Asymmetric cyanohydrin synthesis using an aluminium(salan) complex

Article abstract of DOI:10.1016/j.tetasy.2012.07.011

The asymmetric addition of trimethylsilyl cyanide to aldehydes catalysed by chiral metal(salan) complexes has been investigated. Salan complexes of titanium and vanadium displayed only low catalytic activity, but a bimetallic aluminium(salan) complex gave

Full text of DOI:10.1016/j.tetasy.2012.07.011

Tetrahedron: Asymmetry 23 (2012) 1218–1225
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Tetrahedron: Asymmetry
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Asymmetric cyanohydrin synthesis using an aluminium(salan) complex
⇑
Michael North , Emma L. Stewart, Carl Young
School of Chemistry and University Research Centre in Catalysis and Intensified Processing, Newcastle University, Bedson Building, Newcastle upon Tyne, NE1 7RU England, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 26 July 2012
Accepted 27 July 2012
The asymmetric addition of trimethylsilyl cyanide to aldehydes catalysed by chiral metal(salan) com-
plexes has been investigated. Salan complexes of titanium and vanadium displayed only low catalytic
activity, but a bimetallic aluminium(salan) complex gave high levels of catalytic activity and reasonable
asymmetric induction when used with triphenylphosphine oxide as a cocatalyst. Mechanistic studies
showed that the reactions were first order in catalyst and aldehyde concentrations, but zero order in tri-
methylsilyl cyanide and triphenylphosphine oxide concentrations. A Hammett analysis indicated that
there was no significant change in the electron density at the aldehyde benzylic position during the rate
determining step of the catalytic cycle. On the basis of the kinetic data, a catalytic cycle is proposed which
accounts for the differences observed between [Al(salen)]2O and [Al(salan)]2O based catalysts.
Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
The reduced forms of salen ligands referred to as salan 2 and sal-
alen 3 (Fig. 2) are more flexible than a salen ligand and are more
Over the last 15 years there have been enormous advances in
the development of catalysts for asymmetric cyanohydrin synthe-
sis.1 Oxynitrilases have been cloned and over-expressed, thus facil-
itating the enzymatic addition of hydrogen cyanide to aldehydes2
and numerous purely organic3 or metal-based catalysts4 for the
asymmetric addition of trimethylsilyl cyanide (and other cyanide
sources) to aldehydes and ketones have been developed. Promi-
nent amongst the latter class of catalysts are salen complexes of
metals including titanium,5 vanadium,6 lithium,7 manganese8 and
aluminium.9 Mechanistic studies on the titanium, vanadium and
aluminium(salen) based catalysts indicated that they were catalyt-
ically active as bimetallic complexes10 (Fig. 1) and that for vana-
dium and aluminium based catalysts, Lewis base as well as Lewis
acid catalysis was important to the catalytic activity.11 On the basis
of the bimetallic nature of the catalyst, the groups of Ding12 and
Sun13 prepared titanium(salen) complexes in which the two salen
ligands were covalently linked together and Khan et al. prepared a
macrocycle containing two vanadium(salen) units.14 Complex 1
developed by Ding12 is the most active catalyst yet discovered
for the asymmetric addition of trimethylsilyl cyanide to aldehydes,
with a catalyst loading as low as 0.0005 mol % being sufficient to
catalyse the reaction in some cases. A key feature of the transition
state shown in Figure 1 is that to allow intramolecular cyanide
transfer, the salen ligand has to adopt a non-planar, chiral, cis-b
configuration. It is well known that salen ligands are capable of
adopting a cis-b configuration, though the planar configuration is
generally energetically more favourable.10c,15
prone to forming complexes with a cis-b configuration.16 The cis-b
configuration leaves the other two coordination sites cis—to one an-
other, which is ideal for reaction between coordinated reactants in
either a monometallic complex or within a
l–oxo bridged dimer
as shown in Figure 1. As a result, there has recently been significant
interest in using metal(salan) and metal(salalen) complexes as
asymmetric catalysts. Thus, monometallic iron(salan)17 and bime-
tallic titanium(salan),18 titanium(salalen)19 and niobium(salan)20
complexes have all been used as catalysts for asymmetric epoxida-
tions; VO(salan) complexes,21 monometallic iron(salan)22 or alu-
minium(salalen)23
and
bimetallic
titanium(salan)24
and
iron(salan)25 complexes have been used to catalyse asymmetric sul-
phide oxidation; bimetallic iron(salan) complexes have been used to
catalyse asymmetric naphthol couplings;26 a molybdenum(salan)
complex has been used to catalyse asymmetric pinacol couplings;27
copper(salan) complexes catalyse asymmetric Henry reactions;28 an
aluminium(salalen) complex catalyses the asymmetric hydrophos-
phonylation of aldehydes29 and imines;30 aluminium(salalen) com-
plexes also catalyse asymmetric cyclopropanations31 and
heterobimetallic nickel(salan)–lanthanum complexes32 have been
used to catalyse asymmetric Michael additions. In addition, alumin-
ium(salan)33 and aluminium(salalen)34 complexes as well as tita-
nium, zirconium and hafnium(salalen) complexes35 have been
used as initiators for stereocontrolled lactide polymerisation; tita-
nium(salan),36 zirconium(salan)36,37 and titanium(salalen)38 com-
plexes initiate the stereocontrolled polymerisation of alkenes and
chromium(salan) complexes initiate the stereocontrolled copoly-
merisation of epoxides and carbon dioxide.39
There has only been limited work on the use of metal(salan) or
metal(salalen) complexes in asymmetric cyanohydrin synthesis.
