Enantioselective cyanosilylation of aldehydes catalyzed by novel camphor derived Schiff bases-titanium(IV) complexes

Article abstract of DOI:10.1016/j.tetasy.2014.03.001

Five tridentate Schiff bases have been prepared from (1R,2S,3R,4S)-3-amino- 1,7,7-trimethylbicyclo[2.2.1]heptan-2-ol and salicylaldehydes. X-ray structure investigation revealed differences in their molecular conformation, and their titanium(IV) complexes

Full text of DOI:10.1016/j.tetasy.2014.03.001

Tetrahedron: Asymmetry 25 (2014) 554–562
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Enantioselective cyanosilylation of aldehydes catalyzed by novel
camphor derived Schiff bases-titanium(IV) complexes
⇑
Ewelina Błocka, Mariusz J. Bosiak , Mirosław Wełniak, Agnieszka Ludwiczak, Andrzej Wojtczak
Faculty of Chemistry, Nicolaus Copernicus University, 7 Gagarin Street, 87-100 Torun´, Poland
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 4 February 2014
Accepted 4 March 2014
Five tridentate Schiff bases have been prepared from (1R,2S,3R,4S)-3-amino-1,7,7-trimethylbicy-
clo[2.2.1]heptan-2-ol and salicylaldehydes. X-ray structure investigation revealed differences in their
molecular conformation, and their titanium(IV) complexes have been studied with NMR techniques.
Among them the complex with the Schiff base obtained from 2-hydroxy-3-isopropylbenzaldehyde, is
the most selective catalyst for the cyanosilylation of aliphatic, alicyclic, aromatic, and heteroaromatic
aldehydes. The highest enantioselectivity, >99%, was achieved for the addition of trimethylsilyl cyanide
to cinnamaldehyde.
Ó 2014 Elsevier Ltd. All rights reserved.
1. Introduction
synthesis of many natural products and biologically active com-
pounds.1 At present, the asymmetric cyanosilylation of aldehydes,
In recent years, interest in optically active cyanohydrin has
increased significantly due to their easy conversion into a number
of valuable functional groups (Scheme 1), and their utility in the
catalyzed by metal complexes with chiral auxiliary ligands, fol-
lowed by acidic hydrolysis, seems to be the best cyanohydrin
synthesis.
After the pioneering work by Hayashi and Oguni2 on the cata-
lytic enantioselective cyanosilylation of aldehydes using chiral
Schiff base ligands and Ti(O-i-Pr)4, various chiral catalytic systems
have been developed. However, the enantioselective cyanosilyla-
tion of a broad range of substrates, including aliphatic aldehydes
and ketones, with low catalyst loadings, under mild reaction con-
ditions, is still a challenge. Extensive studies on these systems,
employing a variety of Schiff bases derived from different chiral
amino alcohols or diamine compounds, revealed that the enantio-
selective cyanosilylation of aldehydes is highly dependent on the
type of Schiff base.3
O
HO
∗
OH
R1 R2
HO
∗
R1 R2
R1 OH
CHO
NH2
O
∗
R2
R1 OH
Camphor derivatives are highly interesting ligands for asym-
metric catalysts due to their rigid structure and defined configura-
tion. Hence we decided to investigate camphor derived Schiff bases
in the catalytic asymmetric cyanosilylation of aldehydes.4,5
ZO
NH2
HO
∗
R3
∗
∗
R2
∗
CN
R1 R2
R3
R1 R2
R2
2. Results and discussion
R1
HO
H2N
O
∗
∗
CN
R1 R2
O
Enantiomerically pure amino alcohol (1R,2S,3R,4S)-3-amino-
1,7,7-trimethylbicyclo[2.2.1]heptan-2-ol 4, was prepared in five
steps, according to the literature.6 The chiral Schiff bases 6a–e
were prepared from 4 by condensation with an appropriate com-
mercially available aldehyde in toluene or methanol (Scheme 2).
Schiff bases 6a–c were found to be efficient Ti(IV)—catalyst
ligands in the enantioselective cyanosilylation of aldehydes with
R3
Scheme 1. Various transformations of chiral cyanohydrins.
⇑
Corresponding author. Tel.: +48 512038649; fax: +48 56 6542477.
E-mail address: bosiu@chem.umk.pl (M.J. Bosiak).
http://dx.doi.org/10.1016/j.tetasy.2014.03.001
0957-4166/Ó 2014 Elsevier Ltd. All rights reserved.

E. Błocka et al. / Tetrahedron: Asymmetry 25 (2014) 554–562
555
OH
i
iv
ii
iii
N
N
NH2
OH
NH2
OH
OH
O
O
O
1
3
2
4
5
R3
R2
R1
R4
NH2
OH
N
OH
v
vi
aldehyde
procedure A, B or C
6a: R1 = R2 = R3 = R4 = H
OH
: R1 = Me, R2 = R3 = R4 = H
4
6a-e
6b
6c: R1 = i-Pr, R2 = R3 = R4= H
: R1 = R3 = t-Bu, R2 = R4 = H
6e: R1 = R3 = R4 = H, R2 = N,N-diethyl
6d
Scheme 2. Synthesis of (1R,2S,3R,4S)-3-amino-1,7,7-trimethylbicyclo[2.2.1]heptan-2-ol.4 Reagents and conditions: (i) (1) t-BuOK, 0 °C; (2) i-AmylONO, 0 °C, THF, 18 h; (ii)
H2O, reflux, 16 h; (iii) (1) LiAlH4, 0 °C, 50 min, reflux, 24 h; (2) 10% NaOHaq, H2O, rt; (iv) (1) (Cl3CO)2CO, CH2Cl2, ꢀ5 °C, 1 h, rt, 2.5 h, (2) crystallization; (v) 3 M NaOH, EtOH/
H2O, reflux, 6 h; (vi) procedure A: p-TsOH, anhydrous MgSO4, toluene, reflux, 24 h. Procedure B: Et3N, anhydrous MgSO4, MeOH, rt, 72 h. Procedure C: Et3N, anhydrous MgSO4,
MeOH, rt, 96 h.
trimethylsilylcyanide (TMSCN). The reaction with benzaldehyde
was optimized, by changing solvent, catalyst load, and temperature
(Table 1). In all cases Ti(O-i-Pr)4, was used as the pre-catalyst and
the reaction time was 48 hours. The molar ratio ligand/Ti(O-i-Pr)4,
was 1:1.
Table 2
The asymmetric addition of TMSCN to benzaldehyde catalyzed by Ti(O-i-Pr)4/6b–e in
dichloromethane
Ligand
Catalyst load
(mol %)
Time
(h)
Temperature
(°C)
Yielda
(%)
Eeb (%)/
config.c
When the reaction was carried out at ꢀ20 °C in toluene or THF,
the enantiomeric excess was 7% ee and 19% ee, respectively. Using
dichloromethane as the solvent, under the same conditions, the
enantiomeric excess and yield increased significantly (65% ee,
80%), while at 0 °C the selectivity was lower (55% ee). Next, 6b–e
were examined in the enantioselective cyanosilylation of benzal-
dehydes under the above optimal conditions.
The results presented in Table 2 indicate the significant influ-
ence of the Schiff base structure on the reaction enantioselectivity.
The presence of substituents R1, R2, and R3, in the aromatic ring
leads to increased steric hindrance, thus providing an opportunity
to control the asymmetric induction. The relatively small steric
hindrance of the methyl group in 6b results in the same value of
ee as for 6a. Higher enantioselectivity was achieved for the isopro-
pyl group in 6c at the same position (81% ee), but the two tert-butyl
groups in 6d lead to a significant decrease of enantiomeric excess
(27% ee). The N,N-diethyl substituent at the R2 position gave the
product with the lowest ee value.
6b
6b
6c
6c
6d
6d
6e
20
20
20
20
20
20
20
48
48
48
48
48
48
48
ꢀ20
20
80
73
86
59
79
35
74
65 (S)
69 (S)
81 (S)
32 (S)
27 (S)
17 (S)
8 (S)
ꢀ20
20
ꢀ20
20
ꢀ20
a
Isolated by chromatography.
Enantiomeric excesses were determined for acetyl derivatives by HPLC using a
chiral OD-H column.
b
c
Configurations were established by comparing the signs of the specific rotation
with the literature data.2
Lowering the Ti(O-i-Pr)4/6c load to 1 mol % did not affect the
enantioselectivity of the reaction and only slightly decreased its
yield.
