Asymmetric cyanohydrin synthesis using heterobimetallic catalysts obtained from titanium and vanadium complexes of chiral and achiral salen ligands

Article abstract of DOI:10.1016/j.tet.2007.03.140

Titanium(IV)(salen) and vanadium(V)(salen) complexes are both known to form catalysts for asymmetric cyanohydrin synthesis. When a mixture of titanium and vanadium complexes derived from the same or different salen ligands is used for the asymmetric addit

Full text of DOI:10.1016/j.tet.2007.03.140

Tetrahedron 63 (2007) 5287–5299
Asymmetric cyanohydrin synthesis using heterobimetallic
catalysts obtained from titanium and vanadium
complexes of chiral and achiral salen ligands
Yuri N. Belokon,b William Clegg,a Ross W. Harrington,a Carl Younga and Michael Northa,
*
aSchool of Natural Sciences, Bedson Building, Newcastle University, Newcastle upon Tyne NE1 7RU,
United Kingdom
bA.N. Nesmeyanov Institute of Organo-Element Compounds, Russian Academy of Sciences, 117813,
Moscow, Vavilov 28, Russian Federation
Received 8 January 2007; revised 28 February 2007; accepted 22 March 2007
Available online 27 March 2007
Abstract—Titanium(IV)(salen) and vanadium(V)(salen) complexes are both known to form catalysts for asymmetric cyanohydrin synthesis.
When a mixture of titanium and vanadium complexes derived from the same or different salen ligands is used for the asymmetric addition of
trimethylsilyl cyanide to benzaldehyde, the absolute configuration of the product and level of asymmetric induction can only be explained by
in situ formation of a catalytically active heterobimetallic complex, and is not consistent with two monometallic species acting cooperatively.
Combined use of complexes containing chiral and achiral salen ligands demonstrates that during the asymmetry inducing step of the mech-
anism, the aldehyde is coordinated to the vanadium rather than the titanium ion. The titanium complexes also catalyse the asymmetric addition
of ethyl cyanoformate to aldehydes, a reaction in which vanadium(V)(salen) complexes are not active. For this reaction, use of a mixture of
titanium and vanadium(salen) complexes results in a complete loss of catalytic activity, a result which again can only be explained by in situ
formation of a heterometallic complex. Both the titanium and vanadium based catalysts also induce the asymmetric addition of potassium
cyanide/acetic anhydride to aldehydes. For this reaction, combined use of chiral and achiral complexes indicates that during the asymmetry
inducing step of the mechanism, the aldehyde is coordinated to titanium rather than vanadium, a result which contrasts with the observed
results when trimethylsilyl cyanide is used as the cyanide source.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
developed and used as catalysts for asymmetric cyanohydrin
synthesis.10,11 Closely related titanium(salen) complexes
have also been used as catalysts for the enantioselective
ring opening of meso-epoxides,12 hetero-Diels–Alder reac-
tions,13 the asymmetric addition of dialkylzinc reagents to
a-ketoesters,14 the asymmetric addition of organogallium
reagents to aldehydes,15 and the asymmetric oxidation of
sulfides.16
Cyanohydrins are key synthetic intermediates for the synthe-
sis of pharmaceuticals and natural products. As a result, the
development of asymmetric catalysts for the addition of var-
ious cyanide sources to carbonyl compounds has increased
significantly over the last 10 years.1,2 Metal(salen) com-
plexes are amongst the most versatile catalysts used in
a wide range of reactions,3 and we have previously reported4
the development of bimetallic titanium complex 1 as a
highly effective catalyst for the asymmetric addition of
trimethylsilyl cyanide to aldehydes5 and ketones6 at room
temperature, and for the asymmetric addition of ethyl cyano-
formate7 and potassium cyanide8 to aldehydes at ꢀ40 ꢁC.
Complex 1 has also been used by other workers for the asym-
metric synthesis of cyanohydrin esters and carbonates,9 and
insoluble, polymeric versions of the catalyst have also been
Subsequently, we have shown that vanadium(V)(salen)
complex 2 is an even more enantioselective catalyst for
the asymmetric addition of trimethylsilyl cyanide to alde-
hydes,17 and that complex 2 also catalyses the asymmetric
addition of potassium cyanide to aldehydes.8 Polymeric11
and supported18 versions of this catalyst have been prepared
and vanadium(V)(salen) complexes have also been used as
catalysts for the asymmetric oxidation of sulfides.19 A related
vanadium(V)(salen) complex was shown to catalyse the
asymmetric transfer of hydrogen cyanide from acetone
cyanohydrin to aldehydes.20 For both complexes 1 and 2,
the catalyst derived from (R,R)-cyclohexane diamine
always catalyses the formation of the (S)-enantiomer of the
cyanohydrin.
Keywords: Asymmetric catalysis; Cyanohydrin; Titanium; Vanadium;
Heterometallic complexes.
* Corresponding author. Tel.: +44 191 222 7128; fax: +44 870 131 3783;
e-mail: michael.north@ncl.ac.uk
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.03.140

5288
Y. N. Belokon et al. / Tetrahedron 63 (2007) 5287–5299
tBu
tBu
Herein, we report for the first time the results on heterobi-
metallic titanium and vanadium complexes derived from two
different salen ligands, one of which is achiral and the other
chiral. The catalysis of the addition of various cyanide sour-
ces to benzaldehyde using these heterobimetallic systems is
investigated and the results can only be explained by in situ
formation of a catalytically active heterobimetallic complex
as illustrated in Figure 1A. The structure and stereochemis-
try of the heterobimetallic complexes are analysed in detail
and can be used to predict not only the sense and magnitude
of asymmetric induction, but also the rate of catalysis
observed using the complexes.
tBu
tBu
N
N
O
O
O
N
N
O
Ti
Ti
O
O
tBu
tBu
tBu
tBu
1
EtOSO3
tBu
O
V
N
N
2. Results and discussion
tBu
O
H
O
H
O
2.1. Synthesis of achiral salen complexes of titanium
and vanadium
tBu
tBu
2
To allow further investigation of the mechanism of asym-
metric cyanohydrin synthesis induced by metal(salen)
complexes, it was decided to combine the use of both enan-
tiomers of catalysts 1 and 2 with the corresponding com-
plexes derived from achiral salen ligand 3.24 Ligand 3 was
converted into the corresponding bimetallic titanium(salen)
complex 4 using the same synthetic route developed for
the synthesis of catalyst 1 (Scheme 1). However, treatment
of ligand 3 with vanadyl sulfate in the presence of air, using
the methodology developed for the synthesis of catalyst 2,8
did not result in spontaneous oxidation of the vanadium
ion and formation of the desired vanadium(V)(salen)
complex 5; rather the corresponding vanadium(IV)(salen)
Mechanistic studies on catalysts 1 and 2 demonstrated that
two metal(salen) units were involved in the catalysis and
were consistent with either of the transition state structures
shown in Figure 1, where one metal ion acts as a chiral Lewis
acid and the other as a chiral cyanide source, with cyanide
then being transferred between the two metals onto the co-
ordinated carbonyl compound.21 Whilst catalyst 2 is more
enantioselective than catalyst 1, it accelerates the rate of ad-
dition of trimethylsilyl cyanide to aldehydes to a much lower
extent. Reactions involving catalyst 1 are typically complete
in 30 min, whereas those involving catalyst 2 require at least
16 h to reach completion under identical reaction conditions.
We recently reported,22 however, that when the enantiomer
of catalyst 1 ((S,S)-1) was mixed with catalyst 2, so as to pre-
pare a solution containing equimolar amounts of titanium
and vanadium ions, the resulting mixture catalysed the for-
mation of the (S)-enantiomer of mandelonitrile trimethyl-
silyl ether, a result which was inconsistent with the two
catalysts acting independently or with scrambling of the
salen ligand between the two metals. These results could
only be explained by catalysis involving at least two metal
ions and indicated that catalysis by two different metal
ions was more favourable than catalysis by either homome-
tallic system. Kinetics experiments indicated that catalysis
by the heterometallic system was slower than catalysis using
catalyst 1 alone,22 which was consistent with the in situ for-
mation of a heterobimetallic complex shown in Figure 1A.
However, an alternative mechanism involving sequestration
of titanium ions by vanadium (e.g., by formation of a catalyt-
ically inactive oligomeric complex23) leaving only vana-
dium(salen) complexes to catalyse the reaction through the
bimolecular transition state shown in Figure 1B could not
be completely ruled out.
tBu
tBu
tBu
tBu
N
N
O
O
N
N
O
Ti
Ti
O
O
O
tBu
t
Bu
tBu
tBu
4
1. TiCl4
2. phosphate buffer
N
N
tBu
OH HO
tBu
tBu
tBu
3
1. VO(SO4) / O2, EtOH,
2. PhC(Me)2OOH, HCl
OSiMe3
(salen)M CN
O
V
(salen)M CN
Cl
N
O
N
O
H
R
(salen)M
O
H
R
tBu
O
H
tBu
(salen)M
O
O
O
H
CN
A
tBu
tBu
5
B
Figure 1.
Scheme 1.