⇑
Corresponding author. Tel.: +44 191 222 7128; fax: +44 191 222 6929.
E-mail address: Michael.north@ncl.ac.uk (M. North).
0957-4166/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2012.07.011

M. North et al. / Tetrahedron: Asymmetry 23 (2012) 1218–1225
1219
O
O
O
O
N
N
O
O
M
tBu
tBu
tBu
tBu
N
C
N
N
O
O
O
O
N
N
O
O
O
Ti
Ti
O
R
H
M
O
O
N
N
tBu
tBu
1
Figure 1. Bimetallic transition state for asymmetric cyanohydrin synthesis and bimetallic complex 1.
Thus, Katsuki showed that VO(salalen) complexes would catalyse
O
OSiMe3
CN
the asymmetric transfer of cyanide from acetone cyanohydrin to
aliphatic aldehydes40 and Sun showed that titanium(salan) com-
plexes would catalyse the asymmetric addition of trimethylsilyl
cyanide to aldehydes.41
M(salan) complex /
CH2Cl2
+ Me3SiCN
R
H
R
R
8a-k
7a-k
Ac2O / Sc(OTf) (1 mol%) /
MeCN, RT, 30 min.
2. Results and discussion
a:
b:
c:
g:
h:
i:
R = Ph
R = 4-FC6H4
R = 3,5-F2C6H3
R = CH3(CH2)7
OAc
CN
R = 2-MeC6H4
R = 3-MeC6H4
In view of the high levels of catalytic activity and asymmetric
d: R = 4-MeC6H4
e: R = 4-ClC6H4
f: R = 4-BrC6H4
induction obtained during our previous work on [Ti(salen)O]2
4
j: R = Cy
9a-k
catalysed asymmetric cyanohydrin synthesis,10,11,42 we initially
aimed to prepare the corresponding [Ti(salan)O]2 complex 5
(Fig. 3). However, all attempts to isolate pure complex 5 using tita-
nium tetraisopropoxide or titanium tetrachloride as the titanium
source were unsuccessful. Therefore, salan ligand 643 was treated
with titanium tetraisopropoxide followed by water and then the
solvent was removed to leave a titanium(salan) complex which
was used without purification (Scheme 1). This yellow powder
was then used to catalyse the asymmetric addition of trimethyl-
k: R = CMe3
Scheme 2. Metal(salan) catalysed asymmetric cyanohydrin synthesis.
tBu
tBu
tBu
tBu
tBu
tBu
R2
N
R2
N
R2
R2
N
N
N
O
O
N
N
O
O
Ti
Ti
N
R1
R1
R1
O
O
OH
OH
HO
HO
2
3
Figure 2. General structures of salan 2 and salalen 3 ligands.
tBu
tBu
4
tBu
tBu
NH HN
tBu
tBu
tBu
tBu
H
H
H
H
tBu
tBu
OH
tBu
N
N
O
O
N
N
HO
O
O
Ti
Ti
tBu
O
O
6
1) Ti(OiPr)4, CH2Cl2, RT, 5 h
2) H2O, RT, 16 h
3) evaporate to dryness
tBu
tBu
Ti(salan) complex
5
Scheme 1. Synthesis of a Ti(salan) complex.
Figure 3. Bimetallic Ti(salen) and Ti(salan) complexes.

1220
M. North et al. / Tetrahedron: Asymmetry 23 (2012) 1218–1225
Table 1
Table 2
Synthesis of cyanohydrin trimethylsilyl ether 8a using a Ti(salan) complex
Synthesis of cyanohydrin trimethylsilyl ethers using VO(salan)Cl complex 10
Entry
Catalyst (mol %)
T (°C)
t (h)
Conv. (%)
ee
Entry
Aldehyde
10 (mol %)
T (oC)
t (h)
Conv. (%)
ee
9 (R)
1
2
3
4
5
6
7
8
0.1
0.1
1
1
1
5
5
5
22
22
22
24
240
24
24
24
24
24
24
60
60
75
45
25
100
95
43
10 (R)
9 (R)
1
2
3
4
5
6
7
8
7a
7a
7a
7a
7a
7a
7b
7c
7d
7e
7f
0.1
1
1
5
5
10
5
5
5
5
22
22
0
24
24
24
24
24
24
24
24
24
24
24
44
70
67
92
38
10
18
17
15
33
63
45 (R)
43 (R)
60 (R)
50 (R)
47 (R)
45 (R)
55 (R)
43 (R)
20 (R)
35 (R)
23 (R)
31 (R)
39 (R)
13 (R)
23 (R)
30 (R)
0
0
ꢀ40
ꢀ20
ꢀ20
0
0
0
22
0
ꢀ40
9
10
11
0
0
5
silyl cyanide to benzaldehyde 7a to give cyanohydrin trimethylsilyl
ether 8a (Scheme 2). To determine the enantiomeric excess of com-
pound 8a it was converted into the corresponding cyanohydrin
acetate44 9a and analysed by chiral GC. The results of this study
are presented in Table 1. Under the standard conditions used for
asymmetric cyanohydrin synthesis catalysed by titanium(salen)
complex 4, the titanium(salan) complex gave a moderate conver-
sion of benzaldehyde into mandelonitrile trimethylsilyl ether, but
with very low asymmetric induction (entry 1). Entry 2 shows that
increasing the reaction time to 10 days changed neither the con-
version nor the asymmetric induction, suggesting that the catalyst
was already deactivated within the first 24 h. Increasing the cata-
lyst loading to 1 mol % increased both the conversion and asym-
metric induction (entry 3) and the latter could be further
increased to a maximum of 39% by reducing the reaction temper-
ature (entries 4 and 5). Further increasing the catalyst loading to
5 mol % resulted in higher conversions, but reduced asymmetric
induction (entries 6–8) suggesting that 1 mol % is the optimal
amount of catalyst.
