m, 4H), 3.72-3.68 (m, 1H), 2.71-2.62
(m, 1H), 2.49-2.40 (m, 1H), 2.28-2.22 (m, 1H), 1.82-1.75
(m, 1H), 1.44 (s, 9H), 1.43 (s, 9H), 1.26 (s, 9H), 1.25 (s,
9H). 13C NMR (100.6 MHz, CDCl3, d): 167.2, 167.0,
158.2, 158.0, 140.2, 140.1, 136.7, 136.5, 127.4, 127.1,
126.4, 126.3, 117.7, 117.7, 77.7, 76.5, 63.4, 63.0, 46.7,
43.8, 35.0, 34.1, 34.1, 31.4. 29.5, 29.0. MS m/z: 593
([M+1]+, 91), 537 (10), 360 (15), 328 (43), 272 (9), 234
(59), 218 (60), 202 (22), 147 (12), 73 (25), 57 (100).
HRMS-FAB (m/z): [M+1]+ calcd for C37H57N2O4, 593.4318;
found, 593.4329.
column chromatography (eluent: hexane/acetone 19:1) to
yield the acetylated cyanohydrin, which was used for fur-
ther analysis. Enantiomeric excess was determined by
HPLC analysis using a chiral column (Chiralcel OD-H col-
umn, n-hexane/2-propanol = 90:10 or n-hexane/2-pro-
panol/acetonitrile = 80:1:1, flow rate 0.25 mL/min or 1.0
mL/min).
Method B: The pure cyanohydrin was directly con-
verted into the corresponding pivalates by reaction with
pivaloyl chloride and pyridine in CH2Cl2 at room tempera-
ture for 2 h. After concentration, the residue was purified
by column chromatography (eluent: hexane/acetone 19:1)
to yield the acetylated cyanohydrin, which was used for
further analysis. Enantiomeric excess was determined by
HPLC analysis using a chiral column (Chiralcel OD-H col-
umn, n-hexane/2-propanol = 90:10, flow rate 0.25 mL/
min).
Method C: The pure cyanohydrin was directly con-
verted into the corresponding benzoates by reaction with
benzoyl chloride and pyridine in CH2Cl2 at room tempera-
ture for 12 h. After concentration, the residue was purified
by column chromatography (eluent: hexane/acetone 19:1)
to yield the acetylated cyanohydrin, which was used for
further analysis. Enantiomeric excess was determined by
HPLC analysis using a chiral column (Chiralcel OD-J col-
umn, n-hexane/2-propanol = 90:10, flow rate 0.5 mL/min).
2-Hydroxy-2-phenylacetonitrile 14a. Yield: 23%.
[a] 2D6. 1 = +20.3° (c 1.28, CHCl3). IR (KBr): 3405 (br), 2958,
2927, 1454, 1253, 1191, 1083, 1041, 844, 759, 698 cm-1.
1H NMR (400 MHz, CDCl3, d): 7.50-7.46 (m, 2H), 7.44-
7.40 (m, 3H), 5.48 (s, 1H), 4.03 (br, 1H). 13C NMR (100.6
MHz, CDCl3, d): 135.3, 129.7, 129.1, 126.9, 119.1, 63.3.
GC-MS m/z: 133, 115, 105, 77, 51.
4.4. Typical procedure for the enantioselective addi-
tion of TMSCN to aldehydes catalyzed by the
complex of Ti-ligand
To a solution of ligand (2.5 mmol) and 4 Å MS in THF
(1.5 mL) was added Ti(O-i-Pr)4 (2.5 mmol) and the mixture
was stirred at room temperature for 1 h. Subsequently alde-
hyde (0.5 mmol) was added, and stirred at room tempera-
ture for 30 min. The reaction mixture was cooled to -78 °C,
and trimethylsilylcyanide (1 mmol) was added. Following
stirring for 48 h at this temperature, 2 M HCl (3 mL) was
added to the reaction solution. After further stirring for 1 h
at room temperature; filtrating through celite; extracting
with ethyl acetate (twice); drying with anhydrous magne-
sium sulfate and concentrating the reaction mixture fol-
lowed by column chromatography (eluent: hexane/acetone
9:1) to yield the expected cyanohydrin.