Y. N. Belokon et al. / Tetrahedron 63 (2007) 5287–5299
5289
complex25 was isolated and could then be oxidised to the
desired vanadium(V) complex 5 by treatment with cumene
hydroperoxide.19
that the two metal(salen) units were homochiral, with both
possessing (R)-stereocentres and D-configuration.5,31,32
The two salen ligands were also oriented syn to one another,
thus giving selectively the syn-D(RR)D(RR) stereoisomer.
The D-configuration of the metal(salen) units in complexes
6 and 7 is a direct consequence of the presence of (R,R)-
1,2-disubstituted 1,2-diaminoethanes within the salen li-
gands. The absolute configuration of the two stereocentres
induces a l-conformation on the five-membered chelate
ring and this in turn induces the overall D-configuration on
the metal–ligand unit.
2.2. Structural analysis of bimetallic salen complexes
In monometallic octahedral complexes, the planar, trans-
configuration of a salen ligand is usually energetically pre-
ferred (Fig. 2).26 However, in bis-bridged complexes as
occurs in complexes 1 and 4, this is not possible as the
two bridging oxygens must adopt positions cis to one an-
other.27 The salen ligand can then adopt either cis-a or cis-
b configurations,28 with the latter being preferred in all cases
known to date.29,30 The cis-b configuration of a salen ligand
is chiral and two enantiomeric structures (D or L) are possi-
ble. For bimetallic complexes bearing two different salen
ligands, there are thus four possible stereoisomeric configu-
rations (DD, LL, DL and LD) of the two salen ligands.
However, each of these complexes also exists as syn- and
anti-isomers as shown in Figure 2, thus giving a total of eight
possible stereoisomers.29
In contrast, the crystal structure of complex 9, which differs
from catalyst 4 only by the absence of tert-butyl groups on
the aromatic rings, has been determined by Tsuchimoto,33
and stereochemically analysed by Katsuki et al.34 In this
complex derived from a salen ligand, which is devoid of
stereocentres, the two metal frameworks were found to be
heterochiral with one possessing the D-configuration and
the other the L-configuration, and the two ligands were ori-
ented anti to one another (anti-DL). In this case, since the
1,2-diaminoethane unit is unsubstituted, the d- and l-confor-
mation of an individual five-membered ring chelate will be
of equal energy and there will be no intrinsic preference
for the formation of a D- or L-configuration. Therefore,
the selective formation of the DL-configuration within the
bimetallic complex suggests that this is due to the heterochi-
ral (DL) configuration being intrinsically more stable than
the homochiral (DD or LL) configuration. As complex 9
was the only achiral bimetallic titanium(salen) complex
whose structure had been determined, we obtained the crys-
tal structure of complex 4 (Fig. 3). This complex, which is
exactly centrosymmetric with a planar central Ti2O2 ring,
was also found to exist in a heterochiral, anti-DL configura-
tion in which each salen ligand adopted a cis-b configuration,
exactly analogous to the known structure of complex 9. The
preferential formation of heterochiral (DL) complexes also
appears to be generally true for other bimetallic metal(salen)
complexes derived from achiral ligands,35 though there are
In chiral complexes 6–8 (complexes 6 and 7 are active cata-
lysts for the addition of trimethylsilyl cyanide to aldehydes5
and differ from catalyst 1 only by the absence of tert-butyl
groups on the aromatic rings), X-ray crystallography showed
X
O
M
O
M
A
N
X
X
O
N
N
N
M
X
X
O
N
O
X
X
O
N
O
M
O
O
M
N
O
N
N
X
N
X
M
N
O
X
X
N
O
X
trans
cis-
cis-
B
O
O
M
N
O
O
O
O
N
O
O
O
O
N
M
N
M
N
M
N
O
N
N
O
syn-
syn-
O
M
N
O
M
N
O
M
N
O
M
N
O
O
O
N
O
O
N
O
O
N
N
O
syn-
syn-
N
M
O
N
M
O
N
M
O
N
M
O
O
M
N
O
M
N
O
M
N
O
M
N
O
O
O
O
O
N
O
O
N
N
O
N
anti-
anti-
N
O
O
N
O
N
O
O
N
O
O
O
anti-
anti-
Figure 2. (A) The three configurations of a salen ligand in a monometallic
complex. (B) The eight stereoisomeric complexes of a bimetallic complex
[(salen)M(m-O)2M(salen0)] in which the salen ligand adopts a cis-b configu-
ration.
Figure 3. Molecular structure of complex 4 with 40% probability ellipsoids
and selected atom labels. Hydrogen atoms have been omitted.