One notable feature of the results in Table 1 is that the Ti(salan)
complex derived from (R,R)-salan ligand 6 always gave predomi-
nantly the (R)-enantiomer of cyanohydrin trimethylsilyl ether 8a,
whilst complex 4 (which is derived from the corresponding (R,R)-
salen ligand) always gave predominantly (S)-cyanohydrin trimeth-
ylsilyl ethers.10,11,42
In view of the low levels of asymmetric induction and the
inability to isolate a pure, characterisable titanium(salan) catalyst,
it was decided to investigate the use of vanadium(salan) com-
plexes instead since excellent levels of asymmetric induction had
previously been obtained in asymmetric cyanohydrin synthesis
using VO(salen)X complexes.6 Therefore, VO(salan)Cl complex 10
was prepared as a dark green solid by treatment of salan ligand
6 with VOCl3 (Scheme 3). Complex 10 was then used to convert
benzaldehyde 7a into cyanohydrin trimethylsilyl ether 8a as
shown in Scheme 2 with the results being shown in Table 2.
ther increasing the catalyst loading to 5 mol % did result in good
conversion and improved asymmetric induction (entry 4). Further
lowering the reaction temperature to ꢀ20 °C had a detrimental ef-
fect on both conversion and asymmetric induction, even when the
catalyst loading was increased to 10 mol % (entries 5 and 6).
The conditions of Table 2 entry 4 were then taken as optimal
and applied to aromatic aldehydes 7b–f (Table 2, entries 7–11).
Unfortunately, electron rich aromatic aldehydes 7b–d all gave very
low conversions and only moderate asymmetric induction under
these conditions and electron deficient aromatic aldehydes 7e–f
gave only low levels of asymmetric induction. Again, it was notable
that complex 10 always gave predominantly the (R)-enantiomer of
cyanohydrin trimethylsilyl ethers 8a–f, whilst the corresponding
VO(salen)Cl complex derived from the (R,R)-salen ligand always
gave predominantly (S)-cyanohydrin trimethylsilyl ethers.6
Although the results obtained using isolable VO(salen)Cl catalyst
10 were a significant improvement on those of the Ti(salan) cata-
lyst, they still lacked generality and the asymmetric induction
was moderate at best. Therefore, our attention turned to an alu-
minium(salan) derived catalyst system in which the Lewis basicity
of a cocatalyst was expected to be able to influence the catalytic
activity and asymmetric induction.9,11
Bimetallic aluminium(salan) complex 11 was prepared by treat-
ing ligand 6 with aluminium triethoxide in refluxing toluene
(Scheme 4) and obtained as a pale yellow solid. Table 3 shows
the results of optimisation experiments for the synthesis of cyano-
hydrin trimethylsilyl ether 8a using catalyst 11. Entries 1–4 show
that when used in the absence of a Lewis base cocatalyst, complex
11 is a competent catalyst, but gives at best 55% asymmetric induc-
tion (entry 4), again with the (R)-enantiomer of cyanohydrin tri-
methylsilyl ether predominating in contrast to the results
obtained with the corresponding aluminium(salen) complex 12
derived from the (R,R)-salen ligand.9,11
tBu
tBu
H
H
O
V
VOCl3
N
O
N
O
tBu
tBu
tBu
tBu
THF, RT, 1 h
H
H
H
H
6
Al(OEt)3
N
N
O
O
N
N
tBu
tBu
75%
MePh, Δ, 21 h
O
Cl
6
Al
Al
75%
tBu
tBu
O
O
10
Scheme 3. Synthesis of VO(salan)Cl 10.
t
tBu
Bu
An initial experiment carried out using 0.1 mol % of catalyst 10
at room temperature was not promising, giving cyanohydrin tri-
methylsilyl ether 8a with moderate conversion and low enantiose-
lectivity after a reaction time of 24 h (Table 2, entry 1). Increasing
the catalyst loading to 1 mol % was beneficial to both the conver-
sion and enantioselectivity (entry 2). Lowering the temperature
to 0 °C had no effect on the yield or conversion (entry 3), but fur-
11
Scheme 4. Synthesis of [Al(salan)]2O 11.
