Optimized catalysts for the asymmetric addition of trimethylsilyl cyanide to aldehydes and ketones

Article abstract of DOI:10.1016/S0040-4020(00)01053-X

A bimetallic titanium(IV)salen complex has been developed as an exceptionally active catalyst for the asymmetric addition of trimethylsilyl cyanide to ketones. For the corresponding addition to aldehydes, a vanadium(IV)salen complex was found to give high

Full text of DOI:10.1016/S0040-4020(00)01053-X

TETRAHEDRON
Pergamon
Tetrahedron 57 (2001) 771±779
Optimized catalysts for the asymmetric addition of trimethylsilyl
cyanide to aldehydes and ketones
Yuri N. Belokon',b Brendan Green,c Nicolai S. Ikonnikov,b Michael North,a,p Teresa Parsonsa and
Vitali I. Tararovb
aDepartment of Chemistry, King's College, Strand, London WC2R 2LS, UK
bA.N. Nesmeyanov Institute of Organo-Element Compounds, Russian Academy of Sciences, 117813 Vavilov 28, Moscow, Russia
cDepartment of Chemistry, University of Wales, Bangor, Gwynedd LL57 2UW, UK
Received 31 July 2000; revised 16 October 2000; accepted 2 November 2000
AbstractÐA bimetallic titanium(IV)salen complex has been developed as an exceptionally active catalyst for the asymmetric addition of
trimethylsilyl cyanide to ketones. For the corresponding addition to aldehydes, a vanadium(IV)salen complex was found to give higher levels
of asymmetric induction. In both cases, additional evidence in support of the proposed catalytic cycle is presented. q 2001 Elsevier Science
Ltd. All rights reserved.
1. Introduction
Cyanohydrins are versatile synthetic intermediates which
can readily be converted into a wide range of other bi-
functional compounds including a-amino acids and
Scheme 1.
1,2-diamines.1 In view of their synthetic potential, there has
been considerable interest in recent years in the development
of catalysts for the asymmetric addition of cyanide sources
(usually trimethylsilyl cyanide) to prochiral aldehydes, lead-
ing to chiral, non-racemic cyanohydrin derivatives2 (Scheme
1). Various catalysts have been developed including:
enzymes, peptide derivatives, and transition metal
complexes.3 In contrast, there have been very few reports
of the asymmetric addition of cyanide to prochiral ketones.4
Over recent years we have developed catalysts derived from
salen ligands as catalysts for the asymmetric addition of
trimethylsilyl cyanide to carbonyl compounds.5 Our cata-
lysts are active at room temperature and at high substrate
to catalyst ratios. This work has culminated in the develop-
ment of bimetallic titanium(IV)salen complex 1 as the
optimal catalyst for the asymmetric addition of trimethyl-
silyl cyanide to ketones,6 and vanadium(IV)salen complex 2
as the optimal catalyst for the asymmetric addition of
trimethylsilyl cyanide to aldehydes.7 We have also studied
the mechanisms of these reactions, and have proposed a
catalytic cycle (Scheme 2) and transition state geometry
(Fig. 1) which both explains the high activity of the catalysts
(simultaneous activation of both the carbonyl compound
Keywords: cyanohydrins; asymmetric synthesis; catalysis; transition
metals.
p
Corresponding author. Tel.: 120-7848-1164; fax: 1870-131-3783;
e-mail: michael.north@kcl.ac.uk
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)01053-X

772
Y. N. Belokon' et al. / Tetrahedron 57 (2001) 771±779
and the trimethylsilyl cyanide) and correctly predicts the
absolute con®guration of the cyanohydrin silyl ethers
produced during the reaction.8 In this manuscript, we give
full details of this work, and provide further evidence in
support of the mechanism shown in Scheme 2 being appro-
priate for both titanium- and vanadium-derived catalysts.