2.1. Titanium(IV)/6c complex structure
The Ti(O-i-Pr)4/6c, 1:1 molar ratio, catalytic system was used
for the cyanosilylation of substituted aromatic, aliphatic, cyclic,
and a,b-unsaturated aldehydes. The results are shown in Table 3.
Oguni2 and Flores-Lopez8 examined the cyanosilylation of alde-
hydes catalyzed by titanium tetraisopropoxide/chiral Schiff base
complexes, in 1:1 and 1:2 molar ratios, and identified the catalyt-
ically active complex L⁄Ti(O-i-Pr)2 and the inactive L⁄2Ti.
Cyclic aliphatic aldehydes gave only slightly lower yields and ee
values than the para-substituted aromatic aldehydes. High enanti-
oselectivity was also obtained for the reaction with furan-2-carbal-
dehyde (91% ee).
The best results for the asymmetric cyanosilylation were ob-
tained with cinnamaldehyde (entry 27); this prompted us to exam-
ine the effect of the catalyst load on the enantioselectivity. The
results are shown in Table 4.
We have studied the reaction of 6c with Ti(O-i-Pr)4, and found a
similarity with Flores-Lopez8 results. Figure 1A shows the 13C NMR
spectrum of 6c, and based on 13C NMR, DEPT90, DEPT135, 1H–13
C
HMQC, and HMBC, the following signals were identified: at
167.91 ppm from the imine C–H carbon and at 159.91 ppm from
the quaternary carbon atom coupled with the –OH of the aromatic
Table 1
The asymmetric addition of TMSCN to benzaldehyde catalyzed by Ti(O-i-Pr)4/6a
Ligand
Catalyst load (% mol)
Time (h)
Temperature (°C)
Solvent
Yielda (%)
Eeb (%)/config.c
6a
6a
6a
6a
20
20
20
20
48
48
48
48
ꢀ20
ꢀ20
ꢀ20
0
Toluene
THF
CH2Cl2
CH2Cl2
68
72
80
83
7 (S)
19 (S)
65 (S)
55 (S)
a
b
c
Product isolated by flash chromatography.
Enantiomeric excesses were determined for acetyl derivatives by HPLC using an OD-H or OJ colum.
Configurations were established by comparing the signs of specific rotation with literature data.2

556
E. Błocka et al. / Tetrahedron: Asymmetry 25 (2014) 554–562
The results are in agreement with Oguni’s2 results who found
that ligands containing small substituents at the 3-position of the
salicylaldehyde moiety did not exclusively form L⁄Ti(O-i-Pr)2, but
gave a mixture of products.
Table 3
The asymmetric addition of TMSCN to aldehydes catalyzed by Ti(O-i-Pr)4/6c
Entry
Aldehyde
Yielda (%)
eeb (%)
Configurationc
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
o-Methoxybenzaldehyde
m-Methoxybenzaldehyde
p-Methoxybenzaldehyde
o-Methylbenzaldehyde
m-Methylbenzaldehyde
p-Methylbenzaldehyde
o-Bromobenzaldehyde
m-Bromobenzaldehyde
P-Bromobenzaldehyde
o-Chlorobenzaldehyde
m-Chlorobenzaldehyde
p-Chlorobenzaldehyde
o-Nitrobenzaldehyde
m-Nitrobenzaldehyde
p-Nitrobenzaldehyde
o-Fluorobenzaldehyde
m-Fluorobenzaldehyde
p-Fluorobenzaldehyde
1-Naphthalenoaldehyde
2-Naphthalenoaldehyde
Furan-2-carbaldehyde
Cyclohexanecarbaldehyde
Cyclopentanecarbaldehyde
Butyraldehyde
17
5
91
2
3
7
48
88
28
72
87
55
—
13
97
98
87
49
80
34
rac
2
59
65
62
—
(S)
(S)
(R)
(S)
(R)
(R)
(S)
—
(R)
(S)
(R)
(R)
—
Formation of a certain amount of L⁄2Ti entails the presence of
some quantity of unreacted Ti(O-i-Pr)4, which is responsible for
the formation of the racemic cyanosilylation product.
3. X-ray structures of Schiff bases 6a–c
3.1. Crystal structure of 6c
The configuration of the reported compound was (1R,2S,3R,4S)
as determined by the Flack method, and corresponds to the (1R)-
camphor derivative (Fig. 3). The electron density maps have re-
vealed the presence of the H atom to be positioned between O2
and Schiff base N1, with the O2–H1O2 and N1–H1O2 distances
of 1.268 and 1.396 Å, respectively. Such a proton shift is frequently
observed for other Schiff bases with a hydroxyl group.
76
—
61
—
(S)
—
(S)
—
24
42
47
83
65
50
81
68
10
49
7
15
rac
74
83
35
91
88
78
98
49
45
>99
(S)
(S)
(R)
(S)
(R)
(R)
(S)
(S)
(S)
(S)
The valence geometry of the camphor and phenolic moieties is
typical for such ring systems. The C2–O1 distance of 1.424(2) Å is
typical. The phenolic C13–O2 distance is 1.343(2) Å. In the Schiff
base, the distances between C3–N1 and N1–C11 are 1.461(2) and
1.283(2) Å, respectively, while the C3–N1–C11 angle is
119.83(17) deg. The presence of the intramolecular H-bond
N1. . .O2 affects the position of the Schiff base moiety relative to
the camphor ring system, which can be described with the C2–
C3–N1–C11 torsion angle being 157.99(18) deg. The imine moiety
is planar, with the torsion angle C3–N1–C11–C12 of 179.55(16)
deg. The position of the camphor ring system relative to the imine
moiety is indicated by the torsion angles N1–C11–C12–C13 and
C11–C12–C13–O2 being 5.6(3) and ꢀ1.4(3) deg, respectively. The
position of the isopropyl substituent is indicated by the torsion an-
gles C13–C14–C18–C19 being ꢀ77.8(2) and C13–C14–C18–C20 of
157.49(19) deg. Analysis of the crystal packing revealed the pres-
ence of intermolecular interactions C17–H17A. . .O1[x,y,1+z] with
the C. . .O distance being 3.449(3) Å.
Hexanal
Decanal
Cinnamaldehyde
93
b Enantiomeric excesses were determined for the acetyl derivatives by HPLC using a
Chiracel OD-H or OJ column or by GC using a capillary column b-dex (120 or 325).
c The absolute configuration was determined by comparing the sign of the specific
rotation with literature data.2,7
a
Isolated by flash chromatography.
Table 4
The asymmetric addition of TMSCN to cinnamaldehyde catalyzed by Ti(O-i-Pr)4/6c
after 48 h at ꢀ20 °C.
Entry
Catalyst load (mol %)
Yielda (%)
eeb (%)/config.c
1
2
3
4
20
10
5
93
87
70
65
>99 (S)
>99 (S)
>99 (S)
>99 (S)
3.2. Crystal structure of 6b
1
a
The absolute configuration of 6b could not be reliably deter-
mined by the Flack method, but was assumed to be (1R,2S,3R,4S),
since this was consistent with the chirality of the substrate (1R)-
camphor (Fig. 4), and with 6a and 6c.
Contrary to the structure of 6c, the electron density maps re-
vealed that the H atom was localized on the phenolic O2, and no
additional peak was positioned near the Schiff base N1. The result-
ing intramolecular O2. . .N1 interaction was formed with an
O2. . .N1 distance of 2.5933(19) Å.
The valence geometry of the camphor and phenolic moieties is
typical for such systems. The C2–O1 distance of 1.418(2) Å and the
phenolic C13–O2 is 1.345(2) Å. In the imine moiety, the C3–N1 and
N1–C11 distances are 1.443(2) and 1.268(2) Å, respectively, and
are significantly different from those for 6c mentioned above.
These differences seem to reflect the differences in the imine bond
order, since it is affected by the different proton location between
the reported compounds. The C3–N1–C11 angle of 119.38(16) deg
is almost identical to that reported for 6c.
The O1–H camphor hydroxyl is involved in the intermolecular
H-bond with the phenolic O2–H, with the O1. . .O2[1/2ꢀy,1/
2+x,1/4+z] of 3.055(2) Å. As a result, the position of the imine moi-
ety relative to the camphor ring system is different to that of 6c,
with the C2–C3–N1–C11 torsion angle of 121.61(18) deg. The
intramolecular distances N1. . .O1 and N1. . .O2 are 2.697(2) and
2.5933(19) Å, respectively. The C8 methyl group participates in
Isolated by flash chromatography.