Triphenylphosphine oxide has previously been shown to be an
effective Lewis basic cocatalyst when used with [Al(salen)]2O 12
and is known to activate trimethylsilyl cyanide through the forma-

M. North et al. / Tetrahedron: Asymmetry 23 (2012) 1218–1225
1221
Table 3
tained using 10 mol % triphenylphosphine oxide (entry 11), though
this was slightly reduced compared to the use of 0.1 mol % of com-
plex 11 (compare entries 7 and 11).
Synthesis of cyanohydrin trimethylsilyl ether 8a using [Al(salan)]2O complex 11a
Entry 11 (mol %) Ph3PO (mol %) T (oC) Solvent Conv. (%) ee
A more detailed analysis of the effect of triphenylphosphine
oxide was carried out using 1 mol % of catalyst 11 (Table 3, entries
13–23). Increasing the concentration of triphenylphosphine oxide
steadily increases the asymmetric induction and in this case the
maximum asymmetric induction is reached using 20 mol % of tri-
phenylphosphine oxide (entry 20), with higher concentrations of
triphenylphosphine oxide resulting in a slight decrease in asym-
metric induction. Lowering the reaction temperature from 22 to
0 °C when using 1 mol % of complex 11 and 10 mol % of triphenyl-
phosphine oxide resulted in a slight increase in the enantioselec-
tivity of the reaction, but a decrease in the conversion after 24 h
(Table 3, entry 24). However, further lowering of the reaction tem-
perature had a detrimental effect on the level of asymmetric induc-
tion and a very detrimental impact on the conversion (entries 25
and 26). A similar effect was seen in reactions using 1 mol % of
complex 11 and 20 mol % of triphenylphosphine oxide (entries
27–29).
Finally, the effect of changing the solvent was investigated. Use
of toluene (Table 3, entry 30) gave almost identical results to the
use of dichloromethane (entry 20), but was less convenient and
reducing the reaction temperature again failed to result in an in-
crease in the asymmetric induction (entry 31). Acetonitrile gave
slightly lower conversions and enantioselectivity than either
dichloromethane or toluene (entry 32) and THF gave a very low
conversion and only moderate asymmetric induction (entry 33).
Thus, the optimal conditions were determined to be those of Ta-
ble 3, entry 20 which gave complete conversion of 7a into 8a with
78% asymmetric induction.
1
2
3
4
5
6
7
8
0.1
1
1
0
0
0
0
1
22 CH2Cl2
22 CH2Cl2
45
90
85
95
65
89
96
99
72
100
100
100
89
100
100
100
100
100
100
100
100
100
100
92
44
25
100
67
10
35 (R)
53 (R)
47 (R)
55 (R)
38 (R)
67 (R)
77 (R)
70 (R)
49 (R)
72 (R)
74 (R)
70 (R)
57 (R)
61 (R)
63 (R)
65 (R)
65 (R)
69 (R)
71 (R)
78 (R)
75 (R)
74 (R)
75 (R)
75 (R)
71 (R)
67 (R)
72(R)
0
0
CH2Cl2
CH2Cl2
5
0.1
0.1
0.1
0.1
0.3
0.3
0.3
0.3
1
1
1
1
1
1
1
1
1
1
1
1
1
22 CH2Cl2
22 CH2Cl2
22 CH2Cl2
22 CH2Cl2
22 CH2Cl2
22 CH2Cl2
22 CH2Cl2
22 CH2Cl2
22 CH2Cl2
22 CH2Cl2
22 CH2Cl2
22 CH2Cl2
22 CH2Cl2
22 CH2Cl2
22 CH2Cl2
22 CH2Cl2
22 CH2Cl2
22 CH2Cl2
22 CH2Cl2
5
10
20
1
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
5
10
20
1
2
4
5
6
8
10
20
30
40
60
10
10
10
20
20
20
20
20
20
20
0
CH2Cl2
ꢀ10 CH2Cl2
1
1
1
1
1
1
1
1
ꢀ20 CH2Cl2
0
CH2Cl2
ꢀ10 CH2Cl2
ꢀ30 CH2Cl2
22 MePh
75 (R)
25 (R)
77 (R)
75 (R)
67 (R)
48 (R)
100
100
94
0
MePh
22 MeCN
22 THF
18
a
All reactions carried out for 24 h.
The results in Table 3 can be explained by the interplay of three
effects:
tion of adduct 13 (Fig. 4).45 Therefore, the use of triphenylphos-
phine oxide as a cocatalyst in reactions catalysed by complex 11
was investigated. As shown by entries 5–8 of Table 3, addition of
triphenylphosphine oxide to reactions catalysed by just 0.1 mol %
of aluminium(salan) complex 11 had a very beneficial effect on
both the conversion and asymmetric induction. The optimal results
were obtained when 10 mol % of triphenylphosphine oxide was
added (entry 7), giving cyanohydrin trimethylsilyl ether 8a in
96% yield and with 77% enantiomeric excess. When the amount
of complex 11 used was increased to 0.3 mol %, a similar influence
of triphenylphosphine oxide was seen (Table 3, entries 9–12). In
this case, complete conversion of benzaldehyde 7a into cyanohy-
drin trimethylsilyl ether 8a could be obtained (entries 10–12)
and the maximum level of asymmetric induction was again ob-
ꢁ Catalyst 11 will catalyse the addition of trimethylsilyl cyanide to
aldehyde 7a in the absence of triphenylphosphine oxide (entries
1–4).