2. Synthetic studies on the addition of trimethylsilyl
cyanide to ketones using catalyst 1
Both steric and electronic effects make the addition of
nucleophiles to ketones more dif®cult than the correspond-
ing addition to aldehydes. This is particularly noticeable
where the addition is reversible, since the reaction equi-
librium may favour the starting materials. As a result of
these factors, there are only scattered reports of the asym-
metric catalysis of the addition of cyanide to ketones.
Oxynitrilase enzymes will accept a limited range of ketones
as substrates (with hydrogen cyanide as the cyanide source),
but give chemical yields .15% only for methyl and ethyl
ketones.9 The only previous report of a transition metal
catalyst for this reaction4 employed a titanium triolate and
was only active at high pressures (0.8 GPa). In view of the
unprecedented activity of titanium(IV)salen complex 1 in
Figure 1. Proposed transition state geometry for asymmetric cyanohydrin
synthesis catalyst 1.
the asymmetric addition of trimethylsilyl cyanide to alde-
hydes,5 we decided to investigate whether it could also be
used to catalyse the asymmetric addition of trimethylsilyl
cyanide to ketones at atmospheric pressure.6
Acetophenone was chosen as the test substrate since the
speci®c rotation of the corresponding cyanohydrin had
been correlated with its absolute con®guration.9 As can be
seen from the data in Table 1, using 0.1 mol% of catalyst 1
Scheme 2.

Y. N. Belokon' et al. / Tetrahedron 57 (2001) 771±779
773
Table 1. Addition of trimethylsilyl cyanide to ketones (ArCOR)
in each case the enantiomeric excess under optimal con-
ditions was between 56 and 72%.
Ar
R
1 (mol%)
Time
Yield (%)
ee1 (%)
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Me
Me
Me
Et
0.1
0.5
1.0
0.1
0.5
1.0
0.5
0.5
0.1
0.5
0.1
0.5
0.1
0.5
0.1
0.5
0.1
0.5
1 day
1 day
1 day
2 weeks
4 days
4 days
no reaction
no reaction
4 days
1 day
4 days
2 days
4 days
1 day
4 days
1 day
38
100
100
41
64
100
70
66
62
32
32
30
3. Mechanistic implications of the addition of
trimethylsilyl cyanide to ketones using catalyst 1
Et
Et
We have previously suggested that the transition state for
asymmetric cyanohydrin synthesis using catalyst 1 is as
shown in Fig. 1. In this transition state, the aldehyde is
coordinated to one of the titanium ions and is oriented so
that the small hydrogen atom is located near to the cyclo-
hexanediamine unit. The larger substituent on the aldehyde
is located well away from the backbone of the salen ligand.
Cyanide is then delivered intramolecularly to the re-face of
the coordinated aldehyde, resulting in the formation of the
(S)-enantiomer of the product. The results obtained using
ketone substrates are entirely consistent with this transition
state. Thus, the only substrates are those which on one side
of the carbonyl bond contain a small (methyl or ethyl)
substituent which can be located close to the cyclohexane-
diamine unit in the transition state. Ketones with larger
substituents are not able to ®t into the active site of the
catalyst and hence are not processed as substrates. The
sense of asymmetric induction is also the same for aceto-
phenone as for aldehydes, again consistent with a common
mechanism and transition state.
iPr
tBu
Me
Me
4-MeC6H4
4-MeC6H4
100
100
27
100
82
100
54
100
78
52
66
64
72
54
56
54
60
60
56
2-MeOC6H4 Me
2-MeOC6H4 Me
3-MeOC6H4 Me
3-MeOC6H4 Me
4-MeOC6H4 Me
4-MeOC6H4 Me
4-F3CC6H4
4-F3CC6H4
Me
Me
4 days
1 day
100
1 Determined by chiral gas chromatography of the cyanohydrin trimethyl-
silyl ethers. Chiral gas chromatography was carried out on a DP-TFA-g-
cyclodextrin, fused silica capillary column (32 m£0.2 mm) using helium
as the carrier gas (¯ow rate 1.6 ml/min). In all cases, the injector tempera-
ture was 2308C and an isothermal column temperature of between 105
and 1308C was used.
at room temperature and atmospheric pressure, a moderate
yield of the corresponding cyanohydrin trimethylsilyl ether
could be obtained in 24 h. For comparison, under identical
conditions, both aromatic and aliphatic aldehydes are
converted into the corresponding cyanohydrin trimethylsilyl
ethers in less than 5 min.