Enantiomeric excesses were determined for the acetyl derivatives by GC using a
b
capillary column b-dex (325).
c
Configurations were established by comparing the signs of specific rotations
with literature data.2
ring. When equimolar amounts of titanium tetraisopropoxide and
6c were combined, two titanium complexes, L⁄Ti(O-i-Pr)2 and
L⁄2Ti were observed (Fig. 1B). Signals at 165.05 and 162.73 ppm
were assigned to the imine carbon atoms and signals at 163.85
and 161.93 ppm to the quaternary carbon atoms coupled with
the –OH.
For 6c and Ti(O-i-Pr)4 in a 2:1 molar ratio, the 13C NMR spec-
trum revealed only signals assigned to L⁄2Ti (Fig. 1C). A comparison
of the spectra 1B and 1C proved that the in situ generated catalyst
for the enantioselective cyanosilylation, prepared from an eqiumo-
lar ratio of 6c and Ti(O-i-Pr)4, consisted of two titanium complexes,
of which only one, L⁄Ti(O-i-Pr)2, is catalytically active.
In the 1H NMR spectrum of a 1:1 mixture of 6c and Ti(O-i-Pr)4,
three signals appeared, which were assigned to aldimine protons at
8.50, 8.50, and 8.47 ppm in a 1:1:2 ratio. These signals come from
the catalytically inactive forms of L⁄2Ti and active complex L⁄Ti(O-i-
Pr)2. The absence of a signal at 8.41 ppm indicates that all of 6c has
been consumed during the reaction (see Fig. 2).

E. Błocka et al. / Tetrahedron: Asymmetry 25 (2014) 554–562
557
A
Ligand
168 166 164 162 160 158 156 154
ppm
B
L*(O-i-Pr)2 + L2*Ti
168
166
164
162
160 158
156 154
ppm
C
L2*Ti
165
160
155
[ppm]
150
100
Figure 1. 13C NMR spectra of 6c and complex Ti(O-i-Pr)4/6c.
50
[ppm]
intramolecular interactions with O1 and N1, the C8. . .O1 and
C8. . .N1 distances of 3.014(3) and 3.080(3) Å, respectively, which
are almost identical to those reported for 6c.
The Schiff base moiety is planar, with the torsion angle C3–N1–
C11–C12 of ꢀ178.54(17) deg. The intramolecular H-bond, with the
O2–H. . .N1 results in the co-planar arrangement of the Schiff base
and phenolic ring, with the torsion angles N1–C11–C12–C13 of
3.7(3) deg and C11–C12–C13–O2 of 1.7(3) deg.
(Fig. 5), with the assumed population 50/50%. The alternative intra-
molecular H-bonds are formed with the O2. . .N1 distance of
2.574(2) Å. In the monoclinic polymorph of the reported Schiff
base12 (CCDC-823886), the proton is bonded to the imine nitrogen.
The valence geometry of the camphor and phenolic moieties in
the reported structure is typical for such systems. The C2–O1 dis-
tance of 1.415(2) Å and the phenolic C13–O2 is 1.344(2) Å. In the
imine moiety, the distances of C3–N1 and N1–C11 are 1.453(2)
and 1.274(2) Å, respectively. These values are between those found
for 6c with a proton located between O2 and N1, and 6b where the
O2–H hydroxyl is found, clearly indicating the contribution of
imine protonation to the imine bond order. The C3–N1–C11 angle
of 120.92(16) deg, is similar to the other structures reported here-
in. However in the monoclinic polymorph,12 this angle is
123.76(19) deg, and the C17–O2 distance is 1.299(3) Å, which fur-
3.3. Crystal structure of 6a
The absolute configuration of 6a was assigned to be consistent
with the substrate used and corresponds to (1R,2S,3R,4S).
The electron density maps for 6a revealed two alternative posi-
tions for the H atom bonded to the phenolic O2 and the imine N1

558
E. Błocka et al. / Tetrahedron: Asymmetry 25 (2014) 554–562
1H NMR
Ligand
Figure 4. Asymmetric unit of the crystal structure of 6b with the atom labeling
scheme. Atomic ellipsoids are plotted at 30% probability level (CCDC 987577).
L*(O-i-Pr)2 + L2*Ti
L2*Ti
Figure 5. Asymmetric unit of the crystal structure of 6a with the atom labeling
scheme. Atomic ellipsoids are plotted at 30% probability level (CCDC 987578).
8.55
8.50
8.45
8.40
8.35
8.30
8.25 [ppm]
Figure 2. 1H NMR spectra of 6c and Ti(O-i-Pr)4/6c.
112.6(2) deg. The intramolecular distances N1. . .O1 and N1. . .O2
are 2.675(2) and 2.574(2) Å, respectively; these values are similar
to those found for 6b. The C8 methyl group participates in intramo-
lecular interactions with O1 and N1, the C8. . .O1 and C8. . .N1 dis-
tances of 2.985(2) and 3.125(2) Å, respectively, which are almost
identical to those found for other compounds reported herein.
The Schiff base moiety of 6a is planar, with a torsion angle
C3–N1–C11–C12 of ꢀ178.08(16) deg. As for the other structures
reported herein, the co-planar arrangement of the Schiff base and
phenolic ring was found, with the torsion angles N1–C11–
C12–C13 of 2.2(3) deg and C11–C12–C13–O2 of ꢀ1.1(3) deg. The
Figure 3. Asymmetric unit of the crystal structure of 6c with the atom labeling
scheme. Atomic ellipsoids are plotted at the 30% probability level (CCDC 987576).
ther emphasizes the differences related to the different proton-
ation scheme.
The O1–H camphor hydroxyl is involved in an intermolecular
H-bond O1–H1O1. . .O2[ꢀx,1ꢀy,z] to the phenolic O2–H group,
with the O1. . .O2 distance being 3.239(2) Å. The position of the
imine moiety relative to the camphor ring system is almost identi-
cal to that found for 6b with a C2–C3–N1–C11 torsion angle of
122.97(18) deg, different from that found for 6c (Fig. 6). The corre-
sponding angle reported for the monoclinic polymorph12 is
Figure 6. The superposition of 6c (blue), 6b (green) and 6a (red) Schiff bases
illustrates the differences in the molecular conformation. The least-squares fit was
performed for the camphor ring non-hydrogen atoms.

E. Błocka et al. / Tetrahedron: Asymmetry 25 (2014) 554–562
559
conformation of the (1R)-camphor analogue12 is similar, with the
5.3. General procedure for Schiff base synthesis
5.3.1. Method A
corresponding torsion angles being ꢀ0.8(3); 2.1(3) deg and
ꢀ0.7(3); 4.9(3) for the molecules in the asymmetric unit.
Analysis of the crystal packing reveals C2–H2A. . .
p
[ꢀx,1ꢀy,z]
An appropriate aldehyde (1 equiv) was added under a nitrogen
atmosphere to a solution of (1R,2S,3R,4S)-3-amino-1,7,7-trim-
ethylbicyclo[2.2.1]heptan-2-ol (1 equiv) in dry toluene, followed
by catalytic amounts of p-toluenesulfonic acid and anhydrous
magnesium sulfate. The mixture was stirred for 24 h at reflux. After
cooling to room temperature, the mixture was filtered onto a celite
pad of 1 cm thickness in a fritted glass funnel. The solvent was re-
moved on a rotary evaporator. The crude product was purified by
crystallization.
and C5–H5A. . .
p
[ꢀ1/2ꢀx,1/2+y,ꢀ1ꢀz] interactions involving the
phenolic C12–C17 ring, with distances between the respective H
atom and the ring gravity center being 2.88 and 2.99 Å, and
C–H. . .p angles of 164 and 142 deg.
4. Conclusion
In conclusion, a new class of camphor derived Schiff base
ligands 6a–c has been prepared and used for the titanium(IV)
catalyzed asymmetric cyanosilylations of aldehydes. Two types
of titanium complexes have been formed from the mixture
Ti(O-i-Pr)4/6c; the catalytically active 6c⁄Ti(O-i-Pr)2 and inactive
6c⁄2Ti, with their ratio depending on the starting mixture.
The best enantioselectivity (>99) was achieved for the
addition of trimethylsilylcyanide to cinnamaldehyde catalyzed by
6c⁄Ti(O-i-Pr)2, which was generated from the equimolar mixture
Ti(O-i-Pr)4/6c (1% mol). The selectivity decreased with other molar
ratios of the mixture. Consequently, the catalyst activity depends
on the ligand structure, the ratio of Ti(O-i-Pr)4/ligand, and the reac-
tion conditions.