5290
Y. N. Belokon et al. / Tetrahedron 63 (2007) 5287–5299
two related examples of bimetallic salen complexes (derived
from aluminium36 and manganese37) with bridging OMe
groups, which crystallise as a racemic mixture of syn-DD
and syn-LL configurations instead.
case all of the bridging M–O bonds have the same length
˚
(1.823(2) A). The formation of an anti-DD configuration
in this case may be due to the lack of a dipole moment if
the two salen ligands are arranged anti to one another. If
the two salen ligands are identical (as in the cases of com-
plexes 4 and 6–9), then the two syn-dimers form a pair of
enantiomers whilst the two anti-dimers correspond to a single
achiral meso-compound. Based on the above analysis, the
structures of (salen)M(m-O)2M0(salen0) complexes can be
predicted on the basis of three rules:
R R
N
N
O
O
O
O
N
N
O
O
Ti
Ti
1. An (R,R)-1,2-disubstituted-1,2-ethanediamine within
the salen ligand forces the ligand to adopt the D-config-
uration whilst an (S,S)-1,2-disubstituted-1,2-diamine
within the salen ligand forces the ligand to adopt the
L-configuration.
R
R
6 (R = H)
7 (R = tBu)
2. The heterochiral DL-dimer is thermodynamically more
stable than the corresponding homochiral (DD or LL)
dimers.
3. Heterochiral dimers will have an anti arrangement of the
two ligands and homochiral dimers will have a syn ar-
rangement of the two ligands, unless all of the bridging
M–O and M0–O bonds have the same length in which
case an anti arrangement is preferred.
Ph
P
O
I2Pd PdI2
O
2Ph2
P
O
N
Ph
Ph
Ph
Ph
N
O
Ti
Ti
N
O
O
N
P
P
Ph2 Ph2
8
Thus, by analogy with the known structures of complexes
6–8 and by application of the above rules, complex 1 will
be forced to exist as the syn-D(RR)D(RR) stereoisomer.
O
O
N
N
N
N
O
O
Ti
Ti
The solution-state structure of complex 4 was also investi-
gated using variable concentration and variable temperature
NMR studies in different solvents. We have previously re-
ported that complex 1 dissociates in both chloroform and
dichloromethane and exists as an equilibrium mixture of
bimetallic and monometallic [(salen)Ti]O] species. In con-
trast, in benzene no dissociation could be detected and only
resonances due to the dimeric complex were present.39 How-
ever, for complex 4, similar studies showed only one species
present in either dichloromethane or benzene at concentra-
tions between 0.1 and 0.004 M. At 25 ꢁC, this species gave
O
O
9
The formation of a syn-complex in the case of compounds 6–
8 but an anti-complex in the case of compounds 4 and 9 can
be explained by considering the bridging Ti–O bond
lengths.29 For complexes 6–9, the four central Ti–O bonds
are not of equal length; in each case, the two bridging Ti–O
bonds, which are trans to a nitrogen atom of the salen ligand
have a length of 1.80–1.84 A, whilst the two Ti–O bonds,
which are trans to an oxygen atom of the salen ligand
˚
are longer (1.86–1.92 A). Thus, in these complexes, each
Ti–O–Ti bridge consists of one long and one short Ti–O
bond as this gives the least distorted structure for the
central Ti2O2 unit. If the two salen ligands have the same
configuration (DD or LL) as in complexes 6–8, then only
a syn-dimer allows both the bridging Ti–O–Ti units to
have one long and one short bond. In contrast, if the two
salen ligands have opposite configurations (DL), then only
the anti-dimer allows both the bridging Ti–O–Ti units to
have one long and one short bond. In the case of complex
1
rise to a very simple H NMR spectrum, which included
˚
just one imine CH peak and two aromatic CH’s. This implied
that all four aromatic rings and imines within structure 4
were equivalent, but this is not consistent with any single
structure shown in Figure 2B. The spectrum (in deuterated
dichloromethane) was, however, found to be highly temper-
ature dependent (Fig. 4); on cooling, the aromatic and imine
signals first broadened at temperatures down to ꢀ45 ꢁC and
then reappeared as two imine and four aromatic signals at
temperatures down to ꢀ70 ꢁC. This behaviour was attributed
to the existence of an equilibrating mixture of the anti-DL/
anti-LD dimers. For complex 4, these two structures are
equivalent and would give rise to two imine CH’s and four
aromatic CH’s, as observed at the lowest temperatures. How-
ever, equilibration between the two dimeric structures has
the effect of interconverting the two imines and the aromatic
rings and if this occurs rapidly on the NMR timescale, then
an averaged spectrum consisting of one imine and two aro-
matic CH’s would be observed, as seen at temperatures
above ꢀ55 ꢁC. The equilibration of each salen ligand be-
tween D and L-configuration presumably occurs via an un-
detectably small amount of the monomeric [(salen)Ti]O]
complex.
˚
4, these lengths were found to be 1.8253(16) A and
˚
1.8978(16) A, respectively, which fall within the ranges pre-
viously found for complexes 6–9. A consequence of this
analysis is that the four structures shown in the box in Fig-
ure 2 will be thermodynamically less stable than the other
four structures, and only four (syn-DD, syn-LL, anti-DL
and anti-LD) of the eight possible configurations of a
(salen)Ti(m-O)2Ti(salen0) complex are likely to be formed.
There is only one crystal structure of a bimetallic salen com-
plex, which exists in the anti-DD configuration,38 and in this

Y. N. Belokon et al. / Tetrahedron 63 (2007) 5287–5299
5291
Figure 4. Variable temperature 1H NMR spectra of compound 4 in CD2Cl2. Expansion of the aromatic and imine regions.
In chloroform, the spectrum of complex 4 was, however, very
concentration dependent and showed evidence of the pres-
ence of three different species (Fig. 5). Two of these species
can be attributed to the anti-DL dimer (major complex
‘A’ present at high concentration) and the monometallic
[(salen)Ti]O] complex (minor complex ‘C’ present at high
concentration). The third species present in solution ‘B’ is
assumed to be the syn-DD/syn-LL dimer. At a concentration
of 0.1 M, these three species are present in a ratio of 22.5
(anti-DL dimer): 2.6 (syn-DD/LL dimer): 1 ((salen)Ti]O),
whilst at a concentration of 0.0008 M the corresponding
ratio is 0.9:0.7:1, and at a concentration of 0.000016 M, only
peaks corresponding to the monometallic complex are pres-
ent. The detection of the monometallic and syn-DD/syn-LL
dimers in chloroform but not in dichloromethane is consis-
tent with a relatively polar solvent being required to stabilise
the dipole moment present in these two complexes.
mandelonitrile using acetic anhydride and scandium triflate,
under conditions developed by Kagan et al.40 and proven not
to cause any racemisation (Scheme 2). The O-acetyl mande-
lonitrile could then be easily analysed by chiral gas chroma-
tography. The results of reactions using complexes 1, 2, 4
and 5 either individually or in combination are summarised
in Table 1.
Entries 1–4 in Table 1 provide control experiments, which
demonstrate the activity of catalysts 1, 2, 4 and 5 when used
individually. Although not apparent from the data shown in
Table 1, we have previously shown21,22 that reactions cata-
lysed by complex 1 are faster than those catalysed by com-
plex 2 by about a factor of 10 and this is important for the
analysis of the data obtained for mixed complexes. Whilst
the achiral titanium complex 4 did catalyse the addition of
trimethylsilyl cyanide, the reaction was very slow compared
to the corresponding chiral catalyst 141 (Table 1, entries 1
and 3). To quantify this reactivity difference, the kinetics
of the addition of trimethylsilyl cyanide to benzaldehyde
at 0 ꢁC using catalysts 1 and 4 were studied. Reactions cata-
lysed by complexes 1 and 4 both obeyed first order kinetics
under these conditions (Fig. 6) and the first order rate con-
stants were 2.4ꢂ10ꢀ3 sꢀ1 for complex 1 and 1.7ꢂ10ꢀ6 sꢀ1
for complex 4. Thus, the reaction catalysed by complex 4
was a thousand times slower than that catalysed by complex
1. As discussed above, complex 1 will be forced to exist as
the syn-D(RR)D(RR) stereoisomer, whilst complex 4 is able
2.3. Catalysis of the asymmetric addition of
trimethylsilyl cyanide to benzaldehyde
The use of complexes 1, 2, 4 and 5 as catalysts for the addi-
tion of trimethylsilyl cyanide to benzaldehyde was studied
under the standard conditions (0.1 mol % total catalyst,
CH2Cl2, room temperature, 24 h) that have been developed
for asymmetric cyanohydrin trimethylsilyl ether synthesis
using catalysts 1 and 2.5 To allow the enantiomeric excess of
the product to be determined, it was converted into O-acetyl