2-Acetoxy-2-phenylacetonitrile 15a. Yield: 95%.
[a] 2D5.8 = +4.1° (c 1.16, CHCl3). IR (KBr): 2954, 2919,
2850, 1457, 1373, 1211, 1022, 755, 694, 601, 570 cm-1. 1H
NMR (400 MHz, CDCl3, d): 7.53-7.51 (m, 2H), 7.46-7.45
(m, 3H), 6.41 (s, 1H), 3.09 (s, 3H). 13C NMR (100.6 MHz,
CDCl3, d): 168.9, 131.7, 130.4, 129.2, 127.9, 116.1, 62.8,
20.5. GC-MS m/z: 175, 133, 115, 105, 89, 77, 63, 43, 28,
18. HPLC (Daicel Chiralcel OD-H, hexane/i-PrOH =
90:10, flow rate 0.25 mL/min), tR of R isomer 28.02 min, tR
of S isomer 30.27 min, R:S = 92.4:7.6, ee%: 85%.
Determination the enantiomeric excess (ee%) of
cyanohydrin
Method A: The pure cyanohydrin was directly con-
verted into the corresponding acetates by reaction with ace-
tic anhydride and pyridine in CH2Cl2 at room temperature
for 2 h. After concentration, the residue was purified by
2-Hydroxy-2-(2-methoxyphenyl)acetonitrile 14b.
Yield: 12%. [a] 2D6.3 = +4.2° (c 1.19, CHCl3). IR (KBr): 3413
(br), 2927, 2842, 1600, 1492, 1465, 1253, 1025, 755 cm-1.
1H NMR (400 MHz, CDCl3, d): 7.43-7.38 (m, 2H), 7.03-

734 J. Chin. Chem. Soc., Vol. 57, No. 4A, 2010
Lin and Chen
6.97 (m, 2H) 5.56-5.54 (d, J = 8.8 Hz, 1H), 3.95 (s, 3H),
3.50-3.48 (d, J = 8.8 Hz, 1H). 13C NMR (100.6 MHz,
CDCl3, d): 156.7, 131.2, 128.0, 123.6, 121.1, 118.9, 111.2,
60.2, 55.7. GC-MS m/z: 163, 146, 136, 118, 105, 92, 77, 65,
51.
2938, 2842, 1754, 1515, 1253, 1214, 1176, 1025, 829 cm-1.
1H NMR (400 MHz, CDCl3, d): 7.46-7.44 (d, J = 8.8 Hz,
2H), 6.96-6.94 (d, J = 8.8 Hz, 2H), 6.35 (s, 1H), 3.83 (s,
3H), 2.14 (s, 3H). 13C NMR (100.6 MHz, CDCl3, d): 169.0,
161.1, 129.6, 123.8, 116.4, 114.5, 62.6, 55.4, 20.5. GC-MS
m/z: 205, 163, 146, 135, 116, 103. HPLC (Daicel Chiralcel
OD-H, n-hexane/2-propanol = 9:1, flow rate 0.25 mL/
min), tR of R isomer 32.90 min, tR of S isomer 36.15 min,
R:S = 63.8:36.2, ee%: 27%.
2-Acetoxy-2-(2-methoxyphenyl)acetonitrile 15b.
Yield: 95%. [a] 2D3.9 = +2.18° (c 1.17, CHCl3). IR (KBr):
2942, 2842, 1754, 1496, 1257, 1214, 1022, 755 cm-1. 1H
NMR (400 MHz, CDCl3, d): 7.57-7.55 (dd, J1 = 7.6 Hz, J2 =
1.6 Hz, 1H), 7.45-7.40 (m, 1H), 7.06-7.02 (m, 1H), 6.95-
6.93 (d, J = 8.3 Hz, 1H), 6.70 (s, 1H), 3.88 (s, 3H), 2.17 (s,
3H). 13C NMR (100.6 MHz, CDCl3, d): 168.9, 156.7,
131.8, 128.7, 120.9, 119.9, 116.3, 111.1, 58.1, 55.7, 20.4.