To further study the mechanism of the reaction using
ketones as substrates, a kinetics study of the reaction
using acetophenone as substrate was undertaken. We have
previously shown8 that when benzaldehyde is used as the
substrate, asymmetric cyanohydrin synthesis employing
catalyst 1 shows ®rst order kinetics described by the rate
equation: rateˆkobs[Me3SiCN] where kobsˆ631[1]1.3. The
kinetics study using acetophenone was carried out by moni-
toring the disappearance of the acetophenone chromophore,
and just as in the case of benzaldehyde, the reactions were
found to be described by ®rst order kinetics, showing a zero
order dependence on the concentration of acetophenone and
a ®rst order dependence on the concentration of trimethyl-
silyl cyanide. This is shown by the ®rst order kinetics
plots (ln[Me3SiCN]tˆln[Me3SiCN]02kobst) in Fig. 2. Each
of the lines in Fig. 2 were obtained at a different catalyst
concentration, and have a gradient of 2k[1]a where k is the
The enantiomeric excess of the cyanohydrin trimethylsilyl
ether could be determined by chiral gas-chromatography
using a g-cyclodextrin capillary column and was found to
be 70%; higher than that previously reported for the tita-
nium triolate system under high pressure.4 By increasing the
amount of catalyst to 0.5 or 1.0 mol%, it was possible to
optimize the reaction to give a quantitative conversion of
acetophenone, though at the expense of a slightly reduced
enantioselectivity. The cyanohydrin trimethylsilyl ether was
determined to have the (S)-con®guration (using the (R,R)-
enantiomer of catalyst 1) by hydrolysis to the known cyano-
hydrin,9 which corresponds to the same sense of asymmetric
induction observed for aldehyde substrates.5
The structure of the ketone was then modi®ed to investigate
the effect that this would have on the reaction. Variation of
the alkyl substituent from methyl to ethyl, isopropyl, or tert-
butyl was generally detrimental. Propiophenone was a
substrate for the catalyst (Table 1), though the reaction
was very slow and gave the corresponding cyanohydrin
with only a very low enantiomeric excess. Substrates with
larger alkyl groups were totally unreactive as were the
aliphatic ketones 2-butanone and 3,3-dimethyl-2-butanone.
Variation of the aromatic part of the ketone substrate was
more successful. It proved possible to introduce substituents
onto any position of the aromatic ring and to employ both
electron rich and electron de®cient ketones (Table 1). In
general, 0.5 mol% of catalyst 1 proved to be optimal for
quantitative conversion of these ketones into the corre-
sponding cyanohydrin trimethylsilyl ethers. There is no
apparent trend in the enantioselectivities of these reactions,
Figure 2. First order kinetics plots obtained for acetophenone at various
concentrations of catalyst 1.

774
Y. N. Belokon' et al. / Tetrahedron 57 (2001) 771±779
The second implication is that the equilibrium between the
mononuclear and dinuclear species lies more on the side of
the dinuclear species for reactions involving acetophenone
than for reactions involving benzaldehyde. This arises since
a kinetics analysis shows8 that the order with respect to the
catalyst increases as the equilibrium concentration of the
mononuclear species increases. It seems reasonable that
species 3b should have a lower equilibrium concentration
than 3a on steric grounds since acetals derived from ketones
are generally less stable than those derived from aldehydes.
Thus, all aspects of the asymmetric addition of trimethyl-
silyl cyanide to ketones catalysed by binuclear complex 1
are fully consistent with the catalytic cycle shown in
Scheme 2 and the transition state geometry shown in Fig. 1.