5292
Y. N. Belokon et al. / Tetrahedron 63 (2007) 5287–5299
Figure 5. Variable concentration 1H NMR spectra of compound 4 in CDCl3. Expansion of the aromatic and imine regions. The imine signals of the three species
present have been labelled A, B and C.
to form the thermodynamically more stable anti-DL config-
uration and in dichloromethane, no evidence for significant
populations of other configurations was detected by NMR
spectroscopy. Provided the process by which precatalysts 1
and 4 enter the catalytic cycle is reversible, it is then reason-
able that the more stable catalyst precursor 4 would be less
active than complex 1.
active complex is present in chloroform than in dichlorome-
thane, whilst for complex 4 the reverse is true. This is consis-
tent with the syn-DD/syn-LL configuration of the complexes
being the catalytically active complex. For complex 1, the
syn-DD configuration is the only species detected by NMR
spectroscopy in dichloromethane, whilst in chloroform mo-
nomeric species are also present. In contrast, for complex 4,
the syn-DD/syn-LL configuration is not detectable by NMR
spectroscopyindichloromethane, butispresent inchloroform.
In chloroform solution, however, NMR spectroscopy sug-
gests that complex 4 does exist in the syn-DD/syn-LL con-
figuration as well as the anti-DL configuration. Therefore,
the catalytic activity of complexes 1 and 4 for cyanohydrin
synthesis was also compared in chloroform solution
(Table 1, entries 5 and 6). The chiral catalyst 1 was less re-
active in chloroform (compare entries 1 and 5), whilst the
achiral catalyst 4 was more reactive in chloroform than in
dichloromethane (compare entries 3 and 6). Similarly, the
first order rate constants measured in CDCl3 (Fig. 6) were
1.2ꢂ10ꢀ4 sꢀ1 for complex 1 (a factor of twenty lower than
the corresponding rate constant in dichloromethane) and
1.7ꢂ10ꢀ5 sꢀ1 for complex 4 (ten times greater than the cor-
responding rate constant in dichloromethane). This suggests
that for complex 1, a smaller amount of the catalytically
Entry 7 of Table 1 confirms that mixing equimolar amounts
of catalysts 1 and 2 with opposite absolute configurations
Table 1. Use of catalysts 1, 2, 4 and 5 in the synthesis of mandelonitrile
trimethylsilyl ethera
Entry Catalystb
Conversion (%) Enantiomeric excess (%)
(absolute configuration)
1
2
3
(R,R)-1
(S,S)-2
4
100
82 (S)
91 (R)
0
100c
34 (80c)
4
5
6
7
8
9
10
11
5
86
45
56
62
79
68
100
20
0
(R,R)-1d
62 (S)
0
4d
(R,R)-1+(S,S)-2
(R,R)-1+(R,R)-2
4+(S,S)-2
(R,R)-1+5
(R,R)-1+4
72 (R)
90 (S)
79 (R)
18 (S)
34 (S)
OSiMe3
catalyst 1,2,4,5 (0.1 mol%)
room temperature, CH2Cl2
PhCHO + Me3SiCN
CN
Ph
Ac2O / Sc(OTf)3 (1 mol%) / MeCN
a
Unless otherwise stated, all reactions were conducted at room temperature
in dichloromethane for 24 h using 0.1 mol % of catalyst.
Whenever a mixture of two catalysts was used, the mixture was equimolar
in each metal ion.
After 48 h.
Reaction in chloroform.
OAc
CN
b
Ph
c
d
Scheme 2.

Y. N. Belokon et al. / Tetrahedron 63 (2007) 5287–5299
Complex 1 in CH2Cl2
10
5293
0
-0.5
-1
Complex 4 in CH2Cl2
0
2
4
6
8
12
14
-0.79
-0.795
-0.8
0
50
100
150
200
y= -0.1435x - 0.7721
R2 = 0.999
y = -0.0001x - 0.7898
R2 = 0.9880
-1.5
-2
-0.805
-0.81
-2.5
-3
-0.815
-0.82
time (minutes)
Complex 1 in CDCl
time (minutes)
3
-0.6
-0.65
-0.7
Complex 4 in CDCl3
100 150 200
0
5
10
15
20
25
30
-0.5
-0.55
-0.6
0
50
250
300
y = -0.001x - 0.5629
R2 = 0.9559
y = -0.0071x - 0.6509
R2 = 0.9798
-0.65
-0.7
-0.75
-0.8
-0.75
-0.8
-0.85
-0.9
-0.85
time (minutes)
Complexes 4 and SS-5 in CH2Cl2
10 20 30
time (minutes)
Complexes RR-1 and 5 in CH2Cl2
50 100
-0.8
-0.85
-0.9
-0.7
-0.8
-0.9
-1
0
150
0
40
y = -0.0185x - 0.7322
R2 = 0.9884
y = -0.0014x - 0.8069
R2 = 0.9813
-1.1
-1.2
-1.3
-1.4
-0.95
-1
-1.05
time (minutes)
time (minutes)
Figure 6. First order kinetics’ plots for the asymmetric addition of trimethylsilyl cyanide to benzaldehyde using various catalysts.
results in formation of a species in which the ligand attached
to the vanadium ion determines the absolute configuration of
the O-trimethylsilyl mandelonitrile formed, whilst mixing
catalysts 1 and 2 with the same configuration (entry 8)
also gives an active catalyst.22 Table 1, entries 9 and 10
then illustrate the effect of mixing an achiral salen complex
of one metal with the chiral salen complex of a different
metal. In both cases, the results are inconsistent with the
two metal complexes acting independently (entry 10 in par-
ticular would have given a product with a high enantiomeric
excess in favour of the (S)-enantiomer if this were the case),
but are entirely consistent with the in situ formation of a
heterobimetallic complex (Fig. 1A) as the catalytically
active species. Similarly, the measured first ordeꢀr 4rate
constants (Fig. 6) for these two reactions (3.1ꢂ10 sꢀ1
for a mixture of complexes 4 and (S,S)-2; and 2.3ꢂ10ꢀ5 sꢀ1
for a mixture of complexes (R,R)-1 and 5) were incompatible
with reactions involving just the more reactive species
present in the reaction mixture, as is the previously reported
rate data22 obtained using different ratios of (R,R)-1 and
(S,S)-2.
Assuming that the salen ligand closest to the newly forming
stereocentre has the largest influence on the enantioselectiv-
ity of the reaction, these two results also indicate that in the
transition state, the aldehyde is bound to the vanadium rather
than the titanium ion. When the salen ligand attached to the
vanadium ion is chiral and has (S)-configuration (Table 1,
entry 9), then a product with high enantiomeric excess and
(R)-configuration is formed similar to the situation when
only complex 2 is used as catalyst (compare entries 2 and
9). In contrast, when the salen ligand attached to the vana-
dium ion is achiral, an almost racemic product is formed,
with just a small enantiomeric excess in favour of the (S)-
enantiomer due to the remote influence of the chiral salen
ligand with (R)-configuration attached to the titanium ion.
If the new stereocentre in the product had been created
whilst the aldehyde was coordinated to titanium, a high