GC-MS m/z: 205, 163, 144, 135, 116, 103. HPLC (Daicel
Chiralcel OD-H, n-hexane/2-propanol/acetonitrile = 80:
1:1, flow rate 0.25 mL/min), tR of R isomer 41.21 min, tR of
S isomer 43.92 min, R:S = 38.1:61.9, ee%: 23%.
2-Hydroxy-2-o-tolylacetonitrile 14e. Yield: 23%.
[a] 2D5. 8 = +18.1° (c 1.12, CHCl3). IR (KBr): 3397 (br), 2923,
1492, 1461, 1292, 1245, 1241, 1180, 1037, 937, 752 cm-1.
1H NMR (400 MHz, CDCl3, d): 7.62-7.60 (m, 1H), 7.36-
7.29 (m, 2H), 7.27-7.24 (m, 1H), 5.67 (s, 1H), 2.56 (br,
1H), 2.45 (s, 3H). 13C NMR (100.6 MHz, CDCl3, d): 136.2,
133.0, 131.2, 129.9, 127.0, 126.7, 118.9, 61.4, 18.7.
GC-MS m/z: 147, 129, 120, 91, 65, 51.
2-Hydroxy-2-(3-methoxyphenyl)acetonitrile 14c.
Yield: 8%. [a] 2D6.3 = +12.7° (c 1.02, CHCl3). IR (KBr): 3421
2-Acetoxy-2-o-tolylacetonitrile 15e. Yield: 96%.
[a] 2D4. 1 = +9.2° (c 1.31, CHCl3). IR (KBr): 2935, 1754,
1373, 1211, 1022, 960, 755, 570 cm-1. 1H NMR (400 MHz,
CDCl3, d): 7.57-7.55 (d, J = 7.6 Hz, 1H), 7.38-7.34 (m,
1H), 7.31-7.27 (m, 1H), 7.26-7.24 (m, 1H), 6.51 (s, 1H),
2.43, (s, 3H), 2.18 (s, 3H). 13C NMR (100.6 MHz, CDCl3,
d): 168.9, 136.6, 131.3, 130.5, 129.8, 128.5, 126.8, 116.0,
61.0, 20.3, 18.9. GC-MS m/z: 189, 147, 129, 119, 103, 91,
77, 65, 51. HPLC (Daicel Chiralcel OD-H, n-hexane/2-
propanol/acetonitrile = 80:1:1, flow rate 0.25 mL/min), tR
of R isomer 34.21 min, tR of S isomer 35.30 min, R:S =
27.4:72.6, ee%: 45%.
1
(br), 2927, 2842, 1604, 1492, 1262, 1041, 852 cm-1. H
NMR (400 MHz, CDCl3, d): 7.37-7.33 (t, J = 7.9 Hz, 1H),
7.11-7.09 (d, J = 7.7 Hz, 1H), 7.06-7.05 (m, 1H), 6.97-6.94
(dd, J1 = 8.3 Hz, J2 = 2.2 Hz, 1H), 5.51 (s, 1H), 3.83 (s, 3H),
3.02 (br, 1H). 13C NMR (100.6 MHz, CDCl3, d): 160.1,
136.7, 130.3, 118.7, 118.6, 115.6, 112.0, 63.6, 55.4.
GC-MS m/z: 163, 146, 136, 107, 92, 77, 65, 51.
2-Acetoxy-2-(3-methoxyphenyl)acetonitrile 15c.
Yield: 98%: [a] 2D5.9 = +1.7° (c 0.94, CHCl3). IR (KBr):
2927, 2842, 1754, 1604, 1492, 1211, 1025, 694 cm-1. 1H
NMR (400 MHz, CDCl3, d): 7.38-7.34 (t, J = 7.9 Hz, 1H),
7.10-7.08 (d, J = 7.6 Hz, 1H), 7.03-6.97 (m, 2H), 6.37 (s,
1H), 3.83 (s, 3H), 2.17 (s, 3H). 13C NMR (100.6 MHz,
CDCl3, d): 168.9, 160.1, 133.0, 130.3, 120.0, 116.1, 116.0,
113.2, 62.7, 55.4, 20.5. GC-MS m/z: 205, 163, 146, 135,
116, 108. HPLC (Daicel Chiralcel OD-H, n-hexane/2-pro-
panol = 9:1, flow rate 0.25 mL/min), tR of R isomer 30.60
min, tR of S isomer 35.21 min, R:S = 73.3:26.7, ee%: 47%.