5.3.2. Method B
An appropriate aldehyde (1 equiv) was added under a nitrogen
atmosphere to a solution of (1R,2S,3R,4S)-3-amino-1,7,7-trim-
ethylbicyclo[2.2.1]heptan-2-ol (1 equiv) in methanol, followed by
catalytic amounts of triethylamine and anhydrous magnesium sul-
fate. The mixture was stirred at room temperature for 72 h. The
mixture was filtered onto a Celite pad of 1 cm thickness in a fritted
glass funnel. The solvent was removed on a rotary evaporator. The
crude product was purified by crystallization.
5.3.3. Method C
An appropriate aldehyde (1 equiv) was added under a nitrogen
atmosphere to a solution of (1R,2S,3R,4S)-3-amino-1,7,7-trim-
ethylbicyclo[2.2.1]heptan-2-ol (1 equiv) in methanol, followed by
catalytic amounts of triethylamine and anhydrous magnesium sul-
fate. The mixture was stirred at room temperature for 96 h. The
mixture was filtered onto a Celite pad of 1 cm thickness in a fritted
glass funnel. The solvent was removed on a rotary evaporator. The
crude product was purified by crystallization.
5. Experimental
5.1. General
Infrared (IR) spectra were recorded on a JASCO FT/IR 410 Fourier
transform infrared spectrophotometer and were measured as a
HCB mull. 1H and 13C NMR spectra were recorded on a Bruker Ad-
vance III 400 MHz or Bruker Advance III 700 MHz instrument at
ambient temperature. Chemical shifts in CDCl3 are reported in
the scale relative to CHCl3 (7.26 ppm) for 1H NMR and 77.0 ppm
for 13C NMR. GC was performed on a Perkin–Elmer AutoSystem
XL chromatograph using B-Dex 125 capillary column (30 m,
0.25 mm). The enantiomeric excess was determined by HPLC anal-
ysis. HPLC analysis was performed on Shimadzu LC-10AT chro-
5.3.4. (1R,2S,3R,4S)-3-((E)-(2-Hydroxybenzylidene)amino)-1,7,7-
trimethylbicyclo[2.2.1]heptan-2-ol 6a12
Schiff base 6a was prepared from 2-hydroxybenzaldehyde
(0.5 g; 2.95 mmol) according to method A. The crude product
was purified by crystallization from toluene, 0.65 g; 80%. Mp.
134–137 °C, ½a 2D0
ꢂ
¼ þ104:6 (c 0.182, CHCl3). 1H NMR (400 MHz,
CDCl3): d = 0.89 (s, 3H, CH3), 1.03 (s, 3H, CH3), 1.10–1.18 (m, 2H,
CH2), 1.29 (s, 3H, CH3), 1.57–1.63 (m, 1H, CH), 1.81–1.85 (m, 2H,
CH2), 2.05 (br s, 1H, OH), 3.59 (d, J = 7.6 Hz, 1H, CH), 3.85 (d,
J = 7.2 Hz, 1H, CH), 6.86–6.98 (m, 2H, 2ꢁ CHAr), 7.26–7.35 (m, 2H,
2ꢁ CHAr), 8.37 (s, 1H, (N)CH), 13.30 (br s, 1H, OH). 13C NMR
(700 MHz, CDCl3): d = 12.33 (CH3), 22.53 (CH3), 22.64 (CH3),
27.48 (CH2), 34.56 (CH2), 48.24 (C), 50.30 (C), 54.28 (CH), 77.61
(CH), 82.78 (CH), 118.25 (CH), 119.52 (CH), 119.80 (C), 132.60
(CH), 133.67 (CH), 162.55 (C), 166.90 (CH). IR (HCB film) 3591.03,
2954.56, 2873.94, 1687.09, 1636.12, 1611.01, 1563.28, 1384.61
1170.06, 981.94, 941.76, 852.72, 824.35, 791.84, 655.75,
536.89 cmꢀ1, Anal. Calcd. for C17H23NO2: C, 74.69; H, 8.48; N,
5.12. Found: C, 74.77; H, 8.46; N: 5.14.
matograph using
a
Chiralcel OD-H column (250 ꢁ 4.6 mm).
Optical rotations were measured using a PolAAr 3000 automatic
polarimeter in a 10 cm cell at 589 nm. Melting points were deter-
mined with a Büchi SMP 32 and Barnstead-Thermolyne Mel-Temp
II apparatus in open capillaries and are uncorrected. Elemental
analyses were performed with an Elementary Analysensysteme
GmbH VarioMACRO CHNanalyzer.
5.2. Materials
Experiments with air and moisture sensitive materials were
carried out under a nitrogen atmosphere. Glassware was oven
dried for several hours, assembled hot, and cooled in a stream
of nitrogen. Silica gel 60, Merck (0.06–0.2 mm) was used for pre-
parative column chromatography. Analytical TLC was performed
using Macherey-Nagel Polygram Sil G/UV254 0.2 mm plates. Re-
agents were commercially available from Sigma–Aldrich and
were used without further purification. Solvents were purchased
from POCh Gliwice, Poland and Sigma–Aldrich. Toluene and THF
were distilled from sodium benzophenone ketyl, dichloromethane
was distilled from P2O5, diethyl ether was distilled from lithium
aluminum hydride prior to use. 2-Hydroxy-3-methylbenzalde-
hyde, 3,5-di-tert-butyl-2-hydroxy benzaldehyde, 2-hydroxy-3-iso-
propylbenzaldehyde, 4-(diethylamino)-2-hydroxy benzaldehyde,
and 2-hydroxy-3-isopropylbenzaldehyde were obtained according
to the literature procedures.9–11
5.3.5. (1R,2S,3R,4S)-3-((E)-(2-Hydroxy-3-methylbenzylidene)
amino)-1,7,7-trimethylbicyclo [2.2.1]heptan-2-ol 6b12
Compound 6b was prepared from 2-hydroxy-3-methylbenzal-
dehyde (0.40 g; 2.95 mmol) according to method B. The crude
product was purified by crystallization from methanol, 0.72 g;
86%. Mp. 138–141 °C, ½a D20
ꢂ
¼ þ95:4 (c 0.268, MeOH). 1H NMR
(400 MHz, CDCl3): d = 0.90 (s, 3H, CH3), 1.04 (s, 3H, CH3), 1.10–
1.22 (m, 2H, CH2), 1.32 (s, 3H, CH3), 1.57–1.65 (m, 1H, CH), 1.80–
1.90 (m, 3H, CH2, OH), 2.30 (s, 3H, CH3), 3.60 (d, J = 7.6 Hz, 1H,
CH), 3.84 (dd, J = 7.6 Hz, J = 2.4 Hz, 1H, CH), 6.81 (t, J = 7.6 Hz, 1H,
CHAr), 7.13 (dd, J = 7.6 Hz, J = 1.6 Hz, 1H, CHAr), 7.21 (dd,
J = 7.6 Hz, J = 0.8 Hz, 1H, CHAr), 8.38 (s, 1H, (N)CH), 13.33 (br s,
1H, OH). 13C NMR (700 MHz, CDCl3): d = 12.35 (CH3), 16.56 (CH3),

560
E. Błocka et al. / Tetrahedron: Asymmetry 25 (2014) 554–562
22.67 (2ꢁ CH3), 27.52 (CH2), 34.56 (CH2), 48.22 (C), 50.30 (C), 54.30
(CH), 77.77 (CH), 82.80 (CH), 119.09 (C), 119.12 (CH), 127.15 (C),
130.29 (CH), 134.55 (CH), 160.64 (C), 167.21 (CH). IR (HCB film)
3518.20, 3187.67 2950.47, 2879.55, 2520.16, 1604.16, 1611.20,
1564.94, 1457.34, 1170.09, 1051.74, 955.73, 941.92, 853.43,
790.41, 746.85, 656.33, 525.99 cmꢀ1, Anal. Calcd. for C18H25NO2:
C, 75.22; H, 8.77; N, 4.87. Found: C, 75.31; H, 8.80; N: 4.88.