ꢁ Addition of triphenylphosphine oxide results in only a modest
rate enhancement (compare entries 1 and 6), but a significant
increase in enantioselectivity.
ꢁ Triphenylphosphine oxide is known to be a poor catalyst on its
own for the racemic addition of trimethylsilyl cyanide to alde-
hydes,46 but will show some activity at higher concentrations.
Thus, a high concentration of triphenylphosphine oxide relative
to complex 11 is needed to ensure that the catalysis occurs through
the more enantioselective combined Lewis acid/Lewis base cata-
lysed route, but if the concentration of triphenylphosphine oxide
is too high then it will start to act as a racemic Lewis base catalyst.
The lack of increase of asymmetric induction on lowering the reac-
tion temperature (entries 24–29) could be due to a decrease in the
rate of formation of adduct 13, thus decreasing the relative impor-
tance of the more enantioselective Lewis acid/Lewis base catalysed
reaction.
tBu
tBu
tBu
tBu
tBu
tBu
The optimal conditions were then applied to ten other alde-
hydes (7b–k), giving the results shown in Table 4. In every case,
complete conversion of aldehyde into cyanohydrin trimethylsilyl
ether was observed under these reaction conditions. Electron rich
aromatic aldehydes 7b–d all gave enantioselectivities of 62–68%
(entries 2–4), as did 4-fluorobenzaldehyde 7g (entry 7). Mildly
electron deficient aromatic aldehydes 7e,f gave just slightly lower
enantioselectivities (57–60%, entries 5 and 6), but very electron
deficient 3,5-difluorobenzaldehyde gave a much lower enantiose-
lectivity (entry 8). Primary and secondary aliphatic aldehydes gave
enantioselectivities of 61–62% (entries 9 and 10), but pivaldehyde
gave a lower enantioselectivity (52%, entry 11).
OSiMe3
PPh3
N
N
O
O
N
N
O
Al
Al
CN
O
O
13
tBu
tBu
12
Figure 4. Structure of compounds 12 and 13.

1222
M. North et al. / Tetrahedron: Asymmetry 23 (2012) 1218–1225
Table 4
0.6
Synthesis of cyanohydrin trimethylsilyl ethers using [Al(salan)]2O complex 11 and
Ph3POa
0.5
0.4
0.3
0.2
0.1
0
Entry
Aldehyde (RCHO)
Conv. (%)
ee
1
2
3
4
5
6
7
8
7a (R = Ph)
100
100
100
100
100
100
100
100
100
100
100
78 (R)
62 (R)
65 (R)
68 (R)
60 (R)
57 (R)
66 (R)
32 (R)
61 (R)
62 (R)
52 (R)
7b (R = 2-MeC6H4)
7c (R = 3-MeC6H4)
7d (R = 4-MeC6H4)
7e (R = 4-ClC6H4)
7f (R = 4-BrC6H4)
7g (R = 4-FC6H4)
7h (R = 3,5F2C6H3)
7i (R = Me(CH2)8)
7j (R = cyclohexyl)
7k (R = CMe3)
0
50000
100000
9
10
11
Time (s)
0.6
a
All reactions carried out at 22 °C for 24 h using 1 mol % of complex 11 and
0.5
0.4
0.3
0.2
0.1
0
20 mol % of Ph3PO.
To further investigate the reaction mechanism, a kinetic study
of the asymmetric addition of trimethylsilyl cyanide to benzalde-
hyde 7a was undertaken. These reactions were all carried out at
0 °C using concentrations of all reagents comparable to those used
for the synthetic work (Table 3, entry 27) and the reactions were
monitored by spectrophotometric analysis of samples removed
from the reaction mixture as we have previously reported.10 An
initial kinetic experiment under the conditions of Table 3, entry
27 showed that the reaction obeyed overall first order kinetics
(Fig. 5). By varying the initial concentrations of benzaldehyde or
trimethylsilyl cyanide whilst keeping the concentration of all other
reaction components constant, it was then possible to show that
the reactions were first order in benzaldehyde concentration and
zero order in trimethylsilyl cyanide concentration (Fig. 6). Thus,
the reaction was found to obey the rate equation:
0
10000
20000
30000
Time (s)
Figure 6. Kinetic plots for the addition of Me3SiCN to PhCHO at 0 °C catalysed by
complex 11 in CH2Cl2. Unless specified otherwise, the initial concentrations used
were [PhCHO]0 = 0.49 M, [Me3SiCN]0 = 0.56 M, [11] = 4.9 mM and [Ph3PO] = 0.1 M.