Figure 3. Plot of log(kobs) against log([1]) for reactions carried out using
acetophenone as substrate.
4. Synthetic studies on the addition of trimethylsilyl
cyanide to aldehydes using catalyst 2
rate constant for the reaction and a is the order with respect
to catalyst 1. Hence, log(2gradient)ˆlog(k)1a.log([1]), so
from a plot of log(2gradient) against log([1]), both a and k
can be obtained. As can be seen from Fig. 3, a straight line is
indeed obtained, and the gradient of this line (1.1) corre-
sponds to the order with respect to catalyst 1, and the
intercept on the y-axis (21.88) gives the rate constant as
0.013. Thus, reactions using acetophenone as substrate obey
the rate equation: rateˆ0.013[1]1.1[Me3SiCN].
Catalyst 1 is a highly active catalyst for the asymmetric
addition of trimethylsilyl cyanide to both aldehydes5 and
ketones.6 However, the enantiomeric excesses of the cyano-
hydrins derived from aldehydes do not exceed 90%,
suggesting scope for further improvement in the catalyst.
Our previous studies have optimized the structure of the
salen ligand in catalyst 1 on a trial and error basis.5
However, recently we have developed the mechanistic
understanding of the reaction shown in Scheme 2.8 Given
this appreciation of both the catalytic cycle and origin of
asymmetric induction, we set about rationally designing a
new catalyst which would give higher levels of asymmetric
induction.
The rate equation for acetophenone differs from that for
benzaldehyde in two ways. Firstly, the rate constant is
much lower (0.013 as opposed to 631). This is consistent
with the much lower reactivity of acetophenone compared
with benzaldehyde, since the reactions take days rather than
just a few minutes to reach completion. Secondly, the order
with respect to the catalyst is lower for acetophenone (1.1)
than for benzaldehyde (1.3). This parameter (which for a
bimetallic catalyst must be between 1 and 2) is determined
by the equilibrium between catalytically inactive mono-
nuclear species and catalytically active dinuclear species
in the reaction mixture.8 A lower order for acetophenone
than for benzaldehyde has two implications. Firstly, it
implies that the aldehyde or ketone does react with
compound 1 prior to the rate determining step of the cata-
lytic cycle (otherwise the order would be the same for both
substrates). However, this reaction cannot be part of the
catalytic cycle since the concentration of the carbonyl
compound would then appear in the rate equation. This is
entirely consistent with the mechanism shown in Scheme 2,
where only the three bimetallic species shown in the square
box are actually involved in the catalytic cycle. However,
the formation of these species from complex 1 involves the
intermediate formation of metalloacetal complex 3a,b,
which does involve the carbonyl compound.
The key feature of the mechanism shown in Scheme 2 is that
the catalytically active species are bimetallic complexes
which are in equilibrium with catalytically inactive mono-
nuclear complexes. Reactions carried out using 0.1 mol% of
catalyst 1 at room temperature are very rapid, complete
conversion of an aldehyde to the corresponding cyanohydrin
trimethylsilyl ether being observed in about 5 min. This
suggested that catalyst 1 is too reactive, and that a modi®ed
catalyst with lower reactivity should be more selective. One
way of reducing the activity of the catalyst would be to alter
the equilibrium between the bimetallic and monometallic
complexes in favour of the latter. Hence, it appeared that
if the titanium ions in complex 1 could be changed to
another metal ion which is capable of forming salen
complexes but which has a greater propensity for the for-
mation of mononuclear species, then a less reactive and
more selective catalyst may be generated. A survey of the
Cambridge crystal structure database revealed that whilst in
the solid state, oxo-titanium(IV)salen complexes are always
di- or polynuclear,5,10,11 this is not the case for oxo-vanadium-
(IV)salen complexes. There are numerous examples of
crystal structures of mononuclear oxo-vanadium(IV)salen
complexes,12±14 and also examples of polynuclear com-
plexes.13±15 One particularly intriguing example showed
that it was possible to isomerize a (salen)VˆO complex in
the solid state from monomeric to polymeric by heating or
treatment with acetonitrile vapour, whilst the reverse trans-
formation could be accomplished by grinding the polymeric
crystals or treating them with chloroform vapour.13 Another
example14 had a disordered solid state structure in which

Y. N. Belokon' et al. / Tetrahedron 57 (2001) 771±779
775
Scheme 3.