13C NMR (400 MHz, CDCl3): d = 11.41 (CH3), 12.79 (2ꢁ CH3),
21.39 (CH3), 21.67 (CH3), 26.52 (CH2), 33.54 (CH), 44.55 (2ꢁ
CH2), 47.14 (C), 59.14 (C), 53.10 (CH), 73.54 (CH), 80.83 (CH),
98.84 (CH), 103.44 (CH), 108.44 (C), 133.63 (CH), 152.43 (C),
162.95 (CH), 168.84 (C), IR (HCB film) 3294.11, 2924.36, 2857.14,
2717.08, 2358.54, 2252.10, 1686.71, 1608.39, 1559.59, 1496.50,
1345.45, 1166.43, 1132.86, 980.34, 937.06, 851.96, 792.47,
654.51, 542.65 cmꢀ1, Anal. Calcd. for C21H32N2O2: C, 73.22; H,
9.36; N, 8.13. Found: C, 73.18; H, 9.35; N: 8.14.
5.3.6. (1R,2S,3R,4S)-3-((E)-(2-Hydroxy-3-isopropylbenzylidene)
amino)-1,7,7-trimethylbicyclo [2.2.1]heptan-2-ol 6c
Compound 6c was prepared from 2-hydroxy-3-isopropylbenz-
aldehyde (0.48 g; 2.95 mmol) according to method B. The crude
product was purified by crystallization from methanol, 0.83 g;
5.4. Typical procedure for the asymmetric trimethylsilylcyana-
tion of aldehydes
90%. Mp. 100–103 °C, ½a D20
ꢂ
¼ þ87:4 (c 0.270, MeOH). 1H NMR
At first, Ti(O-i-Pr)4 (0.05 m; 0.18 mmol) was added to a solution
of Schiff base (0.20 mmol) in dry dichloromethane (2.5 ml) and
stirred at room temperature for 1 h under a nitrogen atmosphere.
The mixture was then cooled to an adequate temperature and
TMSCN (0.29 ml; 2.3 mmol) was added followed by the aldehyde
(1.0 mmol). The mixture was stirred at the same temperature for
48 h and poured into a mixture of 1 M HCl (30 ml) and ethyl acetate
(150 ml) and stirred vigorously for 12 h at rt. The layers were sep-
arated, and the aqueous layer was extracted with ethyl acetate
(3 ꢁ 30 ml). The combined extracts were washed with saturated
NaHCO3 (4 ꢁ 50 ml) and brine (2 ꢁ 50 ml), dried over anhydrous
sodium sulfate, and then evaporated. The residue was purified by
column chromatography on silica gel (eluent: hexane/ethyl acetate
5:1 (v/v)). The pure cyanohydrin (1 equiv) was then converted di-
rectly into the corresponding acetate by reaction with acetyl chlo-
ride (0.09 ml), and pyridine (0.004 ml) in dry CH2Cl2 (4 ml) at
room temperature under a nitrogen atmosphere for 1 hour. The
reaction was quenched by water (5 ml) and extracted with CH2Cl2
(3 ꢁ 10 ml). The organic extracts were washed with brine (10 ml)
and dried over anhydrous sodium sulfate. Evaporation of the sol-
vents gave the corresponding acetate. The enantiomeric excess of
the cyanohydrin acetate was determined by an HPLC or GC method.
(400 MHz, CDCl3): d = 0.90 (s, 3H, CH3), 1.04 (s, 3H, CH3), 1.11–
1.22 (m, 2H, CH2), 1.26 (dd, J = 7.0 Hz, J = 2.8 Hz, 2H, CH2), 1.31 (s,
6H, 2ꢁ CH3), 1.37 (S, 3H, CH3), 1.56–1.86 (m, 5H, 2ꢁ CH2, OH),
3.43 (sep, J = 14.0 Hz, 1H, CH), 3.61 (d, J = 7.2 Hz, 1H, CH), 3.84 (d,
J = 4.0 Hz, 1H, CH), 6.88 (t, J = 7.6 Hz, 1H, CHAr), 7.13 (dd,
J = 7.6 Hz, J = 1.4 Hz, 1H, CHAr), 7.29 (dd, J = 7.6 Hz, J = 1.6 Hz, 1H,
CHAr), 8.41 (s, 1H, (N)CH), 13.29 (br s, 1H, OH). 13C NMR
(400 MHz, CDCl3): d = 11.34 (CH3), 21.68 (2ꢁ CH3), 22.50 (CH3),
22.56 (CH3), 26.17 (CH), 26.54 (CH2), 33.57 (CH2), 47.22 (C),
49.31 (C), 53.31 (CH), 76.88 (CH), 81.80 (CH), 118.29 (C), 118.37
(CH), 129.17 (CH), 129.21 (CH), 136.50 (C), 158.57 (C), 166.52
(CH). IR (HCB film) 3378.15, 2956.27, 2879.55, 1686.90, 1628.93,
1610.96, 1560.19, 1439.36, 1384.61, 1403.62, 1261.53, 1170.27,
1095.91, 1046.15, 980.76, 941.63, 853.02, 824.35, 793.01, 749.65,
655.37, 495.10 cmꢀ1, Anal. Calcd. for C20H29NO2: C, 76.15; H,
9.27; N, 4.44. Found: C, 76.34; H, 9.26; N: 4.34.
5.3.7. (1R,2S,3R,4S)-3-((E)-(3,5-Di-tert-butyl-2-hydroxybenzylid-
ene) amino)-1,7,7-trimethylbicyc-lo[2.2.1]heptan-2-ol 6d12
Compound 6d was prepared from 3,5-di-tert-butyl-2-hydroxy-
benzaldehyde (0.69 g; 2.95 mmol) according to method B. The
crude product was purified by crystallization from methanol,
1.04 g; 95%. Mp. 82–85 °C, ½a D20
ꢂ
¼ þ68=2 (c 0.290, MeOH). 1H
5.5. Retention times for the cyanohydrins
NMR (700 MHz, CDCl3): d = 0.91 (s, 3H, CH3), 1.06 (s, 3H, CH3),
1.13–1.21 (m, 2H, CH2), 1.31 (s, 3H, CH3), 1.34 (s, 9H, 3ꢁ CH3),
1.47 (s, 9H, 3ꢁ CH3), 1.59–1.63 (m, 1H, CH), 1.81–1.87 (m, 2H,
CH2), 1.96 (d, J = 5.6 Hz, 1H, OH), 3.62 (d, J = 7.7 Hz, 1H, CH), 3.84
(dd, J = 7.7 Hz, J = 4.9 Hz, 1H, CH), 7.14 (d, J = 2.8 Hz, 1H, CHAr),
7.43 (d, J = 2.8 Hz, 1H, CHAr), 8.45 (s, 1H, (N)CH), 13.18 (br s, 1H,
OH). 13C NMR (400 MHz, CDCl3): d = 11.36 (CH3), 21.66 (CH3),
21.71 (CH3), 26.57 (CH2), 29.41 (3ꢁ CH3), 31.49 (3ꢁ CH3), 33.58
(CH2), 34.14 (C), 35.08 (C), 47.18 (C), 49.31 (C), 53.35 (CH), 77.05
(CH), 81.71 (CH), 118.05 (C), 126.23 (CH), 127.27 (CH), 136.79
(C), 140.21 (C), 157.90 (C), 167.44 (CH), IR (HCB film) 3398.70,
2954.63, 2860.61, 1678.48, 1640.55, 1608.39, 1559.29, 1450.63,
1439.99, 1389.16, 1272.72, 1252.02, 1171.61, 1092.92, 1057.34,
976.50, 941.27, 854.75, 792.18, 656.65, 520.37 cmꢀ1, Anal. Calcd.
for C25H39NO2: C, 77.87; H, 10.19; N, 3.63. Found: C, 77.84; H,
10.16; N: 3.69.
5.5.1. 2-Hydroxy-2-phenylacetonitrile
HPLC conditions: Chiralcel OD-H (250 ꢁ 4.6 mm,
5 lm),
T = 25 °C, eluent: hexane/i-PrOH (99:1), flow rate: 0.7 ml/min,
detection: UV–vis, k = 254 nm, tR = 27.6 min (R), tR = 35.8 min (S).
½
a 2D0
ꢂ
¼ ꢀ8:6 (c 0.500, CHCl3) for the (S)-enantiomer in 81% ee,
{lit.13
½
a 2D4
ꢂ
¼ þ36:8 (c 2.0, CHCl3) for the (R)-enantiomer in 85%
ee}. 1H NMR (400 MHz, CDCl3): d = 3.31 (br s, 1H, OH), 5.53 (s,
1H, CH(CN)), 7.31–7.43 (m, 5H, 5ꢁ CHAr).