2-Hydroxy-2-(4-methoxyphenyl)acetonitrile 14d.
Yield: 10%. [a] 2D6.4 = +8.0° (c 1.19, CHCl3). IR (KBr): 3424
(br), 2938, 2838, 1612, 1511, 1253, 1176, 1029, 833 cm-1.
1H NMR (400 MHz, CDCl3, d): 7.46-7.44 (d, J = 8.8 Hz,
2H), 6. 96-6.94 (d, J = 8.8 Hz, 2H), 5.48-5.47 (d, J = 4.3
Hz, 1H), 3.83 (s, 3H), 2.66 (br, 1H). 13C NMR (100.6 MHz,
CDCl3, d): 160.5, 128.3, 127.5, 119.1, 114.5, 63.0, 55.4.
GC-MS m/z: 163, 145, 135, 107, 92, 77, 63, 51.
2-Hydroxy-2-m-tolylacetonitrile 14f. Yield: 20%.
[a] 2D6. 2 = +1.4° (c 1.05, CHCl3). IR (KBr): 3409 (br), 2923,
2865, 1608, 1488, 1249, 1157, 1037, 790, 748, 698 cm-1.
1H NMR (400 MHz, CDCl3, d): 7.35-7.32 (m, 3H), 7.25-
7.24 (m, 1H), 5.50 (s, 1H), 2.67 (br, 1H), 2.40 (s, 3H). 13
C
NMR (100.6 MHz, CDCl3, d): 139.1, 135.1, 130.5, 129.0,
127.3, 123.7, 119.1, 63.4, 21.3. GC-MS m/z: 147, 132, 119,
91, 65, 51.
2-Acetoxy-2-m-tolylacetonitrile 15f. Yield: 91%.
[a] 2D3. 2 = +1.0° (c 1.23, CHCl3). IR (KBr): 2935, 1754,
1373, 1214, 1022, 971, 898, 790, 698 cm-1. 1H NMR (400
MHz, CDCl3, d): 7.34-7.29 (m, 3H), 7.27-7.26 (m, 1H),
6.37 (s, 1H), 2.40 (s, 3H), 2.17 (s, 1H). 13C NMR (100.6
MHz, CDCl3, d): 168.9, 139.2, 131.6, 131.1, 129.1, 128.5,
124.9, 116.2, 62.9, 21.3, 20.5. GC-MS m/z: 189, 147, 129,
119, 103, 91, 77, 65, 51. HPLC (Daicel Chiralcel OD-H,
n-hexane/2-propanol = 9:1, flow rate 0.25 mL/min), tR of R
isomer 24.32 min, tR of S isomer 26.84 min, R:S = 52.6:
2-Acetoxy-2-(3-methoxyphenyl)acetonitrile 15d.
Yield: 95%. [a] 2D4.1 = -4.7° (c 1.14, CHCl3). IR (KBr):

Salen Catalyst, Asymmetric Trimethylsilylcyanation
J. Chin. Chem. Soc., Vol. 57, No. 4A, 2010 735
47.4, ee%: 5%.
2-(3-Chlorophenyl)-2-acetoxyacetonitrile 15i.