80% of the molecules were mononuclear and 20% were
polymeric. In view of this solid state precedent, it seemed
reasonable that mononuclear oxo-vanadium(IV)salen
complexes may also be more stable in solution than the
corresponding titanium species and hence give rise to a
less reactive and more selective catalyst. Thus we decided
to investigate the use of oxo-vanadium(IV)salen complexes
as catalysts for the asymmetric addition of trimethylsilyl
cyanide to aldehydes.
electron-rich aromatic aldehydes, catalyst 2 consistently
gives products with enantiomeric excesses of 90% or higher.
Electron de®cient aromatic aldehydes and aliphatic alde-
hydes give lower enantioselectivities, but still higher than
those obtained using catalyst 1. In all cases, both catalysts
predominantly gave the (S)-enantiomer of the cyanohydrin
derivative. Other than the difference in enantioselectivities,
the main difference between the two catalysts is the time
required to achieve quantitative conversion: ,5 min for
catalyst 1, but 18 h for catalyst 2. An attempt to use complex
2 to catalyse the asymmetric addition of trimethylsilyl
cyanide to acetophenone was less successful, after 7 days
of reaction, only a 16% conversion was observed and the
enantiomeric excess of the product was only 22%. Thus it
appears that our goal of achieving a more selective catalyst
by reducing its reactivity has been achieved.
Catalyst 2 was prepared by reaction of the corresponding
salen ligand with vanadyl sulphate (Scheme 3) and was
obtained as a green solid. The di-tert-butyl salen ligand
was chosen to allow a direct comparison between catalysts
1 and 2, and the green colour of complex 2 suggests that it
has a mononuclear structure in the solid state13,16 as poly-
nuclear vanadium(IV)salen complexes tend to be orange.
Complex 2 was tested as a catalyst for the asymmetric addi-
tion of trimethylsilyl cyanide to a range of aldehydes under
identical conditions to those previously employed5 for cata-
lyst 1 (0.1 mol% of catalyst, room temperature, dichloro-
methane), and the results are compared in Table 2. In each
case, the reactions gave quantitative conversions of the
aldehyde to the corresponding cyanohydrin trimethylsilyl
ethers, and the ee's of the products were determined by
chiral gas chromatography as previously described.5
5. Mechanistic aspects of the addition of trimethylsilyl
cyanide to aldehydes using catalyst 2
To verify the reason for the increased enantioselectivity of
catalyst 2 and to obtain further mechanistic information on
the reaction, a kinetics study was undertaken using catalyst
2 and benzaldehyde. The kinetics of the reaction could be
monitored by observing the decrease in the benzaldehyde
absorption as previously described8 for kinetics studies
involving catalyst 1. The reactions were again found to
obey ®rst order kinetics, with a ®rst order dependence on
the trimethylsilyl cyanide concentration and a zero order
dependence on the benzaldehyde concentration (Fig. 4).
The order with respect to the catalyst was found to be
1.45 and the rate constant was 76 (Fig. 5).
Comparison of the enantioselectivities obtained using cata-
lysts 1 and 2 clearly shows that the goal of increasing the
enantioselectivity of the catalyst had been achieved since
the enantioselectivities observed using catalyst 2 were
always higher than those obtained using catalyst 1. For
Table 2. Addition of trimethylsilyl cyanide to aldehydes catalysed by
complexes 1 and 2
Compared with the corresponding reaction catalysed by
complex 1,8 the rate constant for the reaction using catalyst
2 is almost a factor of ten lower (76 versus 634), consistent
with the much slower reactions observed using catalyst 2.
The order of reaction with respect to the catalyst is also
higher for catalyst 2 (1.45) than for catalyst 1 (1.3). As
discussed earlier, the magnitude of this component of the
rate equation is determined by the equilibrium between the
mononuclear and binuclear species present in solution. A
number nearer to two corresponds to an increase in the
equilibrium concentration of the catalytically inactive
mononuclear species at the expense of the catalytically
active binuclear species as intended from the design of cata-
lyst 2. Hence, it appears that catalysts 1 and 2 operate by the
same mechanism (since they have the same form of rate
equation), and all aspects of this mechanism are consistent
Aldehyde
ee using catalyst 11
ee using catalyst 21
PhCHO
82
84
76
90
87
50
52
66
94
90
90
95
94
73
77
68
4MeOC6H4CHO
2MeC6H4CHO
3MeC6H4CHO
3MeC6H4CHO
4O2NC6H4CHO
CH3CH2CHO
Me3CCHO
1 Determined by chiral gas chromatography of the cyanohydrin trimethyl-
silyl ethers. Chiral gas chromatography was carried out on a DP-TFA-g-
cyclodextrin, fused silica capillary column (32 m£0.2 mm) using helium
as the carrier gas (¯ow rate 1.6 ml/min). In all cases, the injector tempera-
ture was 2308C and an isothermal column temperature of between 70 and
1558C was used.

776
Y. N. Belokon' et al. / Tetrahedron 57 (2001) 771±779
Figure 4. First order kinetics plots obtained for benzaldehyde at various concentrations of catalyst 2.
with that shown in Scheme 2. Catalyst 2 is less reactive and
correspondingly more enantioselective than catalyst 1 since
it contains a lower equilibrium concentration of the cata-
lytically active binuclear species.
consistent with the mechanism shown in Scheme 2, and
suggest that within the reaction solution, catalyst 2 gives a
higher equilibrium concentration of catalytically inactive
mononuclear species than catalyst 1.
Our work on the asymmetric addition of cyanide to carbonyl
compounds is continuing and further results will be reported
in due course.
6. Conclusions
Bimetallic titanium(IV)salen complex 1 is the only effective
transition metal based catalyst currently available for the
asymmetric addition of trimethylsilyl cyanide to aromatic
methyl ketones. These reactions obey a similar rate equation
to that previously determined for reactions involving cata-
lyst 1 and benzaldehyde, suggesting a common reaction
mechanism. Both the rate equation and the substrate speci-
®city are entirely consistent with the mechanism shown in
Scheme 2. Complex 1 is too reactive to be an optimal cata-
lyst for the asymmetric addition of trimethylsilyl cyanide to
aldehydes. However, based on the mechanistic under-
standing of the reaction, it was possible to develop
vanadium(IV)salen complex 2 as a catalyst which exhibits
higher enantioselectivities for aldehydes. The kinetics of
reactions involving catalyst 2 and benzaldehyde are again
7. Experimental
General experimental details have been reported else-
where.5
7.1. Asymmetric addition of trimethylsilyl cyanide to
ketones catalysed by complex 1
To a solution of trimethylsilyl cyanide (0.19 ml, 1.38 mmol)
and catalyst 1 (0.1±1.0 mol%) in dry dichloromethane
(1.5 ml) was added a ketone (1.25 mmol). The resulting
solution was stirred under an inert atmosphere, and the
progress of the reaction was followed by gas chroma-
tography. Once the reaction was complete (1±4 days), the
solution was poured onto a pad of silica gel and eluted with
EtOAc/hexane (1:5). The resulting solution was evaporated
in vacuo to give the trimethylsilyl ethers of cyanohydrins
whose physical and analytical data was consistent with
those reported in the literature,17 except for the adducts of
2-methoxy and 3-methoxy-acetophenone, which are new
compounds.
7.1.1. 2-(2-Methoxyphenyl)-2-trimethylsilyloxy-propa-
nonitrile: Colourless liquid; dH (CDCl3): 0.22 (9H, s,
Si(CH3)3), 1.82 (3H, s, CH3), 3.84 (3H, s, OCH3), 6.8±7.5
(4H, m, ArH); 13C NMR (CDCl3): 1.35 (Si(CH3)3), 30.14
(CH3), 55.51 (OCH3), 111.58 (ArCH), 111.67 (CN), 120.59
(ArCH), 125.78 (ArCH), 128.32 (ArC), 129.87 (ArCH),
147.83 (ArC); m/z (FAB) 250 (MH1).
7.1.2. 2-(3-Methoxyphenyl)-2-trimethylsilyloxy-propa-
nonitrile: Colourless liquid; dH (CDCl3): 0.11 (9H, s,
Si(CH3)3), 1.77 (3H, s, CH3), 3.75 (3H, s, OCH3), 6.75±7.5
Figure 5. Plot of log(kobs) against log([2]) for reactions carried out using
benzaldehyde as substrate.

Y. N. Belokon' et al. / Tetrahedron 57 (2001) 771±779
777
(4H, m, ArH); 13C NMR (CDCl3): 1.10 (Si(CH3)3), 33.68
(CH3), 55.40 (OCH3), 110.59 (ArCH), 113.91 (ArCH),
116.96 (ArCH), 125.00 (CN), 130.22 (ArCH), 134.47
(ArC), 143.51 (ArC); m/z (FAB) 250 (MH1).
7.4. Asymmetric addition of trimethylsilyl cyanide to
aldehydes catalysed by complex 2
To a solution of catalyst 2 (0.78 mg, 1.28£1023 mmol) in
dry distilled dichloromethane (1.5 ml) under an argon
atmosphere was added the aldehyde (1.28 mmol) followed
by trimethylsilyl cyanide (0.38 ml, 2.85 mmol). The resul-
ting solution was stirred for 24 h at room temperature, after
which the reaction mixture was poured onto a plug of silica
and eluted with hexane: EtOAc (5:1) to give the cyano-
hydrin trimethylsilyl ethers. The analytical data of the
products were consistent with those reported previously,5
and their enantiomeric excesses were determined by chiral
gas chromatography.
7.1.3. (S)-2-Hydroxy-2-phenyl-propanonitrile: (S)-2-
(Trimethyl-silyloxy)-2-phenyl-propanonitrile (100 mg, 0.46
mmol) was stirred at room temperature with 1 M HCl
(2 ml) for 2 h. The solution was then extracted with
dichloromethane (3£5 ml) and the combined organic
extracts dried (MgSO4) and evaporated in vacuo to leave
(S)-2-hydroxy-2-phenyl-propanonitrile as a colourless oil.
Yield 57 mg (85%). ‰aŠ25 2 1:3 (cˆ3.0, CHCl3) (lit.9
D
‰aŠ25 2 1:8 (cˆ 9.8, CHCl3) for a sample of the (S)-
D
enantiomer of 90% enantiomeric excess). Other data was
consistent with that reported in the literature.18
7.5. Kinetics studies using catalyst 2 and benzaldehyde
Standard solutions of benzaldehyde (12.8 mM), trimethyl-
silyl cyanide (0.71 M) and catalyst 2 (0.64 mM) were
prepared in dry dichloromethane. Samples of these solutions
were diluted with dry dichloromethane as necessary to
provide solutions of the concentration required for a par-
ticular experiment. The initial (tˆ0) absorption (at 243 nm)
was determined from a solution containing just the appro-
priate concentration of benzaldehyde and no other reagents.
The solutions of benzaldehyde and complex 2 were mixed
and stirred under an argon atmosphere at 19±208C, then the
trimethylsilyl cyanide solution and suf®cient dry dichloro-
methane were added such that the total reaction volume was
2.0 ml. The reaction was stirred under an argon atmosphere
at 19±208C and 10 mL samples were periodically removed
and immediately diluted into dry dichloromethane (25 ml).
The samples were then analysed by UV spectrophotometry
at 243 nm to determine the concentration of benzaldehyde
in the sample. This was used to calculate the concentration
of the trimethylsilyl cyanide remaining in the solution and
hence provided the data for the graphs shown in Figs. 4 and
5, from which the kinetic parameters of the reaction could
be determined.
7.2. Kinetics studies using catalyst 1 and acetophenone
A typical procedure employed a dry dichloromethane
solution (2.5 ml total volume), comprising trimethylsilyl
cyanide (0.9 M), catalyst 1 (5.5 mM) and acetophenone
(0.8 M). This was stirred at 238C under an inert atmosphere.
At hourly intervals, a 10 ml sample was withdrawn from the
reaction, diluted with dry dichloromethane (25 ml) and
analysed by UV spectrophotometry. From the intensity of
the lmax (240 nm), the concentration of acetophenone was
determined and used to calculate the concentration of
trimethylsilyl cyanide remaining in the solution. This
provided the data for the graphs shown in Figs. 2 and 3,
from which the kinetic parameters of the reaction could be
determined.
7.3. Synthesis of catalyst 2
Solutions of (1R,2R)-N,N0-bis(3,5-di-tert-butylsalicylidene)-
1,2-cyclohexanediamine (1.0 g, 1.8 mmol) in THF (20 ml)
and vanadyl sulphate hydrate (0.6 g, 2.2 mmol) in hot
ethanol (32 ml) were mixed and stirred under re¯ux for
3 h, after which time the solvent was removed in vacuo.
The residue was dissolved in dichloromethane and ®ltered.
The ®ltrate was evaporated in vacuo and absorbed onto a
plug of silica. Elution ®rst with dichloromethane, then with
EtOAc:methanol (2:1) gave catalyst 2 (0.6 g, 53%) as a
Acknowledgements
The authors thank the EU (INCO-COPERNICUS) and the
Russian Fund for Fundamental Research (grant No. 98-03-
32862) for ®nancial support, the EPSRC for a studentship
(to T. P.) and the EPSRC mass spectrometry service
(University of Wales, Swansea) for low and high resolution
mass spectra.
green crystalline solid. ‰aŠ23 2 950 (cˆ0.01, CHCl3); nmax
D
(nujol) 1618 m and 1560 cm21 m; (Found: C, 59.0; H, 7.6;
N, 3.8%. C36H52N2O3V. 2CH2Cl2 requires: C, 58.5; H, 7.2;
N, 3.6%); dH (CDCl3): 1.39 (18H, s, 2£C(CH3)3), 1.54 (18H,
s, 2£C(CH3)3), 1.7±2.2 (8H, m, 4£CH2), 3.81 (1H, m,
HCN), 4.26 (1H, m, HCN), 7.52 (1H, s, ArCH), 7.57 (1H,
s, ArCH), 7.72 (1H, s, ArCH), 7.77 (1H, s, ArCH), 8.55 (1H,
s, HCyN), 8.77 (1H, s, HCyN); 13C NMR (CDCl3): 24.57
(CH2), 28.67 (CH2), 29.27 (CH2), 29.69 (C(CH3)3), 29.91
(C(CH3)3), 31.39 (CH2), 34.49 (2£C(CH3)3), 35.01
(2£C(CH3)3), 35.46 (C(CH3)3), 35.64 (C(CH3)3), 69.98
(CHN), 71.00 (CHN), 121.06 (ArC), 121.57 (ArC), 127.85
(ArCH), 128.36 (ArCH), 131.23 (ArCH), 131.89 (ArCH),
134.99 (ArC), 135.20 (ArC), 144.18 (2£ArC), 156.34
(2£ArC), 161.95 (HCyN), 164.62 (HCyN); m/z (FAB)
611 (M1, 100); Found: 611.3409, C36H52N2O3V requires
611.3418.
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