5.5.2. 2-Hydroxy-2-(2-methoxyphenyl)acetonitrile
HPLC conditions: Chiralcel OD-H (250 ꢁ 4.6 mm,
5 lm),
T = 25 °C, eluent: hexane/i-PrOH (99:1), flow rate: 0.7 ml/min,
detection: UV–vis, k = 220 nm, tR = 19.3 min (R), tR = 21.3 min (S).
1H NMR (400 MHz, CDCl3): d = 3.68 (br s, 1H, OH), 3.86 (s, 3H,
CH3), 5.51 (s, 1H, CH(CN)), 6.90–7.23 (m, 4H, 4ꢁ CHAr).
5.3.8. (1R,2S,3R,4S)-3-((E)-(3-Diethylamino-2-hydroxybenzylid-
ene)amino)-1,7,7-trimethylbicyclo [2.2.1]heptan-2-ol 6e
Compound 6e was prepared from 2-hydroxy-3-N,N-diisopro-
pylbenzaldehyde (0.57 g; 2.95 mmol) according to method B. The
crude product was purified by crystallization from methanol,
5.5.3. 2-Hydroxy-2-(3-methoxyphenyl)acetonitrile
HPLC conditions: Chiralcel OD-J (250 ꢁ 4.6 mm, 5
lm), eluent:
hexane/i-PrOH (90:10), flow rate: 1 ml/min, detection: UV–vis,
k = 220 nm, tR = 24.5 min (R), tR = 25.8 min (S), ½a D20
ꢂ
¼ ꢀ10:2 (c
0.69, CHCl3) for the (S)-enantiomer in 97% ee, {lit.13
½ ꢂ
a 2D5
¼ ꢀ37:2
0.60 g; 57%. Mp. 204–207 °C, ½a D20
ꢂ
¼ þ57:4 (c 0.270, MeOH). 1H
(c 2.36, CHCl3) for the (S)-enantiomer in 90% ee}. 1H NMR
(400 MHz, CDCl3): d = 3.68 (br s, 1H, OH), 3.83 (s, 3H, CH3), 5.52
(s, 1H, CH(CN)), 6.90–7.30 (m, 4H, 4ꢁ CHAr).
NMR (700 MHz, CDCl3): d = 0.80 (s, 3H, CH3), 1.04 (s, 3H, CH3),
1.07–1.12 (m, 2H, CH2), 1.21 (t, J = 7.0 Hz, 6H, 2ꢁ CH3), 1.53–1.57
(m, 1H, CH), 1.76–1.79 (m, 2H, CH2), 2.15 (br s, 1H, OH), 3.36–
3.44 (m, 5H, CH, 2ꢁ CH2), 3.88 (d, J = 7.0 Hz, 1H, CH), 6.03 (d,
J = 2.1 Hz, 1H, CHAr), 6.12 (dd, J = 9.1 Hz, J = 2.8 Hz, 1H, CHAr), 6.90
(d, J = 2.1 Hz, 1H, CHAr), 7.66 (s, 1H, (N)CH), 13.40 (br s, 1H, OH).
5.5.4. 2-Hydroxy-2-(4-methoxyphenyl)acetonitrile
HPLC conditions: Chiralcel OD-J (250 ꢁ 4.6 mm, 5
lm), eluent:
hexane/i-PrOH (90:10), flow rate: 1 ml/min, detection: UV–vis,

E. Błocka et al. / Tetrahedron: Asymmetry 25 (2014) 554–562
561
k = 220 nm, tR = 31.34 min (R), tR = 37.11 min (S), ½a D20
ꢂ
¼ þ23:9 (c
¼ ꢀ44:8
5.5.12. 2-(3-Chlorophenyl)-2-hydroxyacetonitrile
0.54, CHCl3) for the (R)-enantiomer in 98% ee, {lit.13
½
a 2D5
ꢂ
HPLC conditions: Chiralcel OD-H (250 ꢁ 4.6 mm,
5
l
m),
(c 1.30, CHCl3) for the (S)-enantiomer in 93% ee}. 1H NMR
(400 MHz, CDCl3): d = 3.69 (br s, 1H, OH), 3.82 (s, 3H, CH3), 5.51
(s, 1H, CH(CN)), 6.91 (d, J = 7.6 Hz, 2H, 2ꢁ CHAr), 7.26 (d,
J = 7.6 Hz, 2H, 2ꢁ CHAr).
T = 25 °C, eluent: hexane/i-PrOH (95:5), flow rate: 1 ml/min, detec-
tion: UV–vis, k = 254 nm, tR = 34.9 min (R), tR = 38.6 min (S),
½
a 2D0
ꢂ
¼ þ15:5 (c 0.51, CHCl3) for the (R)-enantiomer in 65% ee,
{lit.13
½
a 2D5
ꢂ
¼ ꢀ41:3 (c 1.90, CHCl3) for the (S)-enantiomer in 90%
ee}. 1H NMR (400 MHz, CDCl3): d = 3.68 (br s, 1H, OH), 5.56 (s,
1H, CH(CN)), 7.21–7.50 (m, 4H, 4ꢁ CHAr).
5.5.5. 2-Hydroxy-2-(2-methylphenyl)acetonitrile
HPLC conditions: Chiralcel OD-J (250 ꢁ 4.6 mm, 5
lm), eluent:
hexane/i-PrOH (90:10), flow rate: 1 ml/min, detection: UV–vis,
5.5.13. 2-(4-Chlorophenyl)-2-hydroxyacetonitrile
k = 254 nm, tR = 9.8 min (R), tR = 11.4 min (S), ½a D20
ꢂ
¼ ꢀ28:9 (c
HPLC conditions: Chiralcel OD-J (250 ꢁ 4.6 mm,
5 lm),
0.46, CHCl3) for the (S)-enantiomer in 87% ee {lit.14
½
a 2D5
ꢂ
¼ ꢀ33:1
T = 25 °C, eluent: hexane/i-PrOH (95:5), flow rate: 1 ml/min, detec-
(c 1.10, CHCl3) for the (S)-enantiomer in 80% ee}. 1H NMR
(700 MHz, CDCl3): d = 2.50 (s, 3H, CH3), 3.68 (br s, 1H, OH), 5.52
(s, 1H, CH(CN)), 7.22–7.41 (m, 4H, 4ꢁ CHAr).
tion: UV–vis, k = 254 nm, tR = 24.3 min (R), tR = 31.4 min (S),
½
a 2D0
ꢂ
¼ þ14:8 (c 0.79, CHCl3) for the (R)-enantiomer in 62% ee,
{lit.13
½
a 2D5
ꢂ
¼ ꢀ34:5 (c 1.70, CHCl3) for the (S)-enantiomer in 87%
ee}. 1H NMR (400 MHz, CDCl3): d = 3.56 (br s, 1H, OH), 5.58 (s,
1H, CH(CN)), 7.28–7.40 (m, 4H, 4ꢁ CHAr).
5.5.6. 2-Hydroxy-2-(3-methylphenyl)acetonitrile
HPLC conditions: Chiralcel OD-J (250 ꢁ 4.6 mm, 5
lm), eluent:
hexane/i-PrOH (95:5), flow rate: 1 ml/min, detection: UV–vis,
5.5.14. 2-Hydroxy-2-(3-nitrophenyl)acetonitrile
k = 220 nm, tR = 33.7 min (S), tR = 37.8 min (R), ½a D20
ꢂ
¼ þ8:9 (c
HPLC conditions: Chiralcel OD-J (250 ꢁ 4.6 mm,
5 lm),
0.54, CHCl3) for the (R)-enantiomer in 49% ee, {lit.13
½
a 2D5
ꢂ
¼ ꢀ36:1
T = 25 °C, eluent: hexane/i-PrOH (70:30), flow rate: 1 ml/min,
(c 2.00, CHCl3) for the (S)-enantiomer in 88% ee}. 1H NMR
(700 MHz, CDCl3): d = 2.46 (s, 3H, CH3), 5.51 (s, 1H, CH(CN)),
7.17–7.52 (m, 4H, 4ꢁ CHAr), 7.61 (br s, 1H, OH).
detection: UV–vis, k = 254 nm, tR = 35.1 min (S), tR = 43.7 min (R),
½
a 2D0
ꢂ
¼ ꢀ15:2 (c 0.95, CHCl3), the (S)-enantiomer in 61% ee. 1H
NMR (400 MHz, CDCl3): d = 3.85 (br s, 1H, OH), 5.75 (s, 1H,
CH(CN)), 7.80–8.70 (m, 4H, 4ꢁ CHAr).