Yield: 95%. [a] 2D5. 2 = +2.3° (c 1.41, CHCl3). IR (KBr):
2923, 2854, 1758, 1430, 1369, 1207, 1022, 875, 786, 686
cm-1. 1H NMR (400 MHz, CDCl3, d): 7.51 (s, 1H), 7.45-
7.37 (m, 3H), 6.37 (s, 1H), 2.18 (s, 3H). 13C NMR (100.6
MHz, CDCl3, d): 168.7, 135.2, 133.5, 130.6, 130.5, 127.9,
125.9, 115.6, 62.0, 20.4. GC-MS m/z: 209, 167, 150, 139,
132, 123, 114. HPLC (Daicel Chiralcel OD-H, n-hex-
ane/2-propanol = 9:1, flow rate 0.25 mL/min), tR of R iso-
mer 29.31 min, tR of S isomer 31.49 min, R:S = 73.3:26.7,
ee%: 47%.
2-Hydroxy-2-p-tolylacetonitrile 14g. Yield: 21%.
[a] 2D6. 3 = +13.8° (c 1.05, CHCl3). IR (KBr): 3444 (br), 3031,
2927, 1511, 1415, 1184, 1037, 925, 813, 763, 528 cm-1. 1H
NMR (400 MHz, CDCl3, d): 7.43-7.41 (d, J = 8.0 Hz, 2H),
7.26-7.24 (d, J = 8.0 Hz, 2H), 5.50 (s, 1H), 2.59 (br, 1H),
2.38 (s, 3H). 13C NMR (100.6 MHz, CDCl3, d): 139.8,
132.3, 129.8, 126.7, 119.1, 63.2, 21.2. GC-MS m/z: 147,
131, 119, 105, 91, 77, 65, 51.
2-Acetoxy-2-p-tolylacetonitrile 15g. Yield: 96%.
[a] 2D3. 8 = -2.5° (c 1.27, CHCl3). IR (KBr): 2931, 1754,
1373, 1214, 1018, 960, 813, 566 cm-1. 1H NMR (400 MHz,
CDCl3, d): 7.41-7.39 (d, J = 8.0 Hz, 2H), 7.26-7.24 (d, J =
8.0 Hz, 2H), 6.37 (s, 1H), 2.39 (s, 3H), 2.15 (s, 3H). 13C
NMR (100.6 MHz, CDCl3, d): 169.0, 140.7, 129.9, 128.8,
127.9, 116.3, 62.7, 21.3, 20.5. GC-MS m/z: 189, 147, 129,
119, 103, 91, 77, 65, 51. HPLC (Daicel Chiralcel OD-H,
n-hexane/2-propanol = 9:1, flow rate 0.25 mL/min), tR of R
isomer 25.02 min, tR of S isomer 30.23 min, R:S = 65.0:
35.0, ee%: 30%.
2-(4-Chlorophenyl)-2-hydroxyacetonitrile 14j.
Yield: 37%. [a] 2D6.6 = +6.4° (c 1.09, CHCl3). IR (KBr): 3432
(br), 2931, 2857, 1492, 1407, 1091, 1045, 1014, 836, 790
cm-1. 1H NMR (400 MHz, CDCl3, d): 7.46-7.39 (m, 4H),
5.51 (s, 1H), 3.67 (br, 1H). 13C NMR (100.6 MHz, CDCl3,
d): 135.8, 133.7, 129.3, 128.0, 118.5, 62.8. GC-MS m/z:
167, 139, 132, 111, 75, 51.
2-(4-Chlorophenyl)-2-acetoxyacetonitrile 15j.
Yield: 75%. [a] 2D5. 2 = -2.5° (c 1.11, CHCl3). IR (KBr): 3073,
2927, 2854, 1754, 1492, 1373, 1211, 1091, 1014, 960, 817,
2-(2-Chlorophenyl)-2-hydroxyacetonitrile 14h.
Yield: 32%. [a] 2D6. 8 = -1.09° (c 1.37, CHCl3). IR (KBr):
3424 (br), 2931, 2865, 1473, 1442, 1191, 1072, 1033, 755
cm-1. 1H NMR (400 MHz, CDCl3, d): 7.72-7.68 (m, 1H),
7.43-7.40 (m, 1H), 7.38-7.34 (m, 2H), 5.84 (s, 1H), 3.93
(br, 1H). 13C NMR (100.6 MHz, CDCl3, d): 132.7, 132.6,
131.0, 130.0, 128.3, 127.7, 118.0, 60.7. GC-MS m/z: 167,
150, 139, 132, 111, 105, 75, 61, 51.