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Y. N. Belokon et al. / Tetrahedron 63 (2007) 5287–5299
Table 2. Use of catalysts 1, 2 and 4 in the synthesis of mandelonitrile ethyl
carbonate at room temperature
enantiomeric excess comparable to that obtained using cat-
alyst 1 alone would have been expected in this case (compare
entries 1 and 10).
Entry Catalysta
Conversion (%) Enantiomeric excess (%)
(absolute configuration)
Use of equimolar amounts of chiral 1 and achiral 4 titanium
catalysts (Table 1, entry 11) gave a very low conversion to a
product with an enantiomeric excess of just 34%. Again,
only the in situ formation of a bimetallic complex (Fig. 1A)
can explain this result. In the absence of such a complex, cat-
alytically active species derived from complex 1 would have
dominated the catalysis leading to the formation of (S)-man-
delonitrile trimethylsilyl ether in high yield and with high
enantiomeric excess. The low conversion observed is, how-
ever, consistent with the formation of a bimetallic complex
in which the achiral ligand preferentially adopts the L-con-
figuration, thus forming the thermodynamically preferred
anti-D(RR)L heterochiral complex with catalytic activity
comparable to that observed with complex 4. The moderate
value for the enantiomeric excess of the product is also con-
sistent with little or no preference for the aldehyde to bind to
either titanium ion in the transition state, leading to a product
with enantiomeric excess approximately mid-way between
that observed using complexes 1 and 4 individually (com-
pare entries 1, 3 and 11).
1
2
3
4
5
6
7
8
(R,R)-1
(S,S)-2
100
0
0
20
58
19
100
0
75 (S)
(R,R)-1+(S,S)-2
4
0
0
4c
(R,R)-1+4
(R,R)-1b
4+(S,S)-2
35 (S)
68 (S)
a
Whenever a mixture of two catalysts was used, the mixture was equimolar
in each metal ion, and a total of 5 mol % of catalyst relative to benzalde-
hyde was used.
2.5 mol % of catalyst relative to benzaldehyde was used.
Reaction in chloroform.
b
c
The achiral catalyst 4 is catalytically active for the synthesis
of mandelonitrile ethyl carbonate (Table 2, entry 4), though
with much reduced reactivity compared to complex 1, ex-
actly as observed for catalysis for the addition of trimethyl-
silyl cyanide to benzaldehyde. The achiral catalyst was,
however, significantly more active when used in chloroform
(entry 5), again consistent with more catalytically active spe-
cies being present in the more polar solvent as discussed
above for reactions involving trimethylsilyl cyanide. Use of
an equimolar mixture of complexes 1 and 4 (entry 6) gave
a conversion, which was comparable to that obtained by
complex 4 alone, and a product with enantiomeric excess
approximately half way between those obtained using com-
plexes 1 and 4 alone (compare entries 1, 4 and 6). That this
result could not be due to catalysis just by complex 1 was
confirmed by a control experiment using 2.5 mol % of com-
plex 1 (entry 7). This is the same amount of complex 1 that
was added to the mixed catalyst reaction (entry 6), but the
enantiomeric excess of the product was far higher in the lat-
ter case. The qualitative trend shown in entries 1, 4, 6 and 7
was confirmed by a study of the kinetics of these four reac-
tions (Fig. 7), though in this case the reactions could not
be fitted to a simple reaction order due to the co-catalysis
by cyanide ion liberated during the reaction.42
2.4. Catalysis of the asymmetric addition of ethyl
cyanoformate to benzaldehyde
Complex 1 will also catalyse the asymmetric addition of
ethyl cyanoformate to benzaldehyde,7 giving mandelonitrile
ethyl carbonate as shown in Scheme 3. Optimal enantio-
selectivity in this reaction is observed at ꢀ40 ꢁC, and under
these conditions, complex 2 is totally inactive as a catalyst
for this reaction. However, in this study we chose to work
at room temperature to increase the reaction rates observed
with various bimetallic complexes. Table 2 summarises the
key results obtained using various bimetallic complexes to
catalyse the reaction shown in Scheme 3.
O
catalyst 1 (5.0 mol%)
room temperature,
PhCHO + EtOCOCN
O
OEt
CN
CH2Cl2
Ph
Again, these results are not consistent with the model shown
in Figure 1B, but are entirely compatible with the formation
of a catalytically active bimetallic complex (Fig. 1A), and
Scheme 3.
Entry 1 of Table 2 confirms that catalyst 1 is active for this re-
action, though the enantioselectivity observed at room tem-
perature is about 20% lower than that obtained at ꢀ40 ꢁC.7
Entry 2 similarly confirms that even at room temperature,
complex 2 displays no catalytic activity for the synthesis of
mandelonitrile ethyl carbonate. The key result is shown in
entry 3, where combined use of complexes 1 and 2 resulted
in complete loss of all of the catalytic activity associated
with complex 1. This result cannot be explained by the two
metal(salen) complexes acting separately but cooperatively
(Fig. 1B), if this was the case then complex 1 would still be
present and able to catalyse the reaction. However, this result
can be explained by in situ formation of a heterobimetallic
complex (Fig. 1A), which in this case is catalytically inactive.
Essentially complete formation of the heterobimetallic
complex leaves no complex 1 available to catalyse the
reaction.
50%
40%
30%
20%
10%
0%
0
500
1000
1500
Time (min)
2000
2500
3000
Mixed catalyst (1+4)
Catalyst 4
Catalyst 1
Catalyst 1 (2.5 mol%)
Figure 7. Conversion/time plots for the asymmetric addition of ethyl cyano-
formate to benzaldehyde catalysed by complexes 1 and 4.