5.5.7. 2-Hydroxy-2-(4-methylphenyl)acetonitrile
HPLC conditions: Chiralcel OD-J (250 ꢁ 4.6 mm,
5
l
m),
5.5.15. 2-(2-Fluorophenyl)-2-hydroxyacetonitrile
T = 25 °C, eluent: hexane/i-PrOH (90:10), flow rate: 1 ml/min,
detection: UV–vis, k = 254 nm, tR = 15.0 min (R), tR = 18.1 min (S),
HPLC conditions: Chiralcel OD-J (250 ꢁ 4.6 mm,
5 lm),
T = 25 °C, eluent: hexane/i-PrOH (98:2), flow rate: 1 ml/min, detec-
tion: UV–vis, k = 254 nm, tR = 20.7 min (R), tR = 22.5 min (S). 1H
NMR (700 MHz, CDCl3): d = 3.80 (br s, 1H, OH), 5.82 (s, 1H,
CH(CN)), 7.15–7.67 (m, 4H, 4ꢁ CHAr).
½
a 2D0
ꢂ
¼ þ11:5 (c 0.60, CHCl3) for the (R)-enantiomer in 80% ee,
{lit.13
½
a 2D5
ꢂ
¼ ꢀ42:1 (c 2.04, CHCl3) for the (S)-enantiomer in 93%
ee}. 1H NMR (700 MHz, CDCl3): d = 2.49 (s, 3H, CH3), 5.56 (s, 1H,
CH(CN)), 7.18–7.29 (m, 4H, 4ꢁ CHAr), 11.87 (br s, 1H, OH).
5.5.16. 2-(3-Fluorophenyl)-2-hydroxyacetonitrile
5.5.8. 2-(2-Bromophenyl)-2-hydroxyacetonitrile
HPLC conditions: Chiralcel OD-J (250 ꢁ 4.6 mm,
5 lm),
HPLC conditions: Chiralcel OD-H (250 ꢁ 4.6 mm,
5 lm),
T = 25 °C, eluent: hexane/i-PrOH (95:5), flow rate: 1 ml/min, detec-
tion: UV–vis, k = 220 nm, tR = 28.2 min (R), tR = 31.0 min (S). 1H
NMR (400 MHz, CDCl3): d = 3.88 (br s, 1H, OH), 5.56 (s, 1H,
CH(CN)), 7.11–7.46 (m, 4H, 4ꢁ CHAr).
T = 25 °C, eluent: hexane/i-PrOH (90:10), flow rate: 0.7 ml/min,
detection: UV–vis, k = 215 nm, tR = 9.9 min (S), tR = 11.8 min (R),
½
a 2D0
ꢂ
¼ ꢀ1:2 (c 0.98, CHCl3) for the (S)-enantiomer in 34% ee. 1H
NMR (700 MHz, CDCl3): d = 5.56 (s, 1H, CH(CN)), 6.96 (br s, 1H,
OH), 7.21–7.59 (m, 4H, 4ꢁ CHAr).
5.5.17. 2-(4-Fluorophenyl)-2-hydroxyacetonitrile
HPLC conditions: Chiralcel OD-H, eluent: hexane/i-PrOH (99:1),
flow rate: 0.4 ml/min, detection: UV–vis, k = 220 nm, tR = 41.3 min
5.5.9. 2-(3-Bromophenyl)-2-hydroxyacetonitrile
HPLC conditions: Chiralcel OD-H (250 ꢁ 4.6 mm,
5 lm),
(R), tR = 43.4 min (S), ½a D20
¼ ꢀ16:2 (c 0.79, CHCl3) for the (S)-enan-
ꢂ
T = 25 °C, eluent: hexane/i-PrOH (97:3), flow rate: 0.7 ml/min,
detection: UV–vis, k = 220 nm, tR = 18.2 min (S), tR = 20.9 min (R).
1H NMR (700 MHz, CDCl3): d = 5.54 (s, 1H, CH(CN)), 7.31–7.56
(m, 4H, 4ꢁ CHAr), 7.81 (br s, 1H, OH).
tiomer in 74% ee, {lit.13
½
a 2D5
ꢂ
¼ ꢀ33:6 (c 1.62, CHCl3) for the (S)-
enantiomer in 92% ee}. 1H NMR (400 MHz, CDCl3): d = 4.00 (br s,
1H, OH), 5.53 (s, 1H, CH(CN)), 7.10–7.15 (m, 2H, 2ꢁ CHAr), 7.48–
7.52 (m, 2H, 2ꢁ CHAr).
5.5.10. 2-(4-Bromophenyl)-2-hydroxyacetonitrile
5.5.18. 2-Hydroxy-2-(naphthalene-1-yl)acetonitrile
HPLC conditions: Chiralcel OD-H (250 ꢁ 4.6 mm,
5 lm),
HPLC conditions: Chiralcel OD-J (250 ꢁ 4.6 mm,
5 lm),
T = 25 °C, eluent: hexane/i-PrOH (90:10), flow rate: 0.7 ml/min,
T = 25 °C, eluent: hexane/i-PrOH (95:5), flow rate: 0.4 ml/min,
detection: UV–vis, k = 220 nm, tR = 13.3 min (S), tR = 15.7 min (R),
a 2D0
ꢂ
¼ þ1:7 (c 0.92, CHCl3) for the (R)-enantiomer in 28% ee. 1H
detection: UV–vis, k = 220 nm tR = 70.6 min (S), tR = 77.6 min (R),
½
½
a 2D0
ꢂ
¼ ꢀ60:1 (c 0.89, CHCl3) for the (S)-enantiomer in 83% ee,
NMR (700 MHz, CDCl3): d = 3.69 (br s, 1H, OH), 5.56 (s, 1H,
{lit.13
½
a 2D5
ꢂ
¼ ꢀ67:4 (c 1.00, CHCl3) for the (S)-enantiomer in 82%
CH(CN)), 7.26–7.59 (m, 4H, 4ꢁ CHAr).
ee}. 1H NMR (400 MHz, CDCl3): d = 3.31 (br s, 1H, OH), 6.20 (s,
1H, CH(CN)), 7.51–7.61 (m, 3H, 3ꢁ CHAr), 7.85 (d, J = 7.2 Hz, 1H,
CHAr), 7.93–7.97 (m, 2H, CHAr), 8.17 (d, J = 8.8 Hz, 1H, CHAr).
5.5.11. 2-(2-Chlorophenyl)-2-hydroxyacetonitrile
HPLC conditions: Chiralcel OD-J (250 ꢁ 4.6 mm,
5 lm),
T = 25 °C, eluent: hexane/i-PrOH (95:5), flow rate: 1 ml/min,
5.5.19. 2-Hydroxy-2-(naphthalene-2-yl)acetonitrile
detection: UV–vis, k = 254 nm, tR = 22.4 min (R), tR = 24.0 min (S),
a 2D0
ꢂ
¼ ꢀ1:0 (c 0.98, CHCl3) for the (S)-enantiomer in 59% ee,
HPLC conditions: Chiralcel OD-J (250 ꢁ 4.6 mm,
5 lm),
½
{lit.13
½
a 2D5
ꢂ
¼ ꢀ2:2 (c 2.72, CHCl3) for the (S)-enantiomer in 76%
T = 25 °C, eluent: hexane/i-PrOH (99:1), flow rate: 1 ml/min, detec-
ee}. 1H NMR (400 MHz, CDCl3): d = 3.70 (br s, 1H, OH), 5.59 (s,
1H, CH(CN)), 7.22–7.31 (m, 3H, 3ꢁ CHAr), 7.76 (d, J = 7.6 Hz, 1H,
CHAr).
tion: UV–vis, k = 220 nm, tR = 74.5 min (S), tR = 81.1 min (R),
½
a 2D0
ꢂ
¼ þ18:1 (c 0.67, CHCl3) for the (R)-enantiomer in 35% ee,
{lit.13
½ ꢂ
a 2D5
¼ ꢀ29:1 (c 1.00, CHCl3) for the (S)-enantiomer in 75%

562
E. Błocka et al. / Tetrahedron: Asymmetry 25 (2014) 554–562
ee}. 1H NMR (400 MHz, CDCl3): d = 2.86 (br s, 1H, OH), 5.56 (s, 1H,
CH(CN)), 7.02–7.57 (m, 7H, 7ꢁ CHAr).
detection: UV–vis, k = 220 nm, tR = 30.1 min (R), tR = 34.1 min (S).