1
566 cm-1. H NMR (400 MHz, CDCl3, d): 7.47-7.41 (m,
4H), 6.37 (s, 1H), 2.16 (s, 3H). 13C NMR (100.6 MHz,
CDCl3, d): 168.8, 136.6, 130.2, 129.5, 129.3, 115.7, 62.1,
20.4. GC-MS m/z: 209, 167, 149, 139, 132, 123, 114.
HPLC (Daicel Chiralcel OD-H, n-hexane/2-propanol =
9:1, flow rate 0.25 mL/min), tR of R isomer 31.02 min, tR of
S isomer 34.80 min, R:S = 60.3:39.7, ee%: 21%.
2-(2-Chlorophenyl)-2-acetoxyacetonitrile 15h.
Yield: 95%. [a] 2D4. 8 = +10.4° (c 1.67, CHCl3). IR (KBr):
3073, 2923, 2850, 1758, 1373, 1207, 1056, 1025, 755 cm-1.
1H NMR (400 MHz, CDCl3, d): 7.73-7.71 (m, 1H), 7.47-
7.44 (m, 1H), 7.42-7.37 (m, 2H), 6.70 (s, 1H), 2.19 (3H).
13C NMR (100.6 MHz, CDCl3, d): 168.6, 133.4, 131.7,
130.2, 129.5, 129.4, 127.6, 115.3, 60.2, 20.2. GC-MS m/z:
209, 167, 150, 139, 132, 123, 114, 105. HPLC (Daicel
Chiralcel OD-H, n-hexane/2-propanol = 9:1, flow rate 0.25
mL/min), tR of R isomer 24.33 min, tR of S isomer 26.44
min, R:S = 37.5:62.5, ee%: 25%.
3-(Cyano(hydroxy)methyl)benzonitrile 14k. Yield:
15%. [a] 2D6. 3 = +2.7° (c 0.91, CHCl3). IR (KBr): 3482 (br),
2919, 2850, 2237, 1434, 1149, 1045, 802, 740, 690 cm-1.
1H NMR (400 MHz, CDCl3, d): 7.84 (s, 1H), 7.80-7.78 (d,
J = 7.8 Hz, 1H), 7.73-7.71 (d, J = 7.7 Hz, 1H), 7.61-7.57 (t,
J = 7.8 Hz, 1H), 5.62 (s, 1H), 3.89 (br, 1H). 13C NMR
(100.6 MHz, CDCl3, d): 136.8, 133.2, 131.0, 130.2, 130.1,
118.1, 118.0, 113.1, 62.3. GC-MS m/z: 130, 102, 76, 51.
Cyano(3-cyanophenyl)methyl pivalate 15k. Yield:
92%. [a] 2D5 = +2.3° (c 0.45, CHCl3). IR (KBr): 3070, 2977,
2938, 2877, 2233, 1747, 1481, 1268, 1122, 802, 690 cm-1.
1H NMR (400 MHz, CDCl3, d): 7.79-7.74 (m, 3H), 7.62-
7.58 (t, J = 7.8 Hz, 1H), 6.41 (s, 1H), 1.24 (s, 9H). 13C NMR
(100.6 MHz, CDCl3, d): 176.1, 133.8, 133.6, 131.7, 130.9,
130.3, 117.6, 115.4, 113.7, 61.7, 38.9, 26.8. GC-MS m/z:
242, 158, 141, 114, 102. HPLC (Daicel Chiralcel OD-H,
n-hexane/2-propanol = 9:1, flow rate 0.25 mL/min), tR of R
isomer 36.60 min, tR of S isomer 41.50 min, R:S = 41.5:
58.5, ee%: 17%.
2-(3-Chlorophenyl)-2-hydroxyacetonitrile 14i.