Top: variation of [PhCHO]0; filled squares with solid line [PhCHO]0 = 0.98 M, empty
diamonds with dotted line [PhCHO]0 = 0.49 M, filled triangles with dashed line
[PhCHO]0 = 0.25 M. Bottom: variation of [Me3SiCN]0; filled squares with solid line
[Me3SiCN]0 = 1.12 M, empty diamonds with dotted line [Me3SiCN]0 = 0.56 M, filled
triangles with dashed line [Me3SiCN]0 = 0.28 M.
a
b
16
Rate ¼ kobs½PhCHOꢂ where kobs ¼ k½11ꢂ ½Ph3POꢂ
This contrasts markedly with the kinetics previously determined for
reactions catalysed by aluminium(salen) complex 12,9f,10f which
also obeyed first order kinetics, but for which the rate equation
was found to be:
y = 662.16x - 0.3641
R² = 0.9983
12
8
Rate ¼ kobs½Me3SiCNꢂ
4
y = -0.8504x + 2.2692
To determine the orders with respect to complex 11 and triphenyl-
phosphine oxide concentrations, reactions were carried out at dif-
ferent concentrations of these catalysts whilst keeping the initial
concentrations of all other reaction components constant. The re-
sults shown in Figure 7 show that the reaction is first order in com-
plex 11 concentration and zero order in triphenylphosphine
concentration. Thus, the full rate equation is:
0
0
0.05
0.1
0.15
0.2
0.25
[11] or [Ph3PO]
Figure 7. Plot of [11] or [Ph3PO] against kobs for the addition of Me3SiCN to PhCHO
at 0 °C in CH2Cl2. [PhCHO]0 = 0.49 M, [Me3SiCN]0 = 0.52 M. Solid line and filled
diamonds: [Ph3PO] = 0.1 M, [11] = 0.9–23 mM. Broken line and empty squares:
[11] = 4.9 mM, [Ph3PO] = 0.045–0.226 M.
Rate ¼ k½11ꢂ:½PhCHOꢂ
This also contrasts with the rate equation for aluminium(salen)
complex 12 as in that case the reaction was found to be first order
in both catalyst and triphenylphosphine oxide concentrations.
The kinetic data suggest that for reactions catalysed by complex
11, coordination of the aldehyde to complex 11 is the rate deter-
mining step. Since triphenylphosphine oxide and trimethylsilyl
cyanide are present in much higher concentrations than complex
11, then provided the formation of adduct 13 is fast compared to
the coordination of aldehyde to 11, it will be present at constant
concentration and the mechanism shown in Scheme 5 is consistent
with the kinetic data. This is very similar to the mechanism previ-
ously deduced for reactions catalysed by [Al(salen)]2O 12, but with
a different rate determining step which indicates that [Al(salan)]2O
is less Lewis acidic than [Al(salen)]2O.9f,10f The decrease in Lewis
acidity of the aluminium ions in complex 11 compared to [Al(sale-
n)]2O 12 may also explain the reversal in enantioselectivity be-
0
8000
16000
24000
Time (s)
-0.2
-0.7
-1.2
-1.7
-2.2
y = -0.00006x - 0.69484
R² = 0.99854
Figure 5. First order kinetics plot for the addition of Me3SiCN to PhCHO at 0 °C
catalysed by complex 11 and Ph3PO in CH2Cl2. [PhCHO]0 = 0.49 M,
[Me3SiCN]0 = 0.56 M, [11] = 9.8 mM, [Ph3PO] = 0.1 M.

M. North et al. / Tetrahedron: Asymmetry 23 (2012) 1218–1225
1223
Table 5
slow
(salan)Al
O
H
Al(salan)
(salan)Al
O
11
Al(salan) + PhCHO
fast
Rate data for the construction of
a
Hammett plot for asymmetric cyanohydrin
synthesis catalysed by [Al(salan)]2O complex 11 and Ph3POa
O
OSiMe3
NC
Entry
Aldehyde (RCHO)
r
k1 (ꢃ105)
k2 (ꢃ105)
kavg (ꢃ105)
Ph3PO + Me3SiCN
Ph3P
Ph
1
2
3
4
5
6
7
8
R = Ph
0
2.0
1.0
2.0
3.0
3.0
2.0
3.0
3.0
5.0
4.0
3.0
3.0
2.0
2.0
4.0
3.0
2.0
3.0
3.0
4.0
4.0
3.0
2.5
1.5
2.0
3.5
3.0
2.0
3.0
3.0
4.5
4.0
3.0
R = 4-MeOC6H4
R = 3,4-Me2C6H3
R = 4-MeC6H4
R = 3-MeC6H4
R = 4-MeSC6H4
R = 4-FC6H4
R = 4-ClC6H4
R = 3-FC6H4
R = 3-ClC6H4
R = 3,5F2C6H3
ꢀ0.27
ꢀ0.24
ꢀ0.14
ꢀ0.06
0
0.06
0.23
0.34
0.37
0.68
13
Al(salen)
(salen)Al
O
Me3SiO
O
11 +
Ph
CN
CN
Ph
9
10
11
R3P OSiMe3
a
Scheme 5. Possible mechanism for asymmetric cyanohydrin synthesis catalysed by
complex 11.
All reactions carried out at 0 °C in CH2Cl2 with [ArCHO]0 = 0.49 M;
[Me3SiCN]0 = 0.56 M; [11] = 4.9 mM; [Ph3PO] = 0.1 M. k1 and k2 refer to the rate
constants measured in two separate experiments and kavg is the average of these
measurements and was used to construct the Hammett plot.
tween the two complexes. Thus, [Al(salen)]2O 12 was previously
proposed to coordinate to both the aldehyde and adduct 13, with
cyanide transfer then occurring intramolecularly (Fig. 8). In con-
trast, the mechanism shown in Scheme 5 lacks this interaction be-
tween adduct 13 and an aluminium ion of the [Al(salan)]2O/
aldehyde complex, so cyanide transfer occurs intermolecularly to
the less hindered face of the aldehyde.