Y. N. Belokon et al. / Tetrahedron 63 (2007) 5287–5299
5295
with preferential formation of a heterochiral complex in
which the chiral salen ligand adopts the D-configuration,
whilst the achiral salen ligand adopts the L-configuration,
to give a bimetallic complex with low intrinsic catalytic ac-
tivity.34 Finally, combined use of achiral titanium complex 4
and chiral vanadium complex 2 resulted in formation of
a species, which was catalytically inactive (Table 2, entry
8), a result which is also consistent with formation of a
heterobimetallic complex.
the result obtained using trimethylsilyl cyanide and is
again totally inconsistent with a mechanism involving inter-
molecular cyanide transfer between monometallic species
(Fig. 1B) as that would have been predicted to produce
nearly racemic product in this case. This result is also incon-
sistent with sequestration of titanium ions by vanadium ions
through oligomer formation23 as this would leave an excess
of vanadium ions present to catalyse the reaction resulting in
preferential formation of (R)-mandelonitrile. The low con-
version observed in this case is, however, fully consistent
with the in situ formation of a heterobimetallic complex,
which in this case would be heterochiral (anti-TiD(RR)-
VL(SS)) and hence have low intrinsic catalytic activity as
discussed above.
2.5. Catalysis of the asymmetric addition of potassium
cyanide to benzaldehyde
A unique feature of catalysts 1 and 2 is their ability to cata-
lyse the asymmetric addition of potassium cyanide to alde-
hydes in the presence of an anhydride, thus providing a
one-pot synthesis of non-racemic cyanohydrin esters.8 This
reaction also requires the presence of both water and tert-bu-
tanol as additives with dichloromethane as solvent, and in
view of the different reaction conditions for this transforma-
tion, it was decided to investigate the efficacy of mixtures
of complexes 1, 2, 4 and 5 using benzaldehyde and acetic
anhydride as substrates (Scheme 4).
The achiral complexes 4 and 5 were found to be very poor
catalysts for this reaction (Table 3, entries 4 and 5), with
only a trace of product (<10%) being formed after an 18 h
reaction at ꢀ40 ꢁC. This is again consistent with both of
these species forming dimeric complexes in which the
DL-dimer is formed preferentially34 and is less catalytically
active than the homochiral dimers formed from complexes 1
and 2. Use of complexes 4 and 5 in chloroform rather than
dichloromethane gave significantly higher conversions (en-
tries 6 and 7), which is consistent with a greater proportion
of the catalytically active DD-dimer being present in the
more polar solvent, as suggested by 1H NMR spectroscopy
in the case of complex 4.
1,2,4, or 5 (1.0 mol%)
OAc
CN
-40 °C, CH2Cl2
/
H2O / tBuOH
Ph
PhCHO + KCN + Ac2O
Scheme 4.
When the almost inactive, achiral complexes were mixed
with catalysts 1 and 2, they were able to exert a marked in-
fluence on the asymmetric induction for reactions carried out
in dichloromethane (Table 3, entries 8–11). Thus, mixing
chiral titanium complex 1 with achiral vanadium complex
5, significantly reduced both the rate of reaction and the
enantioselectivity compared to the use of complex 1 alone.
However, the absolute configuration of the product was still
that expected based on the use of (R,R)-1 (entry 8). Similarly,
mixing chiral vanadium complex 2 with achiral titanium
complex 4 also significantly reduced the rate of reaction
and this time the reaction gave essentially racemic product
(entry 9). This clearly indicates that for the asymmetric syn-
thesis of cyanohydrin acetates, it is the stereochemistry of
the ligand attached to titanium that determines the absolute
configuration of the product. When the achiral and chiral
complexes of the same metal were mixed (entries 10 and
11), in both cases the enantiomeric excess of the mandelo-
nitrile acetate was lower than that obtained from use of just
the chiral catalyst 1 or 2 and the absolute configuration of the
product was also that expected based on the stereochemistry
of the chiral ligand. In view of the different reactivities of the
chiral and achiral complexes, these results are again not con-
sistent with the two catalysts acting independently, but are
what would be expected for a bimetallic catalyst of DL-
configuration formed in situ from one metal ion coordinated
to a chiral salen ligand and one metal ion coordinated to an
achiral salen ligand.
Key results of this reaction are shown in Table 3. As entries 1
and 2 illustrate, both catalysts 1 and 2 are active for this
transformation and as for all other reactions involving these
catalysts, the (R,R)-enantiomer of the catalyst leads to the
(S)-enantiomer of mandelonitrile acetate. However, unlike
the addition of trimethylsilyl cyanide to aldehydes, for this
reaction, catalysts 1 and 2 result in similar reaction rates
and give mandelonitrile acetate with 93–94% ee. Remark-
ably, when a mixture of catalysts (R,R)-1 and (S,S)-2 was
used for this reaction (entry 3), it was the stereochemistry
of the salen ligand attached to the titanium ion that deter-
mined the configuration of the product, (S)-mandelonitrile
acetate being obtained with 72% ee. This is the opposite of
Table 3. Use of catalysts 1, 2, 4 and 5 in the synthesis of mandelonitrile
acetate
Entry Catalysta
Conversion (%) Enantiomeric excess (%)
(absolute configuration)
1
2
3
4
5
6
7
8
(R,R)-1
(S,S)-2
(R,R)-1+(S,S)-2
4
100
70
24
<10
<10
27
47
23
93 (S)
94 (R)
72 (S)
0
0
0
5
4b
5b
0
(R,R)-1+5
4+(S,S)-2
(R,R)-1+4
(S,S)-2+5
44 (S)
1 (S)
73 (S)
46 (R)
9
10
11
21
73
40
To further investigate the influence of titanium and vana-
dium containing species in this reaction, a series of reactions
were carried out at different titanium to vanadium ratios, us-
ing complexes 1 and 2 as the metal ion sources. The results
of this study are shown graphically in Figure 8, which clearly
a
Whenever a mixture of two catalysts was used, the mixture was equimolar
in each metal ion, and a total of 1 mol % of catalyst relative to benzalde-
hyde was used.
b
Reaction carried out in chloroform.

5296
Y. N. Belokon et al. / Tetrahedron 63 (2007) 5287–5299
100
80
complexes can be predicted and correctly explains both
the rates of catalysis and the asymmetric induction. For reac-
tions involving the use of trimethylsilyl cyanide as the cyan-
ating agent, the results indicate that the aldehyde is bound
to the vanadium(V) ion during the asymmetry inducing tran-
sition state, whilst cyanide is coordinated to titanium. How-
ever, when potassium cyanide is used as the cyanide source,
the ionic cyanide coordinates to the positively charged vana-
dium(V) ion and the aldehyde is bound to the titanium ion.
In all cases, complexes in which the two salen ligands
have different configurations (D or L) are less catalytically
active than complexes in which the two ligands have the
same configuration.
60
40
20
0
-20
-40
-60
-80
-100
4. Experimental
0
20
40
60
80
100
% (S,S)-V(Salen) 2
4.1. General methods
Figure 8. Variation of the enantiomeric excess of mandelonitrile acetate as
the ratio of complexes (R,R)-1 and (S,S)-2 is varied. Dashed line is predicted
enantiomeric excess if the catalysts acted independently and with equal
rates, black points and solid curve are the experimentally observed results.
1H and 13C NMR spectra were run on a Bruker Avance
300 MHz or JEOL 500 MHz spectrometer in the specified
solvent. 13C NMR assignments were made using DEPTedit-
ing. Infrared spectra were recorded on a Perkin–Elmer FTIR
spectrometer. Only significant absorptions are listed. Low-
and high-resolution mass spectra were recorded by the
EPSRC national mass spectrometry service using LSIMS
with meta-nitrobenzyl alcohol (NOBA) as matrix or ESI ion-
isation techniques. Optical rotations were measured using a
Polaar 2001 Optical Activity automatic polarimeter and are
reported with a concentration value in g/100 mL. Melting
points were obtained using a Barnstead Electrothermal 9100
system. Gas chromatography was carried out using a Hewlett
Packard 5890 series II fitted with a thermal conductivity
detector and using hydrogen as the carrier gas.
indicates that for the potassium cyanide system, the stereo-
chemistry of the salen ligand attached to the titanium ion
is more important than the stereochemistry of the salen li-
gand attached to the vanadium ion in determining the abso-
lute configuration of the product. Thus, all catalyst mixtures
containing at least 30% of (R,R)-titanium complex 1 gave
predominantly the (S)-enantiomer of mandelonitrile acetate.
The potassium cyanide system is unique in that it employs
an ionic cyanide source and it may be that the negatively
charged cyanide ion is strongly attracted to the positively
charged vanadium(V) ion within a heterobimetallic com-
plex. This would then force the aldehyde to coordinate to
the titanium ion. In contrast, for the addition of trimethylsilyl
cyanide to aldehydes discussed above, the most polarised
bond present is the aldehyde carbonyl and this will be most
attracted to the positively charged vanadium(V) ion, thus ac-
counting for the difference in binding regiochemistry and
hence the difference in asymmetric induction observed when
the two cyanide sources are used with a heterobimetallic
catalyst.
4.2. Synthesis of the titanium dichloride complex
of ligand 3
N,N-Bis-(3,5-di-tert-butyl-2-hydroxybenzylidene)-1,2-di-
aminoethane24 (2.0 g, 4.06 mmol) was dissolved in dichloro-
methane (50 mL) and a solution of titanium tetrachloride
(2.0 M in dichloromethane, 4 mL, 1.1 equiv) was added.
The solution was stirred at room temperature for 30 min,
then transferred to a separating funnel and washed with
water (200 mL) and brine (100 mL). The organic layer was
dried (Na2SO4) and evaporated in vacuo to leave the title
compound (2.47 g, 100%) as a red/brown powder. Mp
>370 ꢁC (decomp.); nmax (CHCl3): 3429 (br), 3019 (s), 2966
(s), 2871 (s), 1621 (s) and 1561 cmꢀ1 (s); dH (300 MHz,
CDCl3): 8.26 (2H, s, CH]N), 7.54 (2H, s, ArH), 7.24
(2H, s, ArH), 4.12 (4H, s, NCH2CH2N), 1.45 (18H, s,
2ꢂC(CH3)3), 1.25 (18H, s, 2ꢂC(CH3)3); dC (75 MHz,
CDCl3): 164.7, 161.0, 145.0, 137.5, 131.7, 129.8, 125.8,
58.8, 35.9, 34.8, 31.7, 30.3; m/z (LSIMS): 690 (M+NO-
BAꢀClꢀHCl)+, 573 (MꢀCl)+, 539; Found (LSIMS,
NOBA): 690.3380 and 573.2725; C39H52N3O548Ti (M+NO-
BAꢀClꢀHCl) requires 690.3381 and C32H46ClN2O248Ti
(MꢀCl)+ requires: 573.2722.
3. Conclusions
The stereochemistry of salen ligands present in bimetallic
complexes has been analysed in detail and used to derive
a set of rules, which allow the stereochemistry of (salen)-
M(m-O)2M0(salen0) complexes to be predicted. The X-ray
crystal structure of a bimetallic titanium complex containing
the achiral salen ligand derived from N,N-bis-(3,5-di-tert-
butyl-2-hydroxybenzylidene)-1,2-diaminoethane has been
determined and the stereochemistry of the complex was as
expected on the basis of the rules.
When homometallic(salen) complexes derived from tita-
nium(IV) and vanadium(V) are mixed and used as catalysts
for asymmetric cyanohydrin synthesis, the results can only
be explained by the in situ formation of heterobimetallic
complexes. The stereochemistry of these heterobimetallic
4.3. Synthesis of complex 4
The titanium dichloride complex of ligand 3 (1.0 g,
1.5 mmol) was dissolved in dichloromethane (500 mL).