Yield: 28%. [a] 2D6. 7 = +13.9° (c 1.57, CHCl3). IR (KBr):
3440 (br), 2927, 2854, 1477, 1430, 1191, 1099, 1041, 786,
1
721 cm-1. H NMR (400 MHz, CDCl3, d): 7.50 (s, 1H),
7.39-7.36 (m, 3H), 5.50 (s, 1H), 3.61 (br, 1H). 13C NMR
(100.6 MHz, CDCl3, d): 136.9, 135.1, 130.4, 129.9, 126.7,
124.6, 118. 5, 62.7. GC-MS m/z: 167, 139, 132, 111, 105,
75, 50.

736 J. Chin. Chem. Soc., Vol. 57, No. 4A, 2010
Lin and Chen
4-(Cyano(hydroxy)methyl)benzonitrile 14l. Yield:
d): 7.34-7.30 (m, 2H), 7.26-7.24 (m, 1H), 7.22-7.18 (m,
2H), 5.28-5.25 (t, J = 6.8 Hz, 1H), 2.85-2.81 (m, 2H),
2.27-2.21 (m, 2H), 2.12 (s, 3H). 13C NMR (100.6 MHz,
CDCl3, d): 169.1, 139.0, 128.8, 128.3, 126.7, 116.7, 60.5,
33.7, 30.7, 20.3. HPLC (Daicel Chiralcel OD-H, n-hex-
ane/2-propanol/acetonitrile = 80:1:1, flow rate 1.00 mL/
min), tR of R isomer 22.55 min, tR of S isomer 28.18 min,
R:S = 22.6:77.4, ee%: 55%.
11%. [a] 2D6. 4 = +2.3° (c 1.01, CHCl3). IR (KBr): 3382 (br),
1
2919, 2854, 2233, 1407, 1064, 1049, 848, 420 cm-1. H
NMR (400 MHz, CDCl3, d): 7.75-7.73 (d, J = 8.4 Hz, 2H),
7.68-7.66 (d, J = 8.2 Hz, 2H), 5.63 (s, 1H), 3.87 (br, 1H).
13C NMR (100.6 MHz, CDCl3, d): 140.1, 132.9, 127.2,
118.0, 113.4, 62.5. GC-MS m/z: 130, 102, 76, 50.
Cyano(4-cyanophenyl)methyl pivalate 15l. Yield:
93%. [a] 2D4. 5 = -2.0° (c 0.35, CHCl3). IR (KBr): 2977, 2919,
2-Hydroxy-3-methylbutanenitrile 14o. Yield: 55%.
[a] 2D7. 8 = +9.5° (c 1.37, CHCl3). IR (KBr): 3417 (br), 2969,
2923, 1739, 1465, 1373, 1214, 1064 cm-1. 1H NMR (400
MHz, CDCl3, d): 4.25-4.24 (d, J = 5.8 Hz, 1H), 3.65 (br,
1H), 2.06-1.98 (m, 1H), 1.07-1.06 (d, J = 6.7 Hz, 3H),
1.04-1.03 (d, J = 6.8 Hz, 3H). 13C NMR (100.6 MHz,
CDCl3, d): 119.3, 66.9, 33.0, 17.6, 17.2.
1
2850, 2233, 1747, 1477, 1265, 1118, 821 cm-1. H NMR
(400 MHz, CDCl3, d): 7.77-7.75 (d, J = 5.5 Hz, 2H), 7.64-
7.62 (d, J = 8.2 Hz, 2H), 6.44 (s, 1H), 1.25 (s, 9H). 13C
NMR (100.6 MHz, CDCl3, d): 176.1, 136.7, 133.0, 128.1,
117.7, 115.3, 114.3, 61.9, 38.9, 26.8. GC-MS m/z: 242,
158, 141, 131, 114, 102. HPLC (Daicel Chiralcel OD-H,
n-hexane/2-propanol = 9:1, flow rate 0.25 mL/min), tR of R
isomer 40.55 min, tR of S isomer 44.69 min, R:S = 51.5:
48.5, ee%: 3%.
1-Cyano-2-methylpropyl benzoate 15o. Yield: 93%.