0.3
3-F
3-Cl
0.2
0.1
4-Me
3,5-F2
4-F
3-Me
4-Cl
To probe the Lewis acidity of complex 11 and investigate the
nature of any electron transfer in or before the rate determining
transition state, a Hammett analysis of asymmetric cyanohydrin
synthesis catalysed by complex 11 (1 mol %) and triphenylphos-
phine oxide (20 mol %) at 0 °C was carried out using eleven meta-
or para-substituted aldehydes. The resulting rate data are shown
in Table 5 and the Hammett plot is shown in Figure 9. The absence
of any correlation suggests that there is little change in the electron
density around the benzylic carbon atom of the aldehyde and is
consistent with complex 11 being only a very weak Lewis acid
and cyanide transfer to the aldehyde occurring only after the rate
determining step of the mechanism.
H
0
-0.1
-0.2
-0.3
σ
-0.4
-0.2
0
0.2
0.4
0.6
0.8
4-MeS
3,4-Me2
4-MeO
Figure 9. Hammett plot for asymmetric cyanohydrin trimethylsilyl ether synthesis
catalysed by complex 11 (1 mol %) and Ph3PO (20 mol %) at 0 °C in CH2Cl2.
Melting points were determined on a Stuart SMP3 system. Optical
rotation measurements were conducted on a Polaar 2001 Optical
Activity automatic polarimeter at the sodium D-line using 0.25
and 0.5 dm thermostated cuvettes and a suitable solvent that is re-
ported along with the concentration (g/100 ml). High- and low-res-
olution electrospray ionisation (ES) mass spectra were recorded on a
Waters LCT Premier LCMS spectrometer using direct injection of the
sample dissolved in MeOH. Chiral gas chromatography was per-
formed on a Varian450-GC instrument with a TCD detector using a
Supelco Gamma DEX 120 fused silica capillary column
3. Conclusions
Metal(salan) complexes derived from titanium, vanadium or
aluminium have been shown to catalyse the asymmetric addition
of trimethylsilyl cyanide to aldehydes. In each case, the absolute
configuration of the cyanohydrin trimethylsilyl ether was the
opposite of that obtained with the corresponding metal(salen)
complex. The best results were obtained with [Al(salan)]2O 11 in
the presence of triphenylphosphine oxide as cocatalyst and a ki-
netic study provided evidence for a reaction mechanism and an
explanation of the inverted sense of asymmetric induction.
(30 m ꢃ 0.25 mm ꢃ 0.25
lm film thickness) with hydrogen as a car-
rier gas. Aldehyde concentrations during kinetic studies were calcu-
lated by measuring UV absorbance maxima at the appropriate
wavelength using a Biochrom Libra S12 UV–visible spectrophotom-
eter. 1H and 13C NMR spectra were recorded on a Jeol ECS400 spec-
trometer at resonance frequencies of 400 and 100 MHz,
respectively. All spectra were recorded at room temperature in
CDCl3. Chemical shifts are reported in ppm and are relative to TMS
internally referenced to the residual solvent peak. The multiplicity
of signals is reported as singlet (s), doublet (d), triplet (t), quartet
(q), multiplet (m), broad (br) or a combination of any of these. Spec-
4. Experimental
4.1. Chemicals and instrumentation
Chromatographic separations were performed using silica gel 60
(230–400 mesh, Davisil). Infrared spectra were recorded at room
temperature on a Varian 800 FT-IR Scimitar series spectrometer.
tra were assigned with the aid of DEPT, 1H–1H COSY and 1H–13
C
(salen)Al
O
Al(salen)
C
COSY spectra. Superscripts a and b are used to refer to the two dia-
stereotopic spin systems within a salan ligand in complex 11.
O
N
OSiMe3
H
Ph
P
4.2. Synthesis of a Ti(salan) complex
Ph3
Salan ligand 6 (0.68 g, 1.2 mmol) was dissolved in CH2Cl2
Figure 8. Intramolecular cyanide transfer in asymmetric cyanohydrin synthesis
catalysed by aluminium(salen) complex 12 and Ph3PO.
(3.5 ml) and Ti(OiPr)4 (0.37 g, 1.3 mmol) was added with stirring

1224
M. North et al. / Tetrahedron: Asymmetry 23 (2012) 1218–1225
resulting in the formation of a pale yellow solution. The solution
was stirred at room temperature for 5 h, followed by the addition
of water (10 drops). The resulting solution was sealed and stirred
vigorously for 16 h, resulting in the formation of an orange solu-
tion. The solvent was evaporated in vacuo and the residue dried
on a vacuum line to remove any remaining water, leaving a yellow
residue which was used without purification.
4.6. General procedure for determining the enantiomeric excess
of cyanohydrin trimethylsilyl ethers 8a–k
A cyanohydrin trimethylsilyl ether (1.0 mmol) was dissolved in
MeCN (1 ml), then Sc(OSO2CF3)3 (5 mg, 0.01 mmol) and Ac2O
(0.22 g, 2.1 mmol) were added and the reaction stirred at rt for
1 h. The solution was passed through a short path of silica and
evaporated in vacuo to leave cyanohydrin acetates 9a–k as yellow
oils. Compounds 9a–k were analysed by chiral GC under the con-
ditions previously reported11 to determine their enantiomeric
excesses.