¼ ꢀ3:4 (c 0.61, CHCl3) for the (S)-enantiomer in 45% ee
½ ꢂ
a 2D0
{lit.13
½
a 2D5
ꢂ
¼ þ7:9 (c 4.03, CHCl3) for the (R)-enantiomer in 85%
5.5.20. 2-(Furan-2-yl)-2-hydroxyacetonitrile
ee}. 1H NMR (400 MHz, CDCl3): d = 0.90 (t, J = 7.8 Hz, 3H, CH3),
1.22–1.33 (m, 14H, 7ꢁ CH2), 1.86 (q, J = 7.6 Hz, 2H, CH2), 3.61 (br
s, 1H, OH), 4.26 (t, J = 7.6 Hz, 1H, CH(CN)).
GC conditions: capillary column Supelco B-Dex 325 (30 m,
0.25 mm), isotherm T = 140 °C, gas flow: 35 cm/s, tR = 5.35 min
(R), tR = 5.78 min (S), ½a D20
¼ ꢀ14:7 (c 0.35, CHCl3) for the (S)-enan-
ꢂ
tiomer in 91% ee, {lit.13
½
a 2D5
ꢂ
¼ ꢀ18:7 (c 0.52, CHCl3) for the (S)-
5.6. Reaction of titanium(IV) isopropoxide with 1 or 2 equiv of
ligand 6c (for NMR measurements)
enantiomer in 89% ee}. 1H NMR (400 MHz, CDCl3): d = 3.60 (br s,
1H, OH), 5.79 (s, 1H, CH(CN)), 6.38–6.50 (m, 2H, 2ꢁ CHAr), 7.66
(d, J = 7.6 Hz, 1H, CHAr).
5.6.1. Procedure for the titanium complex of a Schiff base in a
1:1 molar ratio
5.5.21. (E)-2-Hydroxy-4-phenylbut-3-enenitrile
To the solution of orange ligand 4c (0.0715 g, 0.2 mmol) in
CDCl3 (3.5 ml) at 20 °C, 1 equiv of Ti(O-i-Pr)4 (0.0568 g, 0.06 ml,
0.2 mmol) was added. After stirring for 1 h the dark red solution
was transferred into 5 mm NMR tube and the NMR spectrum
was recorded on a 700 MHz Bruker Avance III spectrometer.
GC conditions: capillary column Supelco B-Dex 325 (30 m,
0.25 mm), isotherm T = 130 °C, gas flow: 35 cm/s, tR = 14.38 min
(R), tR = 17.97 min (S), ½a D20
¼ ꢀ21:8 (c 0.97, CHCl3) for the (S)-
ꢂ
enantiomer in 99% ee, {lit.13
½
a 2D5
ꢂ
¼ ꢀ27:3 (c 2.68, CHCl3) for the
(S)-enantiomer in 82% ee}. 1H NMR (400 MHz, CDCl3): d = 3.91
(br s, 1H, OH), 4.92 (d, J = 7.6 Hz, 1H, CH(CN)), 6.25–6.31 (m, 1H,
CH), 6.65 (d, J = 7.2 Hz, 1H, CH), 7.20–7.41 (m 5H, 5ꢁ CHAr).
5.6.2. Procedure for the titanium complex of a Schiff base in a
1:2 molar ratio
To the solution of orange ligand 4c (0.1430 g, 0.4 mmol) in
CDCl3 (3.5 ml) at 20 °C, 2 equiv of Ti(O-i-Pr)4 (0.0568 g, 0.06 ml,
0.2 mmol) was added. After stirring for 1 h the dark red solution
was transferred into 5 mm NMR tube and the NMR spectrum
was recorded on a 700 MHz Bruker Avance III spectrometer.
5.5.22. 2-Cyclopentyl-2-hydroxyacetonitrile
GC conditions: capillary column Supelco B-Dex 325 (30 m,
0.25 mm), isotherm T = 130 °C gas flow: 35 cm/s, tR = 32.1 min
(S), tR = 32.3 min (R), ½a D20
¼ þ3:1 (c 0.470, CHCl3), for the (R)-enan-
ꢂ
tiomer in 78% ee, {lit.15
½
a 2D3
ꢂ
¼ ꢀ10:4 (c 1.15, CHCl3) for the (S)-
enantiomer in 92% ee}. 1H NMR (400 MHz, CDCl3): d = 1.27–1.63
(m, 5H, 4ꢁ CH2, CH), 3.81 (br s, 1H, OH), 4.21 (d, J = 7.6 Hz, 1H,
CH(CN).
5.6.3. Spectroscopic parameters
1H NMR: spectrometer Bruker Avance III 400 MHz, f = 400 MHz,
solvent: CDCl3, programpulse: zg30, ns = 16, acquisition time: 3.99
s. 13C NMR spectrometer Bruker Avance III 400 MHz, f1 = 100 MHz
(13C), f2 = 400 MHz (1H), solvent: CDCl3, the program pulse:
zgpg30, ns = 64, acquisition time: 1.30 s.
5.5.23. 2-Cyclohexyl-2-hydroxyacetonitiyle
GC conditions: capillary column Supelco B-Dex 325 (30 m,
0.25 mm), isotherm T = 150 °C, gas flow: 35 cm/s, tR = 22.3 min
(S), tR = 22.8 min (R). ½a D20
ꢂ
¼ þ2:3 (c 0.56, CHCl3) for the (R)-enan-
References
tiomer in 88% ee, {lit.15
½
a 2D5
ꢂ
¼ þ8:2 (c 2.00, CHCl3) for the (R)-
enantiomer in 90% ee}. 1H NMR (400 MHz, CDCl3): d = 1.27–1.59
(m, 6H, 5ꢁ CH2, CH), 3.90 (br s, 1H, OH), 4.28 (d, J = 7.6 Hz, 1H,
CH(CN)).
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5.5.24. 2-Hydroxypentanonitrile
HPLC conditions: Chiralcel OD-J (250 ꢁ 4.6 mm,
5 lm),
T = 25 °C, eluent: hexane/i-PrOH (95:5), flow rate: 1 ml/min, detec-
tion: UV–vis, k = 220 nm, tR = 23.1 min (R), tR = 26.9 min (S),
½
a 2D0
ꢂ
¼ ꢀ21:8 (c 0.970, CHCl3) for the (S)-enantiomer in 98% ee,
{lit.13
½
a 2D5
ꢂ
¼ þ5:5 (c 3.40, CHCl3) for the (R)-enantiomer in 26%
ee}. 1H NMR (400 MHz, CDCl3): d = 0.91 (t, J = 7.6 Hz, 3H, CH3),
1.30 (qw, J = 7.8 Hz, J = 4.6 Hz, J = 2.2 Hz, 2H, CH2), 1.89 (q,
J = 7.6 Hz, 2H, CH2) 3.86 (br s, 1H, OH), 4.31 (t, J = 7.6 Hz, 1H,
CH(CN)).
6. Bosiak, M. J.; Krzemin´ ski, M. P.; Jaisankar, P.; Zaidlewicz, M. Tetrahedron:
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5.5.25. 2-Hydroxyheptanonitrile
GC conditions: capillary column Supelco b-Dex 120 (30 m,
0.25 mm), isotherm T = 90 °C, gas flow: 35 cm/s, tR = 39.8 min (R),
tR = 40.3 min (S), ½a D20
¼ ꢀ17:8 (CHCl3, c 0.77) for the (S)-enantio-
ꢂ
mer in 49% ee, {lit.14
½
a 2D5
ꢂ
¼ ꢀ13:2 (c 0.40, CHCl3) for the (S)-enan-
tiomer in 57% ee}. 1H NMR (400 MHz, CDCl3): d = 0.89 (t, J = 7.6 Hz,
3H, CH3), 1.22–1.36 (m, 6H, 3ꢁ CH2), 1.82 (q, J = 7.7 Hz, 2H, CH2),
3.88 (br s, 1H, OH), 4.29 (t, J = 7.6 Hz, 1H, CH(CN)).
5.5.26. 2-Hydroxyundecannitrile
HPLC conditions: Chiralcel OD-J (250 ꢁ 4.6 mm,
5 lm),
T = 25 °C, eluent: hexane/i-PrOH (90:10), flow rate: 0.5 ml/min,