[a] 2D6. 3 = +28.5° (c 0.88, CHCl3). IR (KBr): 2973, 2935,
1735, 1253, 1095, 709 cm-1. 1H NMR (400 MHz, CDCl3,
d): 8.06-8.04 (m, 2H), 7.64-7.60 (m, 1H), 7.49-7.46 (m,
2H), 5.44-5.43 (d, J = 5.7 Hz, 1H), 2.35-2.27 (m, 1H),
1.21-1.20 (d, J = 6.7 Hz, 3H), 1.18-1.16 (d, J = 6.8 Hz, 3H).
13C NMR (100.6 MHz, CDCl3, d): 164.7, 133.9, 129.9,
128.6, 128.3, 116.0, 66.7, 31.3, 17.8, 17.5. HPLC (Daicel
Chiralcel OD-H, n-hexane/2-propanol = 9:1, flow rate 0.50
mL/min), tR of R isomer 12.01 min, tR of S isomer 13.73
min, R:S = 87.6:12.4, ee%: 75%.
(E)-2-Hydroxy-4-phenylbut-3-enenitrile 14m.
Yield: 10%. [a] 2D4.6 = +6.25° (c 0.64, CHCl3). IR (KBr):
3421 (br), 2923, 1662, 1029, 968, 748, 694 cm-1. 1H NMR
(400 MHz, CDCl3, d): 7.40-7.33 (m, 5H), 6.90-6.86 (d, J =
15.8 Hz, 1H), 6.27-6.21 (dd, J1 = 15.8 Hz, J2 = 5.8 Hz, 1H),
5.16-5.15 (d, J = 5.8 Hz, 1H), 4.20 (br, 1H). 13C NMR
(100.6 MHz, CDCl3, d): 135.0, 134.8, 129.0, 128.8, 127.1,
122.4, 118.6, 61.7.
(E)-1-Cyano-3-phenylallyl acetate 15m. Yield: 97%.
[a] 2D6. 2 = -23.7° (c 0.51, CHCl3). IR (KBr): 2935, 1751,
1373, 1214, 1022, 968, 748, 694 cm-1. 1H NMR (400 MHz,
CDCl3, d): 7.43-7.42 (m, 2H), 7.38-7.32 (m, 3H), 6.99-
6.95 (d, J = 15.8 Hz, 1H), 6.22-6.17 (dd, J1 = 15.8 Hz, J2 =
ACKNOWLEDGEMENTS
The authors thank Dr. Sankareswaran Srimurugan for
his helpful discussions (Postdoctoral fellowship awarded
by National Science Council of the Republic of China, un-
der contract NSC 96-2811-M-259-001) and Ms. L. M. Hsu,
at the Instruments Center, National Chung Hsing Univer-
sity, for her help in obtaining HRMS, and the National Sci-
ence Council of the Republic of China, for financially sup-
porting this research under contract NSC 96-2113-M-259-
001.
6.7 Hz, 1H), 6.03-6.01 (d, J = 6.7 Hz, 1H), 2.17 (s, 3H). 13
C
NMR (100.6 MHz, CDCl3, d): 168.9, 137.8, 134.4, 129.4,
128.8, 127.2, 118.3, 115.5, 61.5, 20.4. HPLC (Daicel
Chiralcel OD-H, n-hexane/2-propanol/acetonitrile = 80:1:1,
flow rate 1.00 mL/min), tR of R isomer 19.68 min, tR of S
isomer 25.22 min, R:S = 17.8:82.2, ee%: 65%.
2-Hydroxy-4-phenylbutanenitrile 14n. Yield: 18%.
[a] 2D4. 8 = -2.4° (c 1.55, CHCl3) IR (KBr): 3440 (br), 2931,
Received July 17, 2009.
1
2861, 1454, 1072, 748, 698 cm-1. H NMR (400 MHz,
CDCl3, d): 7.35-7.31 (m, 2H), 7.26-7.21 (m, 3H), 4.43-
4.40 (t, J = 6.8 Hz, 1H), 3.51 (br, 1H), 2.88-2.83 (m, 2H),
2.22-2.11 (m, 2H). 13C NMR (100.6 MHz, CDCl3, d):
139.6, 128.7, 128.5, 126.5, 120.0, 60.3, 36.5, 30.6.
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