4.3. Synthesis of VO(salan)Cl complex 10
Salan ligand 6 (0.22 g, 0.4 mmol) was dissolved in THF (3 ml)
and VOCl3 (0.09 g, 0.54 mmol) added with vigorous stirring. The
flask was sealed and stirred for 1 h, resulting in the formation of
a deep green solution. The solvent was evaporated in vacuo and
the residue was dissolved in CH2Cl2 (2 ml) and purified by flash
chromatography on silica eluting first with CH2Cl2 to remove
V(IV) species and then with methanol to give complex 10 (0.85 g,
4.7. General procedure for kinetic experiments
Solutions of catalyst 11 and Ph3PO in CH2Cl2 were added to a
5 ml round bottomed flask fitted with a Suba Seal stopper. CH2Cl2
was added to dilute the reactants to the required concentrations.
An aliquot (0.5 lL) was taken via a microsyringe and diluted into
CH2Cl2 (3 ml); this sample provided the reference for UV measure-
75%) as a dark green solid. Mp >280 °C (decomp.); ½a D23
ꢂ
¼ þ1680
(c 0.01, CHCl3); mmax 2953 and 1628 cmꢀ1; m/z(ESI) 1262 (2M-
2Cl+MeO)+, 615 (M-Cl)+, 376, 340; Found (ESI) 615.3740;
ments. Aldehyde (0.94 mmol) was then added and another aliquot
C
36H56N2O3V (M-Cl)+ requires 615.3730. Traces of paramagnetic
(0.5
(0.14 ml, 1.03 mmol) was added and simultaneously a timer was
started. Samples (0.5 L) were taken and diluted into CH2Cl2
lL) taken to calculate the concentration at time = 0. Me3SiCN
V(IV) species were always present which prevented 1H or 13C
NMR spectra from being recorded.
l
(3 ml) at appropriate intervals and the UV absorbance measured
to determine the concentration of the remaining aldehyde. The
amount of CH2Cl2 used to dissolve the catalyst and Ph3PO in a par-
ticular reaction was varied to ensure that the total initial reaction
volume (CH2Cl2 + aldehyde + Me3SiCN) was kept constant at
2.0 ml.
4.4. Synthesis of [Al(salan)]2O complex 11
Salan ligand 6 (0.38 g, 0.68 mmol, 1 eq) was dissolved in dry tol-
uene (20 ml) and Al(OEt)3 (0.19 g, 1.15 mmol) added. The solution
was stirred under an argon atmosphere and heated at reflux for
5 h, then at 80 °C for a further 16 h. The solution was then cooled
to room temperature and solvent evaporated in vacuo to leave a
yellow solid which was dissolved in CH2Cl2 (25 ml) and washed
with water (2 ꢃ 25 ml), brine (2 ꢃ 25 ml) and dried (Na2SO4) to
leave complex 11 (0.58 g, 75%) as a pale yellow solid. Mp 276–
Acknowledgement
The authors thank the Newcastle University for financial
support.
280° C; ½a 2D3
¼ þ14:8 (c 1.0, CHCl3); mmax 3190, 2960, 2903, 2866
ꢂ
and 1478 cmꢀ1; dH(CDCl3) 0.89–1.85 (6H, m, (CH2)4), 0.94 (9H, s,
(CH3)3), 1.09–1.15 (1H, m, NHa), 1.27 (9H, s, (CH3)3), 1.30 (9H, s,
(CH3)3), 1.61 (9H, s, (CH3)3), 2.15–2.27 (2H, m, NCbH + CbH2CHN),
2.40–2.45 (1H, m, CaH2CHN), 2.65 (1H, qd J 11.7 and 3.1 Hz, NCaH),
3.62 (1H, d J 9.7 Hz, NCaH2), 3.68–3.73 (1H, m, NCbH2), 3.78–3.74
(1H, m, NCaH2), 4.69 (1H, d J 10.9 Hz, NHb), 4.77 (1H, d J 13.1 Hz,
NCbH2), 6.75 (2H, d J 2.4 Hz, 2 ꢃ ArH), 7.13 (1H, d J 2.6 Hz, ArH),
7.34 (1H, d J 2.5 Hz, ArH); dC(CDCl3) 24.46 (CH2), 24.66 (CH2),
29.11 (CaH2), 29.76 (CH3), 30.02 (CbH2), 31.20 (CH3), 31.72 (CH3),
31.75 (CH3), 33.77 (CMe3), 33.89 (CMe3), 34.73 (CMe3), 35.34
(CMe3), 49.09 (NCaH2), 50.93 (NCbH2), 56.63 (NCbH), 58.95 (NaCH),
121.83 (ArC), 123.03 (ArCH), 123.33 (ArCH), 124.68 (ArCH), 124.79
(ArCH), 125.28 (ArC), 136.36 (ArC), 137.24 (ArC), 138.10 (ArC),
138.16 (ArC), 158.00 (ArC), 160.40 (ArC); m/z(ESI) 1189.8
(M+Na)+, 1167.8 (MH+), 607.4, 575.4. Found (ESI): 1167.8297;
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