Y. N. Belokon et al. / Tetrahedron 63 (2007) 5287–5299
5297
Aqueous sodium phosphate buffer solution of pH 7
(100 mL) was added and the mixture stirred vigorously at
room temperature for 1 h, after which time the aqueous layer
was removed and replaced by a fresh portion (100 mL) of the
buffer. The reaction mixture was stirred for a further 1 h, the
aqueous layer was again removed and replaced by a final
portion (30 mL) of the buffer. The reaction mixture was
stirred for a further 30 min, and was then washed with water
(2ꢂ150 mL) and brine (100 mL). The organic phase was
dried (Na2SO4) and evaporated in vacuo. The solid residue
was washed with ether (3ꢂ5 mL) to leave compound 4
(0.81 g, 97%) as a yellow powder. Mp >280 ꢁC (decomp.);
nmax (CHCl3): 3430 (br), 3019 (s), 2963 (s), 2906 (s), 2869
(s), 1628 (s) and 1556 cmꢀ1 (s); dH (300 MHz, C6D6):
7.75 (4H, d J 2.5 Hz, ArH), 7.61 (4H, s, CH]N), 7.02
(4H, d, J 2.5 Hz, ArH), 4.25–4.23 (4H, m, NCH2CH2N),
2.92–2.90 (4H, m, NCH2CH2N), 1.84 (36H, s, 4ꢂC(CH3)3),
1.43 (36H, s, 4ꢂC(CH3)3); dC (125 MHz, C6D6): 164.88,
162.38, 138.61, 138.36, 128.91, 127.37, 122.47, 65.86,
35.87, 34.08, 31.64, 30.66; m/z (ESI, MeOH): 1123.7
(M+Me)+, 1109.7 (MH+), 569.4 (M+2Me)2+; Found (ESI,
MeOH): 1123.6196 and 1109.6061; C65H95N4O648Ti2
(M+Me)+ requires 1123.6205 and C64H93N4O648Ti2 (MH+)
requires 1109.6049.
CH2Cl2): 557.2937; C32H46N2O351V (MꢀClꢀH2O)+ re-
quires 557.2943.
4.5. General procedure for the asymmetric synthesis
of O-trimethylsilyl mandelonitrile
Catalyst (0.1 mol %) was dissolved in dichloromethane
(5 mL). Benzaldehyde (0.1 mL, 0.94 mmol) was added fol-
lowed by trimethylsilyl cyanide (0.15 mL, 1.1 equiv). The
resulting solution was allowed to stir at room temperature
for 24 h and then filtered through a silica filled pipette, elut-
ing with dichloromethane. The solvent was evaporated in
vacuo to leave the title compound as a pale yellow oil. The
1
percentage conversion was determined by H NMR spec-
troscopy by integration of the aldehyde signal of unreacted
benzaldehyde and the CHCN signal of the product. To deter-
mine the enantiomeric excess, a sample of the product (0.1 g,
0.53 mmol) was dissolved in acetonitrile (5 mL) and scan-
dium(III) triflate (2.6 mg, 0.01 equiv) was added followed
by acetic anhydride (108 mg, 2.0 equiv). The reaction mix-
ture was allowed to stir at room temperature for 30 min be-
fore being filtered through a silica filled pipette, eluting with
acetonitrile. The solvent was evaporated in vacuo to leave O-
acetyl mandelonitrile as a colourless oil. The enantiomeric
excess could then be determined by chiral GC using a g-
CD butyryl fused silica capillary column (30 mꢂ0.25 mm)
with hydrogen (1.6 mL/min) as the carrier gas. With an ini-
tial temperature of 100 ꢁC for 2 min, followed by a ramp rate
of 5 ꢁC/min to a final temperature of 180 ꢁC, O-acetyl (R)-
mandelonitrile has a retention time of 15.7 min and O-acetyl
(S)-mandelonitrile has a retention time of 15.9 min.
4.4. Synthesis of complex 5
4.4.1. Synthesis of the V(IV) complex of ligand 3. Vanadyl
sulfate hydrate (0.65 g, 4.0 mmol) was dissolved in warm
ethanol (70 mL). The resulting solution was added to a solu-
tion of N,N-bis-(3,5-di-tert-butyl-2-hydroxybenzylidene)-
1,2-diaminoethane24 (1.8 g, 3.65 mmol) in ethanol (50 mL)
and the reaction was heated to reflux under an inert atmo-
sphere for 3 h. The solvent was removed in vacuo and
the residue was purified by flash chromatography (eluting
with dichloromethane) to give the vanadium(IV) complex
(1.3 g, 64%) as a paramagnetic green solid.25 Mp 184–
188 ꢁC; nmax (CHCl3): 3019 (s), 2975 (w), 1619 (w) and
1523 cmꢀ1 (w).
4.6. Kinetics of the addition of trimethylsilyl cyanide
to benzaldehyde
To a dry sealed round-bottomed flask fitted with a stirrer was
added a solution of the appropriate catalyst (0.00196 mmol)
in dry CH2Cl2 or CHCl3 (1.75 mL). The solution was cooled
to 0 ꢁC and an aliquot (0.7 mL) was taken and diluted
with dry CH2Cl2 (3.0 mL). The absorbance of the diluted
sample was measured at 240–260 nm, this reading being
used for baseline calibration. Freshly distilled benzaldehyde
(0.1 mL, 1.0 mmol) was added to the reaction mixture,
which was stirred for 10 min and the first aliquot (t¼0)
was taken as described above. Then, trimethylsilyl cyanide
(0.15 mL, 1.1 mmol) was added and aliquots were taken at
intervals 1, 2, 3, 4, 5, 7.5, 10, 15, 22 and 33 min. The absor-
bance data were used to construct a first order kinetics plot.
4.4.2. Oxidation of V(IV) to V(V) complex 5. Cumene
hydroperoxide (1.02 mL, 10 equiv) was added to a solution
of the vanadium(IV) complex of ligand 3 (0.39 g, 0.7 mmol)
in dichloromethane (50 mL) and the reaction mixture was
stirred at room temperature for 18 h. The dichloromethane
was evaporated in vacuo and the residue dissolved in aceto-
nitrile (20 mL) and treated with aqueous hydrochloric acid
(2 M, 40 mL). The resulting dark green solution was diluted
with water (100 mL) and extracted with dichloromethane
(200 mL). The organic phase was washed with water
(100 mL) and brine (100 mL), dried over Na2SO4 and passed
through a plug of silica gel, (4 cm deep by 3 cm diameter)
eluting with hexane (100 mL), ethyl acetate (100 mL) and fi-
nally methanol (200 mL). The methanol fraction was evap-
orated in vacuo, giving complex 5 (0.11 g, 28%) as a dark
green powder. Mp 277–285 ꢁC; nmax (CHCl3): 3400 (br),
3019 (s), 2966 (s), 1621 (s) and 1547 cmꢀ1; dH (300 MHz
CDCl3): 8.66 (2H, s, CH]N), 7.66 (2H, s, ArH), 7.42
(2H, s, ArH), 4.54 (2H, br s, NCH2CH2N), 4.23 (2H, br s,
NCH2CH2N), 1.45 (18H, s, 2ꢂC(CH3)3), 1.29 (18H, s,
2ꢂC(CH3)3); dC (75 MHz, CDCl3): 165.1, 163.8, 144.5,
136.4, 132.5, 128.7, 121.5, 61.0, 36.0, 34.8, 31.7, 30.3; m/z
(ESI, CH2Cl2): 557 (MꢀClꢀH2O)+, 279, 207; Found (ESI,
4.7. General procedure for the asymmetric synthesis
of mandelonitrile ethyl carbonate
To a solution of catalyst (5 mol %) in dichloromethane
(3 mL) were added benzaldehyde (0.05 mL, 0.47 mmol)
and ethyl cyanoformate (0.1 mL, 0.94 mmol). The reaction
mixture was stirred at room temperature for 16 h, then the
solution was passed through a Pasteur pipette containing sil-
ica, eluting with dichloromethane (ca. 3 mL). The eluent
was evaporated in vacuo and the residue analysed without
further purification. The percentage conversion was deter-
mined by 1H NMR spectroscopy by integration of the alde-
hyde signal of unreacted benzaldehyde and the CHCN signal
of the product. The enantiomeric excess of the product was

