Enantioselective and diastereoselective syntheses of cyanohydrin carbonates

Article abstract of DOI:10.1016/j.tet.2007.07.016

A new and general synthesis of alkyl cyanoformates is presented starting from the appropriate alcohol and oxalyl chloride. This is used to prepare enantiomerically pure cyanoformates from enantiomerically pure primary and secondary alcohols. Optimal condi

Full text of DOI:10.1016/j.tet.2007.07.016

Tetrahedron 63 (2007) 9724–9740
Enantioselective and diastereoselective syntheses
of cyanohydrin carbonates
Yuri N. Belokon’,a William Clegg,b Ross W. Harrington,b Eisuke Ishibashi,b,c
Hiroshi Nomurac and Michael Northb,c,
*
aA.N. Nesmeyanov Institute of Organo-Element Compounds, Russian Academy of Sciences,
117813 Moscow, Vavilov 28, Russian Federation
bSchool of Natural Sciences, Bedson Building, Newcastle University, Newcastle upon Tyne NE1 7RU, UK
cDepartment of Chemistry, King’s College London, Strand, London WC2R 2LS, UK
Received 24 April 2007; revised 21 June 2007; accepted 6 July 2007
Available online 13 July 2007
Abstract—A new and general synthesis of alkyl cyanoformates is presented starting from the appropriate alcohol and oxalyl chloride. This is
used to prepare enantiomerically pure cyanoformates from enantiomerically pure primary and secondary alcohols. Optimal conditions for the
addition of various achiral cyanoformates to aldehydes catalysed by an enantiomerically pure titanium(salen) catalyst in the presence of
potassium cyanide as a cocatalyst are developed. Under these conditions, two chiral cyanoformates also reacted with aldehydes to give cya-
nohydrin carbonates. The stereochemistry of this process is predominantly determined by the stereochemistry of the titanium(salen) catalyst
and the stereochemistry of two of the cyanohydrin carbonates was confirmed by X-ray crystallography. In a further extension of the chemistry,
a homogeneous system in which the potassium cyanide/18-crown-6 complex is used as the cyanide cocatalyst has been developed and the
kinetics of this reaction show that it displays first order kinetics, provided at least 2 mol % of the potassium cyanide complex are employed.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
cyanide to carbonyl compounds developed to date are our
titanium5,6 and vanadium6–9 based salen complexes 1 and
2, aluminium complexes 3 and 4 of binol functionalised
One of the success stories in asymmetric catalysis over the
last decade has been the development of effective catalysts
for the asymmetric addition of cyanide to aldehydes and
ketones.1,2 Ten years ago, this simple asymmetric carbon–
carbon bond forming reaction could only be accomplished
using volatile cyanide sources (hydrogen cyanide or trime-
thylsilyl cyanide); reactions using synthetic catalysts typi-
cally required the use of 20–100 mol % of catalyst at low
temperature (typically ꢀ20 to ꢀ80 ꢁC) and reaction times
in excess of 100 h were not uncommon.3 Whilst nature
had provided a family of oxynitrilase enzymes to accomplish
the same transformation, these required the use of hydrogen
cyanide, and were often difficult to isolate (with the notable
exception of the oxynitrilase from almonds) and had a nar-
row substrate range, especially with regard to the use of
ketones as substrates.4
with additional Lewis bases developed by Shibasaki
et al.10 and Najera et al., respectively, and complexes of
11
ꢀ
titanium and lanthanide metals with glucose derived chiral
ligands 5 also discovered by Shibasaki et al.12 Of these, com-
plexes 1 and 2 have the advantages of being active at very
high substrate to catalyst ratios (1000:1) and give cyanohy-
drin trimethylsilyl ethers derived from aldehydes with good
enantiomeric excesses at room temperature. As a result, they
have been widely adopted by other research groups13,14 and
oligomeric, ionic liquid soluble15 and insolubilised versions
of the catalysts have been developed.16 Complexes 3 and 4
have been used to prepare cyanohydrin trimethylsilyl ethers
with even higