Synthetic and mechanistic studies on asymmetric cyanohydrin synthesis using a titanium(salen) bimetallic catalyst

Article abstract of DOI:10.1016/j.tet.2004.07.098

A bimetallic titanium(salen) complex 1 was found to catalyse the asymmetric addition of ethyl cyanoformate to aldehydes. Best results were obtained using 5 mol% of the catalyst at -40°C and under these conditions, both aromatic and aliphatic aldehydes were converted into cyanohydrin carbonates with up to 99% enantiomeric excess. The same catalyst could also be used to catalyse the asymmetric addition of potassium cyanide to aldehydes in the presence of propionic anhydride, leading to cyanohydrin esters. Mechanistic studies showed that the enantiomeric excess of the product increased during the early stages of this reaction. However, by adding a 'sacrificial aldehyde' this effect could be eliminated. The structure of the catalyst in solution was investigated using variable concentration, variable temperature and variable solvent NMR studies. These experiments showed that the catalyst exists as a mixture of monometallic 4 and bimetallic 1 species, a result which is consistent with previous mechanistic studies on the asymmetric addition of trimethylsilyl cyanide to aldehydes and ketones catalysed by the same catalyst. A mechanistic rationale for all of these observations is reported. Synthetic and mechanistic studies on the use of titanium(IV) complexes for asymmetric cyanohydrin synthesis are reported. In addition to synthetic studies on the synthesis of both cyanohydrin esters and cyanohydrin carbonates, mechanistic studies concerning the structure of the catalyst in solution are also described.

Full text of DOI:10.1016/j.tet.2004.07.098

Tetrahedron 60 (2004) 10433–10447
Synthetic and mechanistic studies on asymmetric cyanohydrin
synthesis using a titanium(salen) bimetallic catalyst
Yuri N. Belokon’,a A. John Blacker,b Paola Carta,c Lisa A. Clutterbuckc and Michael Northc,
*
aA.N. Nesmeyanov Institute of Organo-Element Compounds, Russian Academy of Sciences, Vavilov 28, 117813 Moscow, Russian Federation
bAvecia Ltd, P.O. Box 521s, Leeds Rd., Huddersfield, West Yorkshire HD2 1GA, UK
cDepartment of Chemistry, King’s College London, Strand, London WC2R 2LS, UK
Received 12 May 2004; revised 25 June 2004; accepted 28 July 2004
Available online 9 September 2004
Abstract—A bimetallic titanium(salen) complex 1 was found to catalyse the asymmetric addition of ethyl cyanoformate to aldehydes. Best
results were obtained using 5 mol% of the catalyst at K40 8C and under these conditions, both aromatic and aliphatic aldehydes were
converted into cyanohydrin carbonates with up to 99% enantiomeric excess. The same catalyst could also be used to catalyse the asymmetric
addition of potassium cyanide to aldehydes in the presence of propionic anhydride, leading to cyanohydrin esters. Mechanistic studies
showed that the enantiomeric excess of the product increased during the early stages of this reaction. However, by adding a ‘sacrificial
aldehyde’ this effect could be eliminated. The structure of the catalyst in solution was investigated using variable concentration, variable
temperature and variable solvent NMR studies. These experiments showed that the catalyst exists as a mixture of monometallic 4 and
bimetallic 1 species, a result which is consistent with previous mechanistic studies on the asymmetric addition of trimethylsilyl cyanide to
aldehydes and ketones catalysed by the same catalyst. A mechanistic rationale for all of these observations is reported.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
catalyse the asymmetric addition of potassium cyanide to an
aldehyde in the presence of an anhydride, thus providing an
asymmetric synthesis of cyanohydrin esters (Scheme 1).8–11
This reaction has the advantage of avoiding the use of
volatile cyanide reagents. In this manuscript, we give full
details of our results using different anhydrides and report
the results of mechanistic studies on this reaction.
Interest in asymmetric cyanohydrin synthesis has increased
significantly in recent years due to the synthetic versatility
of chiral cyanohydrins and their utility as chiral starting
materials for natural product synthesis. Various types of
catalyst are available for this reaction including oxynitrilase
enzymes, cyclic-dipeptides, chiral Lewis-bases and chiral
transition metal complexes.1 However, most of these
methods require the use of either hydrogen cyanide or
trimethylsilyl cyanide as the cyanide source. Both of these
reagents are volatile and hence hazardous, and trimethyl-
silyl cyanide is also expensive, especially for large scale
use. Over the last eight years, we have developed titanium
complex 1 as a highly active catalyst for the addition of
trimethylsilyl cyanide to both aldehydes2–4 and ketones.5
This methodology has been applied to the asymmetric
synthesis of fluorinated norepinephrines and fluorinated
epinephrines.6 A closely related vanadium(salen) complex
was also found to catalyse the asymmetric addition of
trimethylsilyl cyanide to aldehydes.7 We have shown that
complex 1 (and the related vanadium(salen) complex) will
Keywords: Titanium; Salen; Cyanohydrin; Ethyl cyanoformate; Ester.
* Corresponding author at present address: Department of Chemistry,
School of Natural Sciences, Bedson Building, University of Newcastle
upon Tyne, Newcastle upon Tyne, NE1 7RU, UK. Fax: C44-870-131-
3783.
Scheme 1.
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.07.098

10434
Y. N. Belokon’ et al. / Tetrahedron 60 (2004) 10433–10447
Cyanoformate esters (ROCOCN) are known to react with
aldehydes and ketones, to form cyanohydrin carbonates.12
Only recently, however, have asymmetric catalysts for this
reaction been reported. In 2001, Tian and Deng showed that
dimeric cinchona alkaloid derivatives would catalyse the
asymmetric addition of ethyl cyanoformate to ketones,
giving cyanohydrin ethyl carbonates with 59–97% enantio-
meric excess.13 It is notable that this first report involved the
use of ketones rather than aldehydes as substrates. This
reaction does however, require 10–30 mol% of the catalyst
and reactions take up to 7 days. Subsequently, a hetero-
bimetallic complex derived from three binol units, three
lithium ions and a yttrium ion was shown by Shibasaki to
catalyse the asymmetric addition of ethyl cyanoformate to
aldehydes, producing non-racemic cyanohydrin carbon-
ates.14 Best results were obtained at K78 8C using
10 mol% of the catalyst and three additives: water
(30 mol%); butyl-lithium (10 mol%) and tri(2,6-dimethoxy-
phenyl)phosphine oxide (10 mol%). Under these con-
ditions, products with 87–98% enantiomeric excess could
be obtained. A third catalytic system was developed by
We have previously reported the results of extensive studies
to investigate the mechanism by which complex 1 catalyses
the asymmetric addition of trimethylsilyl cyanide to
aldehydes.4 In this manuscript, we present additional
evidence on the structure of complex 1 in solution which
supports this mechanism and we show how the mechanism
can be extended to reactions involving potassium cyanide or
ethyl cyanoformate.
2. Results and discussion
2.1. Asymmetric synthesis of cyanohydrin ethyl
carbonates
Initial studies were carried out using benzaldehyde as the
substrate. The addition of ethyl cyanoformate (2 equiv)
catalysed by complex 1 was studied under various
conditions as shown in Table 1. First reactions were carried
out in dichloromethane at a low temperature to enhance any
enantioselectivity and with 1 mol% of the catalyst as this
amount had previously been found to be optimal for
reactions involving potassium cyanide.8 When the reaction
was carried out at K85 8C, no product was detected (Table 1:
entry 1). Raising the reaction temperature to K73 8C did
give (S)-mandelonitrile ethyl carbonate 2a with a highly
encouraging 94% enantiomeric excess though the reaction
required 48 h to go to completion (Table 1: entry 2). The
absolute configuration of product 2a was determined by
comparison of its specific rotation with literature data.14a At
temperatures above K73 8C, the reaction rate increased, but
at the expense of a reduction in the enantiomeric excess of
the product. Thus, at K40 8C (Table 1: entry 3) the reaction
was complete in 19 h, but the product was obtained with
only 83% enantiomeric excess. Attempts to reduce the
amount of catalyst to 0.1 mol% (the optimal amount for the
addition of trimethylsilyl cyanide to aldehydes2) gave
unsatisfactory results even at room temperature (Table 1:
entries 4 and 5).
´
Najera et al. Thus, an aluminium binol complex was found
to catalyse the asymmetric addition of methyl cyanoformate
to aldehydes at room temperature.15 Cyanohydrin carbon-
ates with up to 80% enantiomeric excess were obtained
from reactions employing 10 mol% of the catalyst along
˚
´
with 4 A molecular sieves. The Najera catalyst has also
recently been reported to be compatible with the use of
diethyl cyanophosphonate as the cyanide source.16 Most
recently, an oxynitrilase enzyme has been used to catalyse
the asymmetric addition of ethyl cyanoformate to benzal-
dehyde, producing mandelonitrile ethyl carbonate with
excellent (95–O99%) enantiomeric excess, but only
moderate (maximum of 66%) chemical yield.17
In view of the above precedents, and the fact that
cyanohydrin carbonates are configurationally stable and
significantly less prone to hydrolysis than cyanohydrin
trimethethylsilyl ethers, it was attractive to investigate the
use of catalyst 1 in the asymmetric addition of ethyl
cyanoformate to aldehydes (Scheme 2) and ketones. Ethyl
cyanoformate is also less expensive than trimethylsilyl
cyanide, and this, combined with the homogeneous nature
of the reactions was expected have significant advantages
for large scale preparations. It is also notable that the
reaction shown in Scheme 2 is 100% atom-economical. In
this manuscript we give full details of this work.18
Whilst the result at K73 8C (Table 1: entry 2) was
encouraging, the long reaction time was felt to be
impractical. Therefore, the effect of increasing the amount
of catalyst was investigated to see if similar enantiomeric
excess could be obtained at a temperature where the rate of
reaction was faster. Gratifyingly, the use of 5 mol% of
catalyst 1 at K40 8C resulted in the complete formation of
(S)-2a with 95% enantiomeric excess after a reaction time of
18 h (Table 1: entry 6). This combination of catalyst mol%,
reaction temperature, and product enantiomeric excess is a
significant improvement on any of the previously known
catalysts13–15 and was taken to be the optimal conditions for
the use of complex 1 since a further increase in the amount
of catalyst used (Table 1: entry 7) was not beneficial.
The effect of the reaction solvent was investigated using
5 mol% of catalyst 1, a reaction temperature of K40 8C, and
1.2 equiv of ethyl cyanoformate. The results are shown in
Table 2. These reactions were significantly slower than the
optimised conditions, an effect which is mainly due to the
reduced concentration of ethyl cyanoformate used (compare
Table 1: entry 6 with Table 2: entry 7). An aromatic solvent
gave product 2a with a very low enantiomeric excess (Table
Scheme 2.

Y. N. Belokon’ et al. / Tetrahedron 60 (2004) 10433–10447
10435
Table 1. The asymmetric addition of ethyl cyanoformate to benzaldehyde catalysed by complex 1a
Entry
Temperature (8C)
1 (mol%)
Time (h)
Completion (%)
eeb (%)
1
2
3
4
5
6
7
K85
K73
K40
K40
25
1
1
1
0.1
0.1
5
19
48
19
72
148
18
51
!3
100
100
!3
!3
100
100
94 (S)
83 (S)
K40
K40
95 (S)
93 (S)
10
a
All reactions were carried out using 2 equiv of ethyl cyanoformate in dichloromethane.
Enantiomeric excesses were determined by chiral GC and are accurate to C/K3%.
b
2: entry 1). Oxygenated solvents gave a greater degree of
enantiomeric excess (Table 3: entry 7). For all of these
reactions, the use of 2 equiv of ethyl cyanoformate was
necessary for the reactions to be complete in less than 20 h.
The quantity of ethyl cyanoformate used could however be
reduced to just 1.2 equiv, at the expense of extended
reaction times of 45–68 h.
asymmetric induction, though the reactions failed to go to
completion after 2 days and ethyl acetate gave a particularly
slow reaction (Table 2: entries 2–4). Only chloroform gave a
high conversion to product with a high enantiomeric excess
(Table 2: entry 5), though even in this case the enantiomeric
excess of product 2a was 7% lower than that obtained when
dichloromethane was used as the solvent (Table 2: entry 7).
Use of the non-polar chlorinated solvent, tetrachloro-
methane, resulted in a very slow reaction even though the
reaction was carried out at K20 8C. Insufficient product was
formed after 4 days to allow the enantiomeric excess to be
determined (Table 2: entry 6). On the basis of these results,
it was apparent that dichloromethane was both the most
effective and the most convenient solvent for these
reactions.
A series of aliphatic aldehydes was also studied as substrates
for this reaction (Table 3: entries 9–12) and all gave
products (2i–l) with similar enantiomeric excesses (76–
84%). The primary aldehyde nonanal gave the product with
the highest enantiomeric excess (Table 3: entry 9), but there
was no significant difference between the enantioselectivity
observed with the secondary and tertiary aldehydes (Table
3: entries 10–12). For aliphatic aldehydes, the amount of
ethyl cyanoformate used could be reduced to 1.2 equiv
without the reaction time being extended beyond 20 h. The
only exception to this was pivaldehyde which is a slow
reacting substrate, presumably for steric reasons (Table 3:
entry 12).
The addition of ethyl cyanoformate to other aldehydes was
then investigated under the optimized conditions (Table 1:
entry 6). The results are shown in Table 3. Electron rich
aromatic aldehydes (all three isomers of methoxybenzalde-
hyde and 4-methylbenzaldehyde) were found to be excellent
substrates for this reaction, giving cyanohydrin carbonates
2b–e in high chemical yield and with excellent enantiomeric
excesses (94–99%) (Table 3: entries 2–5). Cinnamaldehyde
was also found to be an excellent substrate giving
cyanohydrin carbonate 2h with 94% enantiomeric excess
(Table 3: entry 8). The electron deficient aromatic aldehyde
4-trifluoromethylbenzaldehyde was a very fast reacting
substrate (Table 3: entry 6), though it gave product 2f with a
relatively low enantiomeric excess (76%). This may be due
to a competing uncatalysed addition of ethyl cyanoformate
to this particularly reactive aldehyde. 4-Chlorobenzalde-
hyde was however an excellent substrate, giving cyanohy-
drin ethyl carbonate 2g in high yield and with 94%
Two ketones, acetophenone and 2-butanone, were also
investigated as substrates. Catalyst 1 is known to catalyse
the asymmetric addition of trimethylsilyl cyanide to
ketones,5 but no conditions were found under which it
would catalyse the addition of ethyl cyanoformate to either
of these ketones. Even at room temperature and with
prolonged reaction times, only unreacted starting materials
were observed.
2.2. Asymmetric synthesis of cyanohydrin esters
The reaction shown in Scheme 1 provides a very
convenient, one-pot synthesis of configurationally stable
cyanohydrin esters. This reaction was developed using
Table 2. The influence of the solvent on the asymmetric addition of ethyl cyanoformate to benzaldehyde catalysed by complex 1a
Entry
Solvent
Toluene
EtOAc
Ether
Thf
Chloroform
Tetrachloromethanec
Dichloromethane
Time (h)
Conversion (%)
eeb (%)
1
2
3
4
5
6
7
45
90
47
73
53
96
42
100
23
73
49
96
!5
98
30
42
51
52
84
91
a
All reactions were carried out using 1.2 equiv of ethyl cyanoformate.
Enantiomeric excesses were determined by chiral GC and are accurate to C/K3%.
Reaction carried out at K20 8C.
b
c

10436
Y. N. Belokon’ et al. / Tetrahedron 60 (2004) 10433–10447
Table 3. The asymmetric addition of ethyl cyanoformate to aldehydes catalysed by complex 1 in dichloromethane
Entry
Aldehyde (product)
Time (h)
EtOCOCN (equiv)
Yield (%)a
eeb (%)
1
2
3
4
5
6
7
8
PhCHO (2a)
18
18
17
48
48
6
68
45
22
20
18
48
2
2
2
90
92
94
95
67 (95)
84
96
47 (99)
54
95
95
99
98
94
76
94
94
88
79
79
73
4-MeOC6H4CHO (2b)
3-MeOC6H4CHO (2c)
2-MeOC6H4CHO (2d)
4-MeC6H4CHO (2e)
4-(F3C)C6H4CHO (2f)
4-ClC6H4CHO (2g)
PhCH]CHCHO (2h)
C8H17CHO (2i)
1.2
1.2
2
1.2
1.2
2
1.2
1.2
1.2
9
10
11
12
Me2CHCHO (2j)
CyCHO (2k)
Me3CCHO (2l)
23 (88)
82
69
a
After purification by distillation. Number in brackets is the yield before distillation.
Enantiomeric excesses were determined by chiral GC and are accurate to C/K3%.
b
acetic anhydride, and was found to give good to excellent
enantioselectivities with a range of aromatic and aliphatic
aldehydes.8,9,11 Whilst acetic anhydride is the experimen-
tally most convenient anhydride for synthetic work, we
decided to see if the structure of the anhydride had any
influence on the enantioselectivity, rate, or yield of the
reaction.10 Three anhydrides were chosen for an initial
study, propionic anhydride, pivalic anhydride and benzoic
anhydride. Propionic anhydride is only slightly larger than
acetic anhydride, whilst pivalic anhydride is significantly
sterically hindered. Thus, comparison of these two anhy-
drides with acetic anhydride would allow the influence of
steric effects to be investigated. In contrast, benzoic
anhydride was included as it has very different electronic
properties to the three aliphatic anhydrides.19 Both race-
mic20–22 and non-racemic23–25 cyanohydrin esters derived
from all three of these anhydrides have previously been
reported.
An initial study was carried out under the reaction
conditions shown in Scheme 1, using benzaldehyde as the
substrate and the three different anhydrides. The reactions
were monitored by GC and the enantiomeric excess of the
product 3b–d was determined by chiral GC. The results of
this study are shown in Table 4. Compared to previous work
with acetic anhydride (Table 4: entry 1), the use of propionic
anhydride (Table 4: entry 2) or pivalic anhydride (Table 4:
entry 3) was found to have little effect on the enantioselec-
tivity of the reaction. However, benzoic anhydride gave a
product 3d with significantly lower enantiomeric excess
(Table 4: entry 4). Reactions involving propionic, pivalic or
benzoic anhydride were much slower than reactions using
acetic anhydride, requiring at least 48 h to go to completion.
The use of benzoic anhydride resulted in a particularly slow
reaction.
Based on the above results, the use of benzoic anhydride
was discontinued. However, both propionic and pivalic
anhydride were felt to be worthy of further investigation
since although they offered no improvement in enantio-
selectivity in the case of benzaldehyde, this would not
necessarily be the case for other aldehydes. Therefore, a
range of aromatic, aliphatic, and a,b-unsaturated aldehydes
were studied with these two anhydrides, and the results
are shown in Table 5. Two additional aldehydes
Table 4. The asymmetric addition of potassium cyanide to benzaldehyde catalysed by complex 1 in the presence of different anhydrides
Entry
Anhydride
Time (h)
Product
Conversion (%)
eea (%)
1
2
3
4
Acetic
10
48
48
72
3a
3b
3c
3d
93
100
85
908
92
88
56
Propionic
Pivalic
Benzoic
95
a
Enantiomeric excesses were determined by chiral GC and are accurate toC/K3%.

Y. N. Belokon’ et al. / Tetrahedron 60 (2004) 10433–10447
10437
Table 5. The asymmetric addition of potassium cyanide to aldehydes catalysed by complex 1 in the presence of different anhydridesa
Entry
Aldehyde
Anhydride
Product
Time (h)
Conversion (%)
eeb (%)
1
2
3
4
5
6
7
8
PhCH]CHCHO
PhCH]CHCHO
4-(CF3)C6H4CHO
4-(CF3)C6H4CHO
3-MeOC6H4CHO
3-MeOC6H4CHO
4-MeOC6H4CHO
4-MeOC6H4CHO
Me2CHCHO
Me2CHCHO
Me3CCHO
Me3CCHO
2-MeC6H4CHO
3-MeC6H4CHO
4-MeC6H4CHO
4-ClC6H4CHO
C8H17CHO
Propionic
Pivalic
Propionic
Pivalic
Acetic
Propionic
Acetic
Propionic
Acetic
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
3q
3r
3s
3t
48
72
50
50
10
48
10
48
10
62
10
48
28
36
36
16
50
72
73 (62% isolated yield)
50
100
100
99
100
74
100 (71% isolated yield)
62
100
40
100
100
98
95
75
94
62
938
90
938
91
728
17
628
78
81
95
89
90
82
41
9
10
11
12
13
14
15
16
17
18
Propionic
Acetic
Propionic
Propionic
Propionic
Propionic
Propionic
Propionic
Propionic
98
100
74
3u
3v
CyCHO
95
a
All reactions were carried out at K40 8C in dichloromethane in the presence of water (0.5 equiv) and tert-butanol (1.0 equiv).
Enantiomeric excesses were determined by chiral GC and are accurate to C/K3%.
b
(cinnamaldehyde and para-trifluoromethylbenzaldehyde)
5: entries 13–18). Of the aromatic substrates, only the ortho-
substituted aldehyde gave a product 3q with an enantio-
meric excess significantly below 90% (Table 5: entry 13).
For meta- and para-substitued benzaldehydes, products
with enantiomeric excesses O89% were consistently
obtained irrespective of the electronic nature of the
substituent (Table 5: entries 3, 6, 8, 14–16). The primary
aldehyde nonal (Table 5: entry 17) gave product 3u with a
higher enantiomeric excess than that observed for secondary
or tertiary aliphatic aldehydes (compare entry 17 with
entries 10, 12, and 18). Cyclohexane carboxaldehyde gave
product 3v with a rather low enantiomeric excess (Table 5:
entry 18), though not as low as that observed for product 3n
derived from 2-methyl propanal.
were investigated with both propionic and pivalic anhy-
drides (Table 5: entries 1–4). However, the products
obtained using pivaldehyde (3f and 3h) had enantiomeric
excesses at least 20% lower than those obtained using
propionic anhydride (3e and 3g), so the use of pivalic
anhydride was not pursued further. Whilst most of the
cyanohydrin esters were found to be chemically and
configurationally stable, the products obtained from para-
trifluoromethylbenzaldehyde (3g and 3h) were both found
to racemize on standing at room temperature. Thus, over a
period of 3 days, the enantiomeric excess of compound 3g
decreased from 94 to 78% and that of 3h decreased from 62
to 48%.
To allow a further direct comparison between the use of
acetic and propionic anhydrides, four aldehydes previously
used as substrates with acetic anhydride were investigated
using propionic anhydride as well. The first two aldehydes
chosen were the electron rich aromatic aldehydes 3- and 4-
methoxybenzaldehyde. For both of these substrates, the
products derived from acetic (3i and 3k) and propionic (3j
and 3l) anhydrides were obtained with essentially identical
enantiomeric excesses (Table 5: entries 5–8). The other two
aldehydes used in this study were aliphatic, and in this case
a significant difference between the two anhydrides was
observed. In the case of 2-methyl-propanal, product 3m
obtained using acetic anhydride was found to have a much
higher enantiomeric excess (72%) than product 3n (17%)
derived from propionic anhydride (Table 5: entries 9 and
10). By contrast, for cyanohydrin esters 3o and 3p derived
from pivaldehyde, product 3p obtained from propionic
anhydride had a higher enantiomeric excess (78%) than
product 3o (62%) derived from acetic anhydride (Table 5:
entries 11 and 12). Thus, whilst for aromatic aldehydes there
is little or no difference in the enantioselectivity observed
with acetic and propionic anhydrides, for aliphatic alde-
hydes the structure of the anhydride does appear to play a
major role in determining the enantioselectivity of the
process. Finally, four aromatic and two aliphatic aldehydes
not previously used as substrates with acetic anhydride were
investigated as substrates with propionic anhydride (Table
2.3. Variation of enantiomeric excess with time
Reactions carried out at K40 8C using propionic anhydride
were sufficiently slow that they could be easily monitored
by chiral GC. This revealed that the enantiomeric excess of
the product (mandelonitrile propionate 3b) increased
significantly during the course of the reaction as shown in
Figure 1. Thus, after 1 h of reaction, the enantiomeric excess
Figure 1. The variation of the enantiomeric excess of product 3b with time.
Error bars correspond to C/K3%, which is the approximate error in the
enantiomeric excess determined by chiral GC.

10438
Y. N. Belokon’ et al. / Tetrahedron 60 (2004) 10433–10447
of the product was just 44%. After 24 h however, the
enantiomeric excess of compound 3b had increased to 81%.
The most likely explanation for this effect is that complex 1
is only slowly converted into species on the catalytic cycle,
and during the early stages of the reaction, less enantiose-
lective catalysis occurs due to other species. Details of the
mechanisms of these reactions will be discussed in Section
2.5. However, this suggested a way of potentially increasing
the enantiomeric excess of products 3. Addition of a small
amount of one aldehyde (a ‘sacrificial aldehyde’) should
convert complex 1 into a species on the catalytic cycle. A
few hours later, the real aldehyde could be added. In this
way, the enantiomeric excess of the second aldehyde should
not be reduced by competing processes with low or no
enantioselectivity in the early stages of the reaction.
Figure 2. The variation of the enantiomeric excess of products 3b and 3r
with time when benzaldehyde is used as a ‘sacrificial’ aldehyde. Error bars
correspond to C/K3%, which is the approximate error in the enantiomeric
excess determined by chiral GC. Diamonds refer to product 3b, and squares
to product 3r.
To test this hypothesis, a reaction was carried out as shown
in Scheme 3. In this reaction, benzaldehyde functions as the
‘sacrificial aldehyde’ and 3-methylbenzaldehyde as the real
substrate. Initially, catalyst 1 (1 mol% relative to the amount
of 3-methylbenzaldehyde to be added later) and benzal-
dehyde (2 mol%) were added under standard conditions and
allowed to react for 4.5 h. At this stage, 3-methylbenzalde-
hyde (100 mol%) was added and the reaction allowed to
continue. The enantiomeric excess of both products (3b and
3r) was simultaneously monitored by chiral GC, and the
results are shown in Figure 2.
shows, exactly the same effects were observed: the
enantiomeric excess of the sacrificial aldehyde increased
during the reaction, but that of the real substrate stayed
constant. However, the enantiomeric excess of product 3b
obtained in this way (80%) was again lower than that
obtained using benzaldehyde as the only substrate (92%,
Table 4: entry 2).
To try to find a sacrificial aldehyde system which did give
enhanced enantioselectivities, four different sacrificial
aldehydes with differing electronic properties were studied.
In each case, benzaldehyde (90 mol%) was used as the real
substrate and 10 mol% of the sacrificial aldehyde was used.
The reactions were not followed by chiral GC, but Table 6
records the enantiomeric excess of product 3b isolated in
each case. The results of this series of experiments (Table 6:
entries 1–4) were remarkably consistent; product 3b was
obtained with 78–80% enantiomeric excess whatever the
nature of the sacrificial aldehyde. Finally, we carried out an
experiment in which benzaldehyde was used as both the
sacrifical aldehyde (10 mol%) and the real substrate
The experiment was at least partially successful, since it is
quite clear that the enantiomeric excess of product 3r
remains constant at 90% throughout the reaction. At the end
of the reaction, both aldehydes had undergone greater than
90% conversion to cyanohydrin propionates. However, the
enantiomeric excess of product 3r obtained in this way was
actually slightly lower than the 95% obtained using only 3-
methylbenzaldehyde as substrate (Table 5: entry 14). One
explanation for this is that the catalytically active species
formed in the reaction depend on the aldehyde from which
they are formed. For example, a molecule of cyanohydrin
could be bound to a titanium ion during the catalytic cycle.
The catalyst obtained in this sacrificial experiment would
then be different to that obtained in a normal reaction and so
could exhibit different enantioselectivity. To further inves-
tigate this effect, the experiment was reversed: 3-methyl-
benzaldehyde (2 mol%) was used as the sacrificial aldehyde
and benzaldehyde as the actual substrate. As Figure 3
Figure 3. The variation of the enantiomeric excess of products 3b and 3r
with time when 3-methylbenzaldehyde is used as a ‘sacrificial’ aldehyde.
Error bars correspond to C/K3%, which is the approximate error in the
enantiomeric excess determined by chiral GC. Diamonds refer to product
3r, and squares to product 3b.
Scheme 3.

Y. N. Belokon’ et al. / Tetrahedron 60 (2004) 10433–10447
Table 6. The use of different sacrificial aldehydes for the asymmetric
synthesis of product 3b
10439
Entry
Sacrificial aldehyde
eea of 3b (%)
1a
2
3
4
5
Nonal
Cinnamaldehyde
4-Methoxybenzaldehyde
4-Trifluoromethylbenzaldehyde
Benzaldehyde
80
80
80
78
80
a
Enantiomeric excesses were determined by chiral GC and are accurate
to C/K3%.
(90 mol%). This was expected to give product 3b with 92%
enantiomeric excess (cf. Table 4: entry 2), but actually again
gave product 3b with just 80% enantiomeric excess (Table
6: entry 5).
To explain these results, we propose that the sacrificial
aldehyde does achieve its role of converting precatalyst 1
into species which lie on the catalytic cycle, but that these
species are unstable in the absence of a high concentration
of aldehyde. Thus, by the time that the real substrate is
added (typically 4–5 h), some of the catalyst has decom-
posed, resulting in a reduced mol% of the catalyst being
available to carry out the catalysis, and hence a lower
enantiomeric excess of the final product.
2.4. Structure of the catalyst and its significance
During the course of this work, we studied the nature of
catalyst 1 in solution. It has previously been determined by
X-ray crystallography that the catalyst exists as a bimetallic
complex in the solid state.3 Kinetic studies on the
asymmetric addition of trimethylsilyl cyanide to aldehydes
and ketones catalysed by complex 1 however, indicated that
the catalyst dissociated in solution to form both mono-
metallic and bimetallic species.4
Figure 4. 1H NMR spectra of compound 1 in CDCl3 at different
concentrations. *Signal due to CHCl3.
1
Routine H NMR spectra (recorded in CDCl3) obtained
rise to two imine signals and four aromatic signals. Thus, in
both cases the salen ligand lacks C2 symmetry. These results
indicate that catalyst 1 exists in chloroform solution as an
equilibrium mixture of dimeric 1 and monomeric 4 species
as shown in Scheme 4. At high concentrations, formation of
the dimeric species is favoured, whilst at lower concen-
trations, formation of the monomeric species becomes more
favourable. Dimeric species 1 has overall C2 symmetry, but
within each salen ligand the two aromatic rings are
diastereotopic due to the cis-b conformation forced upon
the ligand by the two bridging oxygens.3 The monomeric
complex 4 is square pyramidal and so again lacks C2-
symmetry. Asymmetric cyanation reactions carried out
using catalyst 1 are typically carried out at a catalyst
concentration between 8!10K4 and 1!10K2 M depending
on the cyanide source. (With trimethylsilyl cyanide only
0.1 mol% of catalyst is needed;3 the potassium cyanide/acetic
anhydride system requires 1 mol% catalyst;8 and for use of
ethyl cyanoformate as the cyanide source, 5 mol% of catalyst
is necessary18). These concentrations are all covered by the
spectra shown in Figure 4a–d in which a significant amount of
both monomeric and dimeric species are present. The
equilibrium constant between the dimeric 1 and monomeric
4 species (calculated using data from the spectrum obtained at
0.02 M) was determined to be 3!10K3 M.
during the preparation of batches of catalyst 1 exhibited
significant variability which initially led to concerns about
the purity of the catalyst and its true structure. However, a
variable concentration NMR study showed that the 1H NMR
spectrum of the catalyst was highly concentration depen-
dent, with the changes in the aromatic and imine hydrogen
region (6–9 ppm) being particularly pronounced. A repre-
sentative set of spectra recorded in deuterated chloroform
are shown in Figure 4.
At the highest concentration studied (0.0822 M), four
aromatic peaks and two imine signals are observed as
expected for bimetallic structure 1. Only very small peaks
corresponding to any other species are visible in the spectrum
(Fig. 4a). However, as the concentration of the NMR solution
isdecreased,theintensityofthe minorpeaksincreases(Fig.4b
and c), until at a concentration of 5!10K4 M, all the signals
are of comparable intensity (Fig. 4d). At still lower
concentrations, the signals corresponding to the originally
minor species become dominant (Fig. 4e), until at the lowest
concentration we could acquire a spectrum (8.3!10K6 M),
the original signals virtually disappear from the spectrum
(Fig. 4f).
Both species present in the spectra shown in Figure 4 give

10440
Y. N. Belokon’ et al. / Tetrahedron 60 (2004) 10433–10447
Scheme 4.
A variable temperature study of catalyst 1 in CDCl3 at
0.01 M concentration was also undertaken. Between 213
and 333 K, no significant changes in chemical shift were
observed. However, as the temperature was lowered, the
signals for the minor species 4 became significantly sharper
and decreased in intensity. Thus, at 333 K the ratio of the
minor to major signals is 0.25:1 and this decreases to 0.1:1
at 213 K. This is consistent with the equilibrium shown in
Scheme 4, since at higher temperatures, more energy is
available to break the relatively weak Ti–O bonds, and
hence the amount of monomeric species 4 present will
increase. The X-ray structure of compound 1 shows that the
central Ti2O2 unit is rectangular, with two normal Ti–O
bonds and two longer bonds.3 Cleavage of the latter is all
that would be required for formation of the monomeric
species.
Scheme 5.
simple spectrum consisting of just two imine signals and
four aromatic signals as shown in Figure 5. This
concentration corresponds to that used for Figure 4b
where the signals for the monomeric species were clearly
visible. To prove that the species present in d6-benzene was
bimetallic species 1 rather than the monomeric species 4, a
solvent titration was carried out at constant concentration.
As the %chloroform in the solvent decreased, the intensity
of the minor signals also decreased and they became
undetectable when the %chloroform was less than 20%.
Reactions involving catalyst 1 are usually carried out in
dichloromethane rather than chloroform or benzene. There-
fore, NMR spectra of catalyst 1 were recorded at various
concentrations in CD2Cl2. The results were very similar to
the spectra obtained in CDCl3, with peaks corresponding to
monomeric species 4 increasing in intensity as the
concentration was reduced. The equilibrium constant in
dichloromethane was calculated as 8!10K4 M which is a
factor of four lower than that observed in chloroform.
This result may also be relevant to the amount of catalyst
needed for the various asymmetric cyanation reactions.
Thus, reactions using trimethylsilyl cyanide are sufficiently
enantioselective that they can be carried out at 20 8C.3 Only
0.1 mol% of the catalyst is needed in these reactions, and at
this ‘high’ temperature this will give rise to a relatively high
concentration of monometallic complex 4. Formation of the
monometallic complex is essential to allow it to react with
the aldehyde and start the catalytic cycle4 as shown in
Scheme 5. In contrast, reactions using potassium cyanide8
or ethyl cyanoformate18 exhibit optimal enantioselectivity
at K40 8C. These reactions also require much more catalyst
1–5 mol% and it may be that the reason for this is to
maintain the required concentration of monometallic
species at the lower temperature.
Figure 5. 1H NMR spectrum of compound 1 in C6D6 at a concentration of
0.02 M. *Signal due to benzene.
The dissociation of complex 1 is solvent dependent as in d6-
benzene, a 0.02 M solution of complex 1 exhibited a very

Y. N. Belokon’ et al. / Tetrahedron 60 (2004) 10433–10447
10441
To further prove that the species observed by NMR in
CDCl3 were catalytically relevant, the asymmetric addition
of potassium cyanide and acetic anhydride to benzaldehyde
was carried out under the conditions of Scheme 1 (R1ZPh,
R2ZMe) except that the solvent was changed to chloro-
form. Under these conditions, an 85% conversion of
benzaldehyde into O-acetyl (S)-mandelonitrile 3a with
72% enantiomeric excess was observed after a reaction
time of 4 days. This reaction is slower and less
enantioselective than that carried out under the optimized
conditions8 (93% yield with 90% enantiomeric excess in
10 h), but does prove that the species detected in chloroform
are catalytically relevant. The asymmetric addition of ethyl
cyanoformate to benzaldehyde catalysed by complex 1
could also be carried out in chloroform (Table 2: entry 4).
cyanoformate can react with the titanium bound cyanohy-
drin to give products 2 and complex 7. In the potassium
cyanide/anhydride system however, this step cannot be
quite so straightforward. Acylation of the titanium bound
cyanohydrin 6 would give products 3 and titanium complex
11 (Scheme 7). Complex 11 could either react with
potassium cyanide to give bis-cyanide 7, or directly react
with another molecule of aldehyde to reform complex 5.
There is however a further possibility. Since the potassium
cyanide chemistry is carried out in the presence of water and
tert-butanol, complex 6 could be protonated to form a free
cyanohydrin and complex 11. The free cyanohydrin would
then be acylated in a non-catalytic step to give the observed
product. One consequence of this mechanism is that the
enantiomeric excess of product 3 would directly depend on
the rate at which the free cyanohydrin was protected by
reaction with the anhydride. This fits the observed results
since the most reactive anhydrides gave the products with
highest enantiomeric excess (acetic anhydrideRpropionic
anhydrideOpivalic anhydrideObenzoic anhydride). It is
also possible that more than one of these routes operate
simultaneously, or that the exact process by which the
cyanohydrin ester is formed differs from substrate to
substrate.
2.5. Mechanistic analysis
The mechanism shown in Scheme 5 for the addition of
trimethylsilyl cyanide to aldehydes catalysed by complex 1
can reasonably be assumed to form the basis of reactions
involving ethyl cyanoformate and potassium cyanide/an
anhydride as well. There are however, two areas where the
mechanism must be modified:
The results of experiments using a sacrificial aldehyde in the
potassium cyanide system can be explained as follows. The
role of the sacrificial aldehyde is to allow the formation of
complex 5 by the route shown in Scheme 6. Complex 5 is
one of the three key bimetallic complexes on the catalytic
cycle, and its formation appears to take about 4–5 h at K
40 8C (based on Fig. 1). During this time, other titanium
containing species (e.g., 1, 4, 8) are present in the reaction
mixture and could give rise to less enantioselective catalysts
resulting in the enantiomeric excess of the product derived
from the sacrificial aldehyde being observed to increase
with time. Assuming that at least one of complexes 5–7 is
unstable in the absence of excess aldehyde and therefore
causes the partial decomposition of the catalyst prior to the
addition of the real substrate, the observed enantiomeric
excess of the product derived from the real substrate would
be expected to be constant throughout the reaction, but
lower than that observed if only one aldehyde was used.
1. How is catalyst 1 converted into one of complexes 5–7
present in the catalytic cycle in the absence of
trimethylsilyl cyanide?
2. How is the cyanohydrin derivative removed from
complex 6?
We have previously shown9 that reaction of catalyst 1 with
acetic anhydride generates bimetallic bis-acetate 8. Reac-
tion of compound 8 with potassium cyanide and an aldehyde
would lead to species 5 as shown in Scheme 6. To start the
catalytic cycle when ethyl cyanoformate is used as the
cyanide source, it is possible that a complex such as 9 is
formed and collapses to titanium bis-cyanide complex 10.
Thiscould then enter the catalytic cycle asshown inScheme 5.
Conversion of complex 6 into bis-cyanide 7 in the presence
of ethyl cyanoformate presents no difficulty as the ethyl
3. Conclusions
Catalyst 1 has been shown to catalyse the asymmetric
addition of ethyl cyanoformate to a range of aliphatic and
aromatic aldehydes. Optimal results were obtained using
5 mol% of catalyst 1 in dichloromethane at K40 8C and
under these conditions, twelve aldehydes were converted
Scheme 6.
Scheme 7.

10442
Y. N. Belokon’ et al. / Tetrahedron 60 (2004) 10433–10447
into (S)-cyanohydrin ethyl carbonates with 75–99% enan-
tiomeric excess.
spectra, the peak assignments were made with the assistance
of DEPT experiments.
The same catalyst was shown to catalyse the asymmetric
addition of potassium cyanide to aldehydes in the presence
of an anhydride, leading to cyanohydrin esters. For this
process, only 1 mol% of the catalyst was required and best
results were again obtained at K40 8C. Of the anhydrides
studied, acetic anhydride generally gave the fastest reaction
rates and highest enantioselectivities. Propionic anhydride
gave much slower reaction rates, but for aromatic aldehydes
gave products with comparable enantiomeric excesses (81–
95%) to those obtained using acetic anhydride. When
aliphatic aldehydes were used as substrates, the results were
more variable and there was no obvious correlation between
anhydride structure and enantioselectivity. The other
anhydrides studied gave products with significantly lower
enantiomeric excesses.
Infrared spectra were recorded on a Perkin–Elmer FT-IR
Paragon 1000 spectrometer, as a thin film between NaCl
plates in the reported solvent, or as KBr disks. The
characteristic absorption is reported as broad (br), strong
(s), medium (m) or weak (w). Low and high resolution mass
spectra were recorded at the EPSRC national service at the
University of Wales, Swansea, or on a Bruker Apex III
FTMS or Jeol AX505W spectrometer within the chemistry
department at King’s College. The sample was ionized by
electron ionization (EI), chemical ionization (CI) fast atom
bombardment (FAB) or electrospray ionization (ES). The
major fragment ions are reported and only the molecular
ions are assigned.
Optical rotations were recorded on a Perkin–Elmer 343
polarimeter in a thermostated cell of length 1 dm at 20 8C
using the sodium D-line, and a suitable solvent that is
reported along with the concentration (in g/100 mL).
The structure of catalyst 1 was investigated in various
solvents to complement a previous X-ray study and to
provide mechanistic information. In chloroform, a concen-
tration dependent equilibrium between the dimeric 1 and
monometallic 4 forms of the catalyst was detected. In
dichloromethane, the equilibrium is shifted in favour of the
undissociated form 1, and in benzene only the undissociated
complex is detected. The equilibrium is also temperature
dependent, with the monometallic form of the catalyst 4
being less favoured at lower temperatures. These results
provide an explanation for the observation that whilst the
asymmetric addition of trimethylsilyl cyanide to aldehydes
(at room temperature) is catalysed by just 0.1 mol% of
catalyst 1, the corresponding additions of potassium cyanide
and ethyl cyanoformate (both of which have to be carried
out at K30 to K40 8C to obtain good asymmetric induction)
require much larger amounts of catalyst 1.
Chromatographic separations were performed with silica
gel 60 (230–400 mesh) and thin-layer chromatography was
performed on polyester backed sheets coated with silica gel
60 F254, both supplied by Merck. Chiral GC was carried out
on a Hewlett Packard 5890 gas chromatograph fitted with a
thermal conductivity detector, using a g-CD butyryl, fused
silica capillary column (30 m!0.25 mm) and hydrogen as
the carrier gas (flow rate 2.3 mL/min).
4.2. General procedure for the asymmetric addition of
ethyl cyanoformate to aldehydes
A stirred solution of aldehyde (4.7 mmol) in dichloro-
methane (20 mL) and (R,R)-1 (0.264 g, 0.22 mmol,
5 mol%) was cooled to K84 8C and EtOCOCN (0.93 mL,
9.42 mmol) was added in one portion. The yellow solution
was then allowed to warm to K40 8C and was stirred
vigorously for 19 h. The reaction mixture was then passed
through a pad of silica eluting with dichloromethane. The
eluent was concentrated in vacuo and the resulting orange–
brown liquid was micro-distilled to give the cyanohydrin
ethyl carbonate as a clear liquid.
For the potassium cyanide system, it was found that the
enantiomeric excess of the product increased during the
course of the reaction. Experiments in which two different
aldehydes were used suggest that this is due to the slow
conversion of precatalyst 1 into catalytically active species
under the reaction conditions. A complete mechanistic
rationale for asymmetric cyanohydrin synthesis (using three
different cyanide sources) induced by precatalyst 1 which
explains all of the observed effects has been presented.
4.2.1. O-Ethoxycarbonyl (S)-2-hydroxy-2-phenyl-aceto-
nitrile 2a. Yield 0.87 g, 90%; [a]2D0ZK20.1 (c 1.8, CHCl3)
[lit.14a [a]2D0ZC16.2 (c 2.8, CHCl3) for (R)-enantiomer
with 94% ee]; dH 1.26 (3H, t JZ7.1 Hz, CH3), 4.2–4.3 (2H,
m, OCH2), 6.19 (1H, s, OCHCN), 7.2–7.5 (5H, m, ArH); dC
153.82 (CO3), 131.64 (ArC), 131.04 (ArCH), 129.68
(ArCH), 128.29 (ArCH), 116.19 (CN), 66.76 (OCH),
66.03 (OCH2), 14.51 (CH3); m/z (EI) 205 (MC, 35), 116
(78), 133 (55), 105 (100). Found (ES) 206.0829, C11H12NO3
(MHC) requires 206.0817. GC conditions: initial tempera-
ture 100 8C, ramp rate 0.2 8C/min. TR 121.8 (minor isomer)
and 124.2 (major isomer) min.
4. Experimental
4.1. General methods
1H NMR and 13C NMR spectra were recorded on a Bruker
Avance 360 Spectrometer, (1H 360 MHz, 13C 90 MHz).
Variable temperature experiments were carried out on a
Bruker Avance 400 Spectrometer, (1H 400 MHz). The
solvent for a particular spectrum is given in parentheses.
Spectra were referenced to TMS and chemical-shift (d)
values, expressed in parts per million (ppm), are reported
downfield of TMS. 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. For 13C NMR
4.2.2. O-Ethoxycarbonyl (S)-2-hydroxy-2-(4-methoxy-
phenyl)acetonitrile 2b. Yield 1.02 g, 92%; [a]2D0ZC1.8
(c 1.8, CHCl3); nmax (CHCl3) 2981 s, 2845 m, 2250 w, 1753
s, 1611 s, 1580 m, and 1512 cmK1 s; dH 1.15 (3H, t JZ
7.2 Hz, CH3), 3.76 (3H, s, OCH3), 4.3–4.4 (2H, m, OCH2),

Y. N. Belokon’ et al. / Tetrahedron 60 (2004) 10433–10447
10443
6.13 (1H, s, OCHCN), 6.88 (2H, d JZ8.8 Hz, ArH), 7.41
(2H, d JZ8.8 Hz, ArH); dC 161.73 (CO3), 153.86 (ArC),
130.11 (ArCH), 123.73 (ArC), 116.34 (CN), 114.97
(ArCH), 66.53 (OCH), 65.86 (OCH2), 55.82 (OCH3),
14.50 (CH3); m/z (ES) 253 (MCNHC4 , 15), 146 (100).
Found (ES) 253.1186, C12H17N2O4 (MCNHC4 ) requires
253.1183. GC conditions: initial temperature 100 8C, ramp
rate 0.4 8C/min. TR 46.3 (major isomer) and 47.3 (minor
isomer) min.
(ArCH), 125.39 (q JZ68 Hz, CF3), 126.72 (ArCH), 115.51
(CN), 66.71 (OCH2), 65.86 (OCH), 14.46 (CH3); m/z (EI)
273 (MC, 18), 201 (100), 173 (99), 134 (35). Found (ES)
274.0674, C12H11NO3F3 (MHC) requires 274.0691. GC
conditions: initial temperature 100 8C, ramp rate 0.4 8C/
min. TR 80.2 (minor isomer) and 83.5 (major isomer) min.
4.2.7. O-Ethoxycarbonyl (S)-2-hydroxy-2-(4-chloro-
phenyl)acetonitrile 2g. Yield 1.08 g, 96%; [a]2D0ZK2.9
(c 1.3, CHCl3); nmax (CHCl3) 3096 m, 3071 m, 2986 s, 2875
m, 2249 w, 1758 s, 1599 s, and 1582 cmK1 m; dH 1.29 (3H, t
JZ7.2 Hz, CH3), 4.2–4.3 (2H, m, OCH2), 6.17 (1H, s,
OCHCN), 7.2–7.5 (4H, m, ArH); dC 153.68 (CO3), 137.31
(ArC), 130.17 (ArC), 129.96 (ArCH), 129.65 (ArCH),
115.78 (CN), 66.17 (OCH2), 66.01 (OCH), 14.49 (CH3); m/z
(EI) 241 ((37Cl)MC, 15), 239 ((35Cl)MC, 50), 211 (17), 167
(70), 150 (97), 139 (100), 114 (38). Found (ES) 257.0685,
C11H14N2O335Cl (MCNHC4 ) requires 257.0687. GC con-
ditions: initial temperature 100 8C, hold at initial tempera-
ture for 2 min then ramp rate 0.2 8C/min. TR 129.1 (minor
isomer) and 131.5 (major isomer) min.
4.2.3. O-Ethoxycarbonyl (S)-2-hydroxy-2-(3-methoxy-
phenyl)acetonitrile 2c. Yield 1.04 g, 94%; [a]2D0ZK11.3
(c 1.2, CHCl3); nmax (CHCl3) 3095 s, 2975 s, 2835 s, 2342
w, and 1755 cmK1 s; dH 1.38 (3H, t JZ7.1 Hz, CH3), 3.86
(3H, s, OCH3), 4.2–4.3 (2H, m, OCH2), 6.25 (1H, s,
OCHCN), 7.0–7.4 (4H, m, ArH); dC 160.53 (CO3), 153.80
(ArC), 132.92 (ArC), 130.79 (ArCH), 120.36 (ArCH),
116.79 (ArCH), 116.13 (CN), 113.48 (ArCH), 66.64 (OCH),
66.05 (OCH2), 55.84 (OCH3), 14.52 (CH3); m/z (EI) 235
(MC, 30), 146 (100), 134 (93). Found (ES) 236.00902,
C12H14NO4 (MHC) requires 236.0923. GC conditions:
initial temperature 100 8C, ramp rate 0.3 8C/min. TR 174.3
(minor isomer) and 178.6 (major isomer) min.
4.2.8. O-Ethoxycarbonyl (S)-2-hydroxy-4-phenyl-but-3-
enonitrile 2h. Yield 0.51 g, 47%; [a]2D0ZK23.4 (c 1.9,
CHCl3); nmax (CHCl3) 3060 m, 2987 s, 2862 m, 2341 w,
2206 w, 1957 w, 1754 s, 1655 m, 1619 m, 1577 m, 1556 m,
and 1541 cmK1 m; dH 1.29 (3H, t JZ7.1 Hz, CH3), 4.1–4.2
(2H, m, OCH2), 5.81 (1H, d JZ6.8 Hz, OCHCN), 6.14 (1H,
dd JZ15.8, 6.8 Hz, PhCH]CH), 6.92 (1H, d JZ15.9 Hz,
PhCH]), 7.2–7.4 (5H, m, ArH); dC 153.50 (CO3), 138.80
(ArCH), 134.67 (ArC), 129.94 (]CH), 129.36 (ArCH),
127.67 (ArCH), 118.25 (]CH), 115.51 (CN), 65.96
(OCH2), 65.36 (OCH), 14.53 (CH3); m/z (EI) 231 (MC,
3), 158 (64), 142 (100), 131 (70), 115 (90). Found (ES)
249.1235, C13H17N2O3 (MCNHC4 ) requires 249.1234. GC
conditions: initial temperature 100 8C, hold at initial
temperature for 2 min then ramp rate 0.2 8C/min. TR 212.8
(minor isomer) and 220.0 (major isomer) min.
4.2.4. O-Ethoxycarbonyl (S)-2-hydroxy-2-(2-methoxy-
phenyl)acetonitrile 2d. Yield 1.05 g, 95%; [a]2D0ZC57.0
(c 1.4, CHCl3); nmax (CHCl3) 2976 s, 2839 s, 2508 w, 2248
w, 1760 s, and 1598 cmK1 s; dH 1.26 (3H, t JZ7.1 Hz,
CH3), 3.81 (3H, s, OCH3), 4.2–4.3 (2H, m, OCH2), 6.51
(1H, s, OCHCN), 6.85 (1H, dd JZ8.3, 1.6 Hz, ArH), 6.96
(1H, dt JZ8.2, 1.6 Hz, ArH), 7.38 (1H, dt JZ8.2, 1.6, Hz,
ArH), 7.51 (1H, dd JZ8.2, 1.6 Hz, ArH); dC 157.41 (CO3),
154.17 (ArC), 132.69 (ArCH), 129.53 (ArCH), 121.63
(ArCH), 120.17 (ArC), 116.58 (CN), 111.75 (ArCH), 66.06
(OCH2), 62.35 (OCH), 56.04 (OCH3), 14.79 (CH3); m/z (EI)
235 (MC, 10), 145 (73), 135 (100), 116 (26), 91 (28). Found
(CI) 253.1188, C12H17N2O4 (MCNHC4 ) requires 253.1183.
GC conditions: initial temperature 100 8C, hold at initial
temperature for 2 min then ramp rate 0.2 8C/min. TR 163.5
(minor isomer) and 167.6 (major isomer) min.
4.2.9. O-Ethoxycarbonyl (S)-2-hydroxy-decanonitrile 2i.
Yield 0.61 g, 54%; [a]2D0ZK66.0 (c 1.0, CHCl3); nmax
(CHCl3) 2925 s, 2861 s, 2351 w, and 1756 cmK1 s; dH 0.90
(3H, t JZ6.8 Hz, CH3), 1.36 (3H, t JZ7.2 Hz, CH3), 1.3–
1.6 (12H, m, (CH2)6), 1.9–2.0 (2H, m, CH2), 4.2–4.4 (2H,
m, OCH2), 5.20 (1H, t JZ6.7 Hz, OCHCN); dC 154.01
(CO3), 116.96 (CN), 65.74 (OCH2), 65.10 (OCH), 32.75
(CH2), 32.12 (CH2), 29.56 (CH2), 29.43 (CH2), 29.16
(CH2), 24.78 (CH2), 24.98 (CH2), 14.50 (CH3), 14.47
(CH3); m/z (CI) 242 (MHC, 20), 168 (20), 122 (58), 98 (90),
81 (100). Found (ES) 259.2013, C13H27N2O3 (MCNHC4 )
requires 259.2016. GC conditions: initial temperature
100 8C, ramp rate 0.4 8C/min. TR 101.3 (minor isomer)
and 103.1 (major isomer) min.
4.2.5. O-Ethoxycarbonyl (S)-2-hydroxy-2-(4-methyl-
phenyl)acetonitrile 2e. Yield 0.69 g, 67%; [a]2D0ZK5.1
(c 2.0, CHCl3); nmax (CHCl3) 2986 s, 2874 m, 2247 w, 1756
s, 1616 s, 1576 w, and 1516 cmK1 s; dH 1.33 (3H, t JZ
7.1 Hz, CH3), 2.41 (3H, s, CH3Ar), 4.3–4.4 (2H, m, OCH2),
6.25 (1H, s, OCHCN), 7.18 (2H, d JZ7.9 Hz, ArH), 7.45
(2H, d JZ8.2 Hz, ArH); dC 153.86 (CO3), 141.33 (ArC),
130.30 (ArCH), 128.76 (ArC), 128.31 (ArCH), 116.28
(CN), 66.69 (OCH), 65.91 (OCH2), 21.70 (CH3Ar), 14.50
(CH3CH2); m/z (EI) 219 (MC, 50), 146 (40), 130 (100), 119
(90), 103 (38), 77 (23). Found (CI) 237.1232, C12H17N2O3
(MCNHC4 ) requires 237.1234. GC conditions: initial
temperature 100 8C, hold at initial temperature for 2 min
then ramp rate 0.2 8C/min. TR 109.5 (minor isomer) and
111.1 (major isomer) min.
4.2.10. O-Ethoxycarbonyl (S)-2-hydroxy-3-methyl-buta-
nonitrile 2j. Yield 0.18 g, 23%; [a]2D0ZK59.8 (c 1.2,
CHCl3); nmax (CHCl3) 2976 m, 2881 m, 2236 w, and
1758 cmK1 s; dH 1.1–1.2 (6H, m, (CH3)2), 1.34 (3H, t JZ
7.2 Hz, CH3CH2), 2.1–2.2 (1H, m, CHMe2), 4.3–4.4 (2H,
m, OCH2), 5.05 (1H, d JZ5.8 Hz, OCHCN); dC 154.12
(CO3), 116.05 (CN), 70.36 (OCH), 65.75 (OCH2), 31.61
(Me2CH), 18.04 (CH3CH), 17.65 (CH3CH), 14.50
(CH3CH2); m/z (ES) 172 (MHC, 100), 145 (7), 128 (6),
4.2.6. O-Ethoxycarbonyl (S)-2-hydroxy-2-(4-trifluoro-
methylphenyl)acetonitrile 2f. Yield 1.08 g, 84%; nmax
(CHCl3) 2982 m, 2939 m, 2356 w, 1760 s, and 1621 cmK1
m; dH 1.37 (3H, t JZ7.1 Hz, CH3), 4.3–4.4 (2H, m, OCH2),
6.35 (1H, s, OCHCN), 7.69–7.77 (4H, m, ArH) dC 153.61
(CO3), 135.38 (ArC), 133.05 (q JZ8 Hz, ArCCF3), 128.55

10444
Y. N. Belokon’ et al. / Tetrahedron 60 (2004) 10433–10447
82 (13), 57 (33). Found (CI) 189.1229, C8H17N2O3 (MC
NHC4 ) requires 189.1234. GC conditions: initial temperature
60 8C, ramp rate 5.0 8C/min. TR 16.1 (minor isomer) and
16.2 (major isomer) min.
4.3.2. O-Pivaloyl (S)-2-hydroxy-2-phenyl-acetonitrile
3c.24a Yield 85%; [a]D25K1.1 (c 3.0, CHCl3); nmax (neat)
2978 s, 1809 m, and 1742 cmK1 s; dH 1.26 (9H, s, (CH3)3),
6.40 (1H, s, CH), 7.4–7.6 (5H, m ArCH); dC 174.25 (CO2),
132.43 (ArC), 130.54 (ArCH), 129.55 (ArCH), 127.80
(ArCH), 116.61 (CN), 63.14 (OCH), 40.49 (C), 26.94
(CH3); m/z (EI) 217 (MC, 75), 116 (68), 57 (100). Found
(ES) 240.0996, C13H15NO2Na (MCNaC) requires
240.1000. GC conditions: initial temperature 100 8C, hold
at initial temperature for 2 min then ramp rate 0.4 8C/min.
TR 18.6 (minor isomer) and 18.8 (major isomer) min.
4.2.11. O-Ethoxycarbonyl (S)-2-hydroxy-2-cyclohexyl-
ethanonitrile 2k. Yield 0.81 g, 82%; [a]2D0ZK32.2 (c
1.3, CHCl3); nmax (CHCl3) 2934 s, 2857 s, 2245 m, and
1756 cmK1 s; dH 1.2–1.3 (6H, m, (CH2)3), 1.33 (3H, t JZ
7.2 Hz, CH3), 1.7–2.0 (5H, m, CH2CHCH2), 4.2–4.3 (2H,
m, OCH2), 5.04 (1H, d JZ5.8 Hz, OCHCN); dC 154.16
(CO3), 116.21 (CN), 69.63 (OCH), 65.71 (OCH2), 40.52
(CH), 28.34 (CH2), 28.16 (CH2), 26.06 (CH2), 25.68 (CH2),
25.60 (CH2), 14.49 (CH3); m/z (CI) 212 (MHC, 100), 129
(46), 95 (33), 83 (79), 55 (90). Found (CI) 229.1548,
C11H21N2O3 (MCNHC4 ) requires 229.1547. GC conditions:
initial temperature 60 8C, hold at initial temperature for
2 min then ramp rate 0.2 8C/min. TR 274.0 (minor isomer)
and 276.4 (major isomer) min.
4.3.3. O-Benzoyl (S)-2-hydroxy-2-phenyl-acetonitrile
3d.25a Yield 98%; [a]D25K9.3 (c 2.0, CHCl3); nmax (neat)
3065 m, 1785 s, and 1598 cmK1 s; dH 6.61 (1H, s, CH), 7.3–
7.4 (6H, m, ArH), 7.5–7.6 (2H, m, ArH), 8.0–8.0 (2H, m,
ArH); dC 162.78 (CO2), 135.30 (ArC), 134.99 (ArC), 131.32
(ArCH), 130.68 (ArCH), 129.32 (ArCH), 128.98 (ArCH),
128.27 (ArCH), 116.68 (CN), 63.80 (OCH), m/z (ES) 475
(2MCHC, 55), 411 (15), 260 (MCNaC, 40), 249 (100).
Found (ES) 238.0873, C15H12NO2 (MHC) requires
238.0868. GC conditions: initial temperature 100 8C, hold
at initial temperature for 2 min then ramp rate 5.0 8C/min.
TR 17.3 (minor isomer) and 18.0 (major isomer) min.
4.2.12. O-Ethoxycarbonyl (S)-2-hydroxy-3,3-dimethyl-
butanonitrile 2l. Yield 0.60 g, 69%; [a]2D0ZK48.5 (c 2.0,
CHCl3); nmax (CHCl3) 2976 s, 2237 w, and 1754 cmK1 s; dH
1.05 (9H, s, C(CH3)3), 1.26 (3H, t JZ7.1 Hz, CH3CH2),
4.2–4.3 (2H, m, OCH2), 4.85 (1H, s, OCHCN); dC 151.32
(CO3), 116.14 (CN), 73.57 (OCH), 65.65 (OCH2), 35.27
(CMe3), 25.48 (CH3CH2), 14.51 (C(CH3)3); m/z (CI) 186
(MHC, 88), 96 (43), 57 (100), 41 (49). Found (CI)
203.1396, C9H19N2O3 (MCNHC4 ) requires 203.1390. GC
conditions: initial temperature 100 8C, hold at initial
temperature for 2 min then ramp rate 0.2 8C/min. TR 13.9
(minor isomer) and 14.2 (major isomer) min.
4.3.4. O-Propanoyl (S)-2-hydroxy-4-phenyl-but-3-enoni-
trile 3e. Yield 62%; [a]2D5K2.0 (c 1.0, CHCl3); nmax (neat)
2989 m, and 1760 cmK1 s; dH 1.11 (3H, t JZ7.3 Hz,
CH2CH3), 2.4–2.5 (2H, m, CH2CH3), 6.06 (1H, d JZ
7.5 Hz, CHCN), 6.17 (1H, dd JZ15.8, 6.7 Hz,
PhCH]CH), 6.96 (1H, d JZ15.8 Hz, PhCH]), 7.2–7.5
(5H, m, ArH); dC 172.84 (CO2), 138.15 (ArC), 134.83
(]CH), 129.78 (ArCH), 129.24 (ArCH), 127.57 (ArCH),
118.87 (]CH), 116.00 (CN), 61.81 (OCH), 27.54 (CH2),
9.15 (CH3); m/z (EI) 215 (MC, 14), 159 (51), 141 (93), 115
(100), 57 (74). Found (ES) 238.0911, C13H13NO2Na (MC
NaC) requires 238.0838. GC conditions: initial temperature
100 8C, hold at initial temperature for 2 min then ramp rate
2.0 8C/min. TR 43.0 (minor isomer) and 44.9 (major isomer)
min.
4.3. General procedure for the asymmetric addition of
potassium cyanide and an anhydride to aldehydes
To a stirred mixture, cooled at K90 8C, of KCN (2.54 g,
39.2 mmol) and catalyst 1 (118 mg, 0.098 mmol) in dry
dichloromethane (20 mL), t-BuOH (0.98 mL, 10.3 mmol),
water (0.1 mL, 4.4 mmol), aldehyde (9.8 mmol) and
anhydride (39.2 mmol) were added. The reaction was
warmed to K40 8C, monitored by chiral GC at suitable
intervals and allowed to stir until the reaction was O90%
complete. Solid salts were filtered and washed thoroughly
with dichloromethane. The filtrate was passed through a pad
of silica (10 mm!50 mm) eluting with dichloromethane to
remove catalyst 1. The solvent was evaporated in vacuo, and
the residue purified by distillation or flash chromatography
(ethyl acetate/hexane 1/5) to give the (S)-cyanohydrin ester.
4.3.5. O-Pivaloyl (S)-2-hydroxy-4-phenyl-but-3-enoni-
trile 3f. Yield 50%; [a]2D5C10.1 (c 4.0, CHCl3), nmax
(neat) 2976 s, 1744 s, and 1480 cmK1 s; dH 1.19 (9H, s,
(CH3)3), 5.94 (1H, d ?Z6.7 Hz, CHCN), 6.12 (1H, dd JZ
15.8, 6.7 Hz, PhCH]CH), 6.89 (1H, d JZ15.8 Hz,
PhCH]), 7.2–7.4 (5H, m, ArH); dC 176.89 (CO2), 138.03
(]CH), 134.87 (ArC), 129.77 (ArCH), 129.24 (ArCH),
127.58 (ArCH), 118.90 (]CH), 116.05 (CN), 61.92 (OCH),
39.30 (CMe3), 27.30 (CH3); m/z (ES) 509 (2MCNaC, 12),
488 (31), 467 (36), 266 (MCNaC, 85), 245 (100), 223 (67),
209 (45), 142 (85). Found (ES) 509.2430 and 266.1148,
4.3.1. O-Propanoyl (S)-2-hydroxy-2-phenyl-acetonitrile
3b.23a Yield 99%; [a]D25K5.09 (c 1.1, CHCl3); nmax (neat)
2987 m, and 1756 cmK1 s; dH 1.20 (3H, t JZ7.5 Hz,
CH2CH3), 2.4–2.5 (2H, m, CH2CH3), 6.62 (1H, s, CH), 7.4–
7.6 (5H, m, ArH); dC 170.67 (CO2), 131.29 (ArC), 129.69
(ArCH), 128.59 (ArCH), 127.16 (ArCH), 115.65 (CN),
62.13 (OCH), 26.70 (CH2), 7.70 (CH3); m/z (EI) 189 (MC,
15), 133 (30), 116 (34), 57 (100)). Found (ES) 212.0685,
C11H11NO2Na (MCNaC) requires 212.0685. GC con-
ditions: initial temperature 100 8C, hold at initial tempera-
ture for 2 min then ramp rate 5.0 8C/min. TR 14.5 (minor
isomer) and 14.9 (major isomer) min.
C30H34N2O4Na
(2MCNaC)
requires
509.2416,
C15H17NO2Na (MCNaC) requires 266.1157. GC con-
ditions: initial temperature 100 8C, hold at initial tempera-
ture for 2 min then ramp rate 5.0 8C/min. TR 25.5 (minor
isomer) and 25.7 (major isomer) min.
4.3.6. O-Propanoyl (S)-2-hydroxy-2-(4-trifluoromethyl-
phenyl)-acetonitrile 3g. Yield 99%; [a]2D5K1.1 (c 12.0,
CHCl3); nmax (neat) 2989 m, and 1760 cmK1 s; dH 1.16 (3H,
t JZ7.5 Hz, CH2CH3), 2.4–2.5 (2H, m, CH2CH3), 6.45 (1H,
s, CH), 6.6–7.7 (4H, m, ArH); dC 172.64 (CO2), 135.99

Y. N. Belokon’ et al. / Tetrahedron 60 (2004) 10433–10447
10445
(ArC), 132.70 (q JZ33 Hz, CF3), 126.69 (ArCH), 125.41
(ArCH), 116.00 (CN), 62.39 (OCH), 27.47 (CH2), 9.08
(CH3); m/z (EI) 257 (MC, 25), 238 (30), 201 (75), 184 (80),
57 (100). Found (ES) 280.0555, C12H10NO2F3Na (MC
NaC) requires 280.0551. GC conditions: initial temperature
100 8C, hold at initial temperature for 2 min then ramp rate
3.0 8C/min. TR 21.2 (minor isomer) and 22.0 (major isomer)
min.
4.3.11. O-Propanoyl (S)-2-hydroxy-3,3-dimethyl-butano-
nitrile 3p. Yield 99%; [a]2D5K3.8 (c 2.0, CHCl3); nmax
(neat) 2971 s, 2878 s, and 1754 cmK1 s; dH 1.09 (9H, s,
(CH3)3), 1.18 (3H, t JZ7.5 Hz, CH2CH3), 2.38 (2H, q JZ
7.6 Hz, CH3CH2), 5.07 (1H, s, OCH); dC 171.59 (CO2),
116.56 (CN), 69.59 (OCH), 35.08 (CMe3), 32.84 (CH2),
25.60 (CH3), 8.42 (CH3); m/z (CI) 170 (MHC, 42), 113 (15),
57 (100). GC conditions: initial temperature 100 8C, hold at
initial temperature for 2 min then ramp rate 5.0 8C/min. TR
20.7 (minor isomer) and 21.2 (major isomer) min.
4.3.7. O-Pivaloyl (S)-2-hydroxy-2-(4-trifluoromethyl-
phenyl)-acetonitrile 3h. Yield 99%; [a]2D5K5.4 (c 2.0,
CHCl3); nmax (neat) 2979 s, 1808 m, and 1749 cmK1 s; dH
1.29 (9H, s, (CH3)3), 6.48 (1H, s, CH), 7.66 (2H, d JZ
8.3 Hz, ArCH), 7.74 (2H, d JZ8.3 Hz ArCH); dC 175.31
(CO2), 136.19 (ArC), 132.99 (q JZ33 Hz, CF3), 128.25
(ArC), 126.72 (ArCH), 122.41 (ArCH), 116.02 (CN), 62.46
(OCH), 39.29 (C), 27.18 (CH3); m/z (ES) 308 (MCNaC,
100), 184 (40). Found (ES) 308.0867, C14H14NO2F3Na
(MCNaC) requires 308.0869. GC conditions: initial
temperature 100 8C, hold at initial temperature for 2 min
then ramp rate 0.4 8C/min. TR 21.3 (minor isomer) and 21.6
(major isomer) min.
4.3.12. O-Propanoyl (S)-2-hydroxy-2-(2-methylphenyl)-
acetonitrile 3q. Yield 99%; [a]2D5K13.0 (c 6.0, CHCl3);
nmax (neat) 2984 m, and 1753 cmK1 s; dH 1.23 (3H, t JZ
7.4 Hz, CH2CH3), 2.4–2.5 (2H, m, CH2CH3), 2.45 (3H, s,
CH3Ar), 6.55 (1H, s, OCH), 7.2–7.4 (3H, m, ArH), 7.5–7.6
(1H, m, ArH); dC 172.78 (CO2), 137.05 (ArC), 131.70
(ArC), 130.83 (ArCH), 130.36 (ArCH), 128.89 (ArCH),
127.18 (ArCH), 116.49 (CN), 61.34 (OCH), 27.40 (CH2),
19.29 (ArCH3), 9.16 (CH3); m/z (EI) 203 (MC, 10), 129
(100), 103 (48). Found (ES) 226.0837, C12H13NO2Na (MC
NaC) requires 226.0838. GC conditions: initial temperature
100 8C, hold at initial temperature for 2 min then ramp rate
5.0 8C/min. TR 19.4 (minor isomer) and 19.9 (major isomer)
min.
4.3.8. O-Propanoyl (S)-2-hydroxy-2-(3-methoxyphenyl)-
acetonitrile 3j. Yield 87%; [a]2D5K2.1 (c 3.0, CHCl3); nmax
(neat) 2984 m, 2945 m, and 1754 cmK1 s; dH 1.19 (3H, t JZ
7.6 Hz, CH2CH3), 2.4–2.5 (2H, m, CH2CH3), 3.84 (s, 3H,
OCH3), 6.40 (1H, s, CH), 7.0–7.4 (4H, m, ArH); dC 172.80
(CO2), 160.49 (ArC), 133.58 (ArC), 130.74 (ArCH), 120.58
(ArCH), 116.60 (ArCH), 116.31 (CN), 113.61 (ArCH),
62.99 (OCH), 55.81 (OCH3), 27.51 (CH2), 9.14 (CH3); m/z
(EI): 219 (MC, 42), 163 (100), 146 (39), 57 (34). Found
(ES) 242.0787, C12H13NO3Na (MCNaC) requires
242.0782. GC conditions: initial temperature 100 8C, hold
at initial temperature for 2 min then ramp rate 5.0 8C/min.
TR 15.1 (minor isomer) and 15.3 (major isomer) min.
4.3.13. O-Propanoyl (S)-2-hydroxy-2-(3-methylphenyl)-
acetonitrile 3r. Yield 98%; [a]2D5K2.0 (c 1.0, CHCl3); nmax
(neat) 2985 m, 2945 m, and 1753 cmK1 s; dH 1.26 (3H, t JZ
5.9 Hz, CH2CH3), 2.32 (3H, s, CH3Ar), 2.4–2.5 (2H, m,
CH2CH3), 6.32 (1H, s, OCH), 7.2–7.3 (4H, m, ArH); dC
172.84 (CO2), 139.60 (ArC), 132.21 (ArC), 131.49 (ArCH),
129.51 (ArCH), 128.81 (ArCH), 122.30 (ArCH), 116.49
(CN), 61.18 (OCH), 27.53 (CH2), 21.72 (ArCH3), 9.14
(CH3); m/z (ES) 226 (MCNaC, 100). Found (ES) 226.0837,
C12H13NO2Na (MCNaC) requires 226.0838. GC con-
ditions: initial temperature 100 8C, hold at initial tempera-
ture for 2 min then ramp rate 5.0 8C/min. TR 16.3 (minor
isomer) and 16.5 (major isomer) min.
4.3.9. O-Propanoyl (S)-2-hydroxy-2-(4-methoxyphenyl)-
acetonitrile 3l. Yield 71%; [a]2D5C12.7 (c 11.4, CHCl3);
nmax (neat) 3022 w, 2944 m, and 1752 cmK1 s; dH 1.23 (3H,
t JZ7.5 Hz, CH2CH3), 2.4–2.5 (2H, m, CH2CH3), 3.89 (3H,
s, OCH3), 6.43 (1H, s, CH), 6.9–7.0 (2H, m, ArH), 7.4–7.5
(2H, m, ArH); dC 172.82 (CO2), 160.48 (ArC), 133.57
(ArC), 130.75 (ArCH), 120.28 (ArCH), 116.62 (CN), 63.01
(OCH), 55.82 (OCH3), 27.52 (CH2), 9.14 (CH3); m/z (EI)
219 (MC, 32), 163 (35), 146 (100). Found (ES) 242.0783,
C12H13NO3Na (MCNaC) requires 242.0782. GC con-
ditions: initial temperature 100 8C, hold at initial tempera-
ture for 2 min then ramp rate 5.0 8C/min. TR 16.9 (minor
isomer) and 17.3 (major isomer) min.
4.3.14. O-Propanoyl (S)-2-hydroxy-2-(4-methylphenyl)-
acetonitrile 3s. Yield 98%; [a]2D5C3.5 (c 6.0, CHCl3); nmax
(neat) 2985 m, 2845 m, and 1755 cmK1 s; dH 1.18 (3H, t JZ
7.5 Hz, CH2CH3), 2.15 (3H, s, CH3Ar), 2.3–2.5 (2H, m,
CH2), 6.40 (1H, s, CHO), 7.26 (2H, d JZ8.0 Hz, ArCH),
7.46 (2H, d JZ8.1 Hz, ArCH); dC 172.87 (CO2), 140.99
(ArC), 130.26 (ArC), 129.39 (ArCH), 128.20 (ArCH),
116.79 (CN), 63.05 (OCH), 27.51 (CH2), 21.65 (ArCH3),
9.10 (CH3); m/z (ES) 226 (MCNaC, 100), 130 (22). Found
(ES) 226.0790, C12H13NO2Na (MCNaC) requires
226.0838. GC conditions: initial temperature 100 8C, hold
at initial temperature for 2 min then ramp rate 5.0 8C/min.
TR 16.4 (minor isomer) and 16.6 (major isomer) min.
4.3.10. O-Propanoyl (S)-2-hydroxy-3-methyl-butanoni-
trile 3n.23a Yield 99%; [a]D25C3.0 (c 5.0, CHCl3); nmax
(neat) 2970 s, 2879 s, and 1754 cmK1 s; dH 1.07 (6H, d JZ
6.8 Hz, (CH3)2CH), 1.17 (3H, t JZ7.6 Hz, CH3CH2), 2.1–
2.2 (1H, m, CHMe2), 2.3–2.5 (2H, m, CH2CH3), 5.17 (1H, d
JZ5.8 Hz, OCH); dC 173.03 (CO2), 116.48 (CN), 66.55
(OCH), 31.44 (CH), 27.43 (CH2), 18.12 (CH3), 17.73 (CH3),
9.17 (CH3); m/z (CI) 156 (MHC, 26), 57 (100). GC
conditions: initial temperature 60 8C, hold at initial
temperature for 2 min then ramp rate 5.0 8C/min. TR 14.1
(minor isomer) and 14.5 (major isomer) min.
4.3.15. O-Propanoyl (S)-2-hydroxy-2-(4-chlorophenyl)-
acetonitrile 3t. Yield 99%; [a]2D5C13.3 (c 3.0, CHCl3);
nmax (neat) 2986 s, 2945 s, and 1754 cmK1 s; dH 1.15 (3H, t
JZ7.4 Hz, CH2CH3), 2.4–2.5 (2H, m, CH2CH3), 6.37 (1H,
s, OCH), 7.4–7.5 (4H, m, ArH); dC 172.72 (CO2), 136.99
(ArC), 130.79 (ArC), 129.91 (ArCH), 129.61 (ArCH),
116.24 (CN), 62.43 (OCH), 27.49 (CH2), 9.22 (CH3); m/z
(EI) 225 ((37Cl)MC, 18), 223 ((35Cl)MC, 51), 150 (100), 57
(90). Found (ES) 246.0293, C11H10NO325ClNa ((35Cl)MC

10446
Y. N. Belokon’ et al. / Tetrahedron 60 (2004) 10433–10447
NaC) requires 246.0230. GC conditions: initial temperature
100 8C, hold at initial temperature for 2 min then ramp rate
5.0 8C/min. TR 21.9 (minor isomer) and 23.0 (major isomer)
min.
mass spectrometry service at the University of Wales,
Swansea.
4.3.16. O-Propanoyl (S)-2-hydroxy-decanonitrile 3u.
Yield 74%; [a]D25K3.7 (c 10.6, CHCl3); nmax (neat) 2928
s, 2850 m, and 1752 cmK1 s; dH 0.88 (3H, t JZ7.1 Hz,
CH3(CH2)7), 1.19 (3H, t JZ7.5 Hz, CH2CH3), 1.30–1.32
(12H, m, (CH2)6), 1.9–2.0 (2H, m, CH2CH), 2.4–2.5 (2H, m,
CH2CO), 5.34 (1H, t JZ6.8 Hz, OCH); dC 173.06 (CO2),
117.44 (CN), 61.37 (OCH), 32.71 (CH2), 32.15 (CH2),
29.47 (CH2), 29.19 (CH2), 27.48 (CH2), 24.92 (CH2), 23.01
(CH2), 17.73 (CH2), 14.45 (CH3), 9.16 (CH3); m/z (CI) 226
(MHC, 24), 81 (51), 57 (100). Found (ES) 248.1617,
C13H23NO2Na (MCNaC) requires 248.1628. GC con-
ditions: initial temperature 100 8C, hold at initial tempera-
ture for 2 min then ramp rate 5.0 8C/min. TR 16.6 (minor
isomer) and 17.2 (major isomer) min.
References and notes
1. For a comprehensive review see: North, M. Tetrahedron:
Asymmetry 2003, 14, 147–176.
2. (a) Belokon’, Y.; Ikonnikov, N.; Moscalenko, M.; North, M.;
Orlova, S.; Tararov, V.; Yashkina, L. Tetrahedron: Asymmetry
1996, 7, 851–855. (b) Belokon’, Y.; Flego, M.; Ikonnikov, N.;
Moscalenko, M.; North, M.; Orizu, C.; Tararov, V.; Tasinazzo,
M. J. Chem. Soc., Perkin Trans. 1 1997, 1293–1295. (c)
Belokon’, Y. N.; Yashkina, L. V.; Moscalenko, M. A.;
Chesnokov, A. A.; Kublitsky, V. S.; Ikonnikov, N. S.; Orlova,
S. A.; Tararov, V. I.; North, M. Russ. Chem. Bull. 1997, 46,
1936–1938. (d) Tararov, V. I.; Hibbs, D. E.; Hursthouse,
M. B.; Ikonnikov, N. S.; Malik, K. M. A.; North, M.;
Orizu, C.; Belokon’, Y. N. Chem. Commun. 1998,
387–388. (e) Tararov, V. I.; Orizu, C.; Ikonnikov, N. S.;
Larichev, V. S.; Moscalenko, M. A.; Yashkina, L. V.; North, M.;
Belokon’, Y. N. Russ. Chem. Bull. 1999, 48, 1128–1130.
3. Belokon’, Y. N.; Caveda-Cepas, S.; Green, B.; Ikonnikov,
N. S.; Khrustalev, V. N.; Larichev, V. S.; Moscalenko,
M. A.; North, M.; Orizu, C.; Tararov, V. I.; Tasinazzo,
M.; Timofeeva, G. I.; Yashkina, L. V. J. Am. Chem. Soc.
1999, 121, 3968–3973.
4.3.17. O-Propanoyl (S)-2-hydroxy-2-cyclohexyl-aceto-
nitrile 3v.23a Yield 95%; [a]D25K7.5 (c 13.6, CHCl3); nmax
(neat) 3025 w, 2931 m, 1813 m, and 1752 cmK1 s; dH 1.19
(3H, t JZ7.4 Hz, CH3), 1.1–1.4 (6H, m, (CH2)3), 1.7–2.0
(4H, m, (CH2CHCH2), 2.4–2.5 (3H, m, CH(CH2)2C
CH3CH2), 5.20 (1H, d JZ6.0 Hz, OCH); dC 170.84
(CO2), 116.61 (CN), 65.73 (OCH), 40.30 (CH), 29.06
(CH2), 28.69 (CH2), 28.40 (CH2), 27.01 (CH2), 26.35
(CH2), 25.61 (CH2), 9.09 (CH3); m/z (CI) 196 (MHC, 80),
113 (45), 57 (100). GC conditions: initial temperature
100 8C, hold at initial temperature for 2 min then ramp rate
5.0 8C/min. TR 16.7 (minor isomer) and 16.9 (major isomer)
min.
4. Belokon’, Y. N.; Green, B.; Ikonnikov, N. S.; Larichev,
V. S.; Lokshin, B. V.; Moscalenko, M. A.; North, M.;
Orizu, C.; Peregudov, A. S.; Timofeeva, G. I. Eur. J. Org.
Chem. 2000, 2655–2661.
5. (a) Belokon’, Y. N.; Green, B.; Ikonnikov, N. S.; North, M.;
Tararov, V. I. Tetrahedron Lett. 1999, 40, 8147–8150. (b)
Belokon’, Y. N.; Green, B.; Ikonnikov, N. S.; North, M.;
Parsons, T.; Tararov, V. I. Tetrahedron 2001, 57, 771–779.
6. Lu, S.-f.; Herbert, B.; Haufe, G.; Laue, K. W.; Padgett,
W. L.; Oshunlei, O.; Daly, J. W.; Kirk, K. L. J. Med.
Chem. 2000, 43, 1611–1619.
4.4. General procedure for the use of a sacrificial
aldehyde
To a stirred mixture, cooled to K40 8C, of KCN (2.54 g,
39.21 mmol), complex 1 (9 mg, 0.098 mmol), t-BuOH
(0.098 mL, 10.3 mmol) and water (0.1 mL, 4.4 mmol), in
dry dichloromethane (20 mL), the sacrificial aldehyde (2 or
10 mol%, 0.16 mmol or 0.83 mmol) and propionic anhy-
dride (5.03 mL, 39.3 mmol) were added. The reaction was
left for 3–5 h at K40 8C and monitored by GC chiral
analysis. The real aldehyde (90 or 98 mol%, 8.5 or
9.25 mmol) was then added and the reaction was monitored
by TLC (ethyl acetate/hexane) and chiral GC (for both
aldehydes) until the reaction was complete (ca 48 h). The
reaction was warmed to room temperature; solids were
removed by filtration and washed thoroughly with dichloro-
methane. To remove the catalyst, the filtrate was passed
through a pad of silica (10 mm!50 mm) eluting with
dichloromethane. The solvent was evaporated in vacuo, and
the resulting yellowish residue purified by flash chroma-
tography (ethyl acetate/hexane) or distillation.
7. Belokon’, Y. N.; North, M.; Parsons, T. Org. Lett. 2000, 2,
1617–1619.
8. Belokon’, Y. N.; Gutnov, A. V.; Moskalenko, M. A.;
Yashkina, L. V.; Lesovoy, D. E.; Ikonnikov, N. S.; Larichev,
V. S.; North, M. Chem. Commun. 2002, 244–245.
9. Belokon’, Y. N.; Carta, P.; Gutnov, A. V.; Maleev, V.;
Moskalenko, M. A.; Yashkina, L. V.; Ikonnikov, N. S.;
Voskoboev, N. V.; Khrustalev, V. N.; North, M. Helv. Chim.
Acta 2002, 85, 3301–3312.
10. For a preliminary report of some of this work see: Belokon’,
Y. N.; Carta, P.; North, M. Lett. Org. Chem. 2004, 1, 81–83.
11. The potassium cyanide methodology has been patented
(WO0210095 and WO03099435) and is licenced to Avecia
Ltd. The technology is being commercialised under the
tradename CACHy.
12. See for examples: (a) Okimoto, M.; Chiba, T. Synthesis 1996,
1188–1190. (b) Poirier, D.; Berthiaume, D.; Boivin, R. P.
Synlett 1999, 1423–1425. (c) Berthiaume, D.; Poirier, D.
Tetrahedron 2000, 56, 5995–6003. (d) Deardorff, D. R.;
Taniguchi, C. M.; Tafti, S. A.; Kim, H. Y.; Choi, S. Y.;
Downey, K. J.; Nguyen, T. V. J. Org. Chem. 2001, 66,
7191–7194.
Acknowledgements
The authors thank the EPSRC and Avecia Ltd for financial
support and research studentships (to LC and PC). Low and
high resolution mass spectra were recorded by the EPSRC

Y. N. Belokon’ et al. / Tetrahedron 60 (2004) 10433–10447
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22. For the synthesis of racemic cyanohydrin benzoates see: (a)
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´ ´
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(a) Kanerva, L. T.; Kiljunen, E.; Huuhtanen, T. T. Tetra-
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Belokon’, Y. N.; Blacker, A. J.; Clutterbuck, L. A.; North, M.
Org. Lett. 2003, 5, 4505–4507.
19. Trifluoroacetic anhydride was not included in this study as we
have previously shown that it reacts with catalyst 1 to produce
a catalytically inactive (salen)Ti(OCOCF3)2 complex.9
20. For the synthesis of racemic cyanohydrin propionates see: (a)
24. For the synthesis of non-racemic cyanohydrin pivalates see:
(a) Veum, L.; Kuster, M.; Telalovic, S.; Hanefeld, U.;
Maschmeyer, T. Eur. J. Org. Chem. 2002, 1516–1522. (b)
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`
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(a) Warmerdam, E. G. J. C.; Brussee, J.; Kruse, C. G.; van der
Gen, A. Tetrahedron 1993, 49, 1063–1070. (b) Nakamura, K.;
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21. For the synthesis of racemic cyanohydrin pivalates see: (a)
Dinizo, S. E.; Freerksen, R. W.; Pabst, W. E.; Watt, D. S.