5298
Y. N. Belokon et al. / Tetrahedron 63 (2007) 5287–5299
determined by chiral GC using a g-CD butyryl fused
silica capillary column (30 mꢂ0.25 mm) with hydrogen
(1.6 mL/min) as the carrier gas. With an initial temperature
of 100 ꢁC for 2 min, followed by a ramp rate of 0.2 ꢁC/min to
a final temperature of 130 ꢁC, (R)-mandelonitrile ethyl car-
bonate has a retention time of 120 min and (S)-mandelo-
nitrile ethyl carbonate has a retention time of 123 min.
Acknowledgements
The authors thank the EPSRC for funding through a DTA
studentship (to C.Y.) and partial postdoctoral funding for
R.W.H., and the EPSRC national mass spectrometry service
at the University of Wales, Swansea for low- and high-
resolution mass spectra. Use of the EPSRC’s Chemical Data-
base Service at Daresbury is also gratefully acknowledged.
4.8. Kinetics of the addition of ethyl cyanoformate
to benzaldehyde
References and notes
Toastirringsolutionofcatalyst(5 mol %)indichloromethane
(6 mL) was added ethyl cyanoformate (0.18 mL, 1.96 mmol)
followed by benzaldehyde (0.1 mL, 0.98 mmol). At selected
time intervals, a sample of the reaction mixture (0.5 mL)
was removed and filtered through a silica column (ca. 6 cm)
eluting with further dichloromethane (ca. 5 mL). The result-
ing colourless eluent was evaporated in vacuo and then ana-
lysed by H NMR spectroscopy using the aldehyde signal
(10 ppm) and cyanohydrin ethyl carbonate signal (6.2 ppm)
to calculate the percentage conversion.
1. For recent reviews of the synthesis and applications of chiral
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2003, 14, 147–176; (b) Brunel, J.-M.; Holmes, I. P. Angew.
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1
ꢀ ꢀ
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ꢀ
Chem. 2006, 1949–1958; (c) Baeza, A.; Casas, J.; Najera, C.;
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4.9. General procedure for the asymmetric synthesis
of mandelonitrile acetate
A sample of catalyst (1 mol %) was dissolved in dichloro-
methane (10 mL) and cooled to ꢀ78 ꢁC. Potassium cyanide
(0.245 g, 3.6 mmol), tert-butanol (0.135 mL) and water
(0.01 mL) were added and the reaction was transferred
to a cryostatically cooled bath at ꢀ40 ꢁC. Benzaldehyde
(0.1 mL, 0.94 mmol) and acetic anhydride (0.356 mL,
3.6 mmol) were added and the resulting mixture stirred
vigorously at ꢀ40 ꢁC overnight. The resulting mixture was
filtered through a silica filled pipette washing with fur-
ther dichloromethane (5 mL), evaporated in vacuo and the
residue analysed without further purification. The percent-
ꢀ
Asymmetry 2006, 17, 1089–1103; (h) Rodrıguez, B.; Pasto,
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ꢁ
2006, 17, 151–160; (i) Li, Q.; Liu, X.; Wang, J.; Shen, K.;
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S. S.; Kwak, J. M. Tetrahedron 2006, 62, 49–53.
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1
age conversion was determined by H NMR spectroscopy
by integration of the aldehyde signal of unreacted benzalde-
hyde and the CHCN signal of the product. The enantiomeric
excess of the product was determined by chiral GC as dis-
cussed above for the product of trimethylsilyl cyanide
addition to benzaldehyde.
4.10. X-ray crystallography
Crystal data for 4: C64H92O6N4Ti2$2CH2Cl2, M¼1279.1,
monoclinic, space group P21/c, a¼13.124(2), b¼22.928(4),
3
ꢁ
˚
˚
c¼11.6837(18) A, b¼92.838(2) , V¼3511.3(9) A , Z¼2
(crystallographically centrosymmetric dimers), T¼150 K,
m(Mo Ka, l¼0.71073 A)¼0.43 mmꢀ1. Measured data:
˚
25,105 (Bruker SMART diffractometer, q<25ꢁ, corrected
semi-empirically for absorption), 6184 unique (Rint¼0.031),
383 refined parameters, R (F, F2>2s)¼0.045, Rw (F2, all
data)¼0.115, goodness-of-fit¼1.12, final difference map
features within ꢃ0.70 eAꢀ3. H atoms were constrained.
˚
Standard software (Bruker SMART, SAINT, SADABS and
SHELXTL) and procedures were used. CCDC-612829 con-
tains supplementary crystallographic data of this paper.
These data can be obtained free of charge via www.ccdc.
cam.ac.uk/conts/retrieving.html (or from the Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge
CB2 1EZ, UK; fax: +44 1223 336 033; or deposit@ccdc.
cam.ac.uk).

Y. N. Belokon et al. / Tetrahedron 63 (2007) 5287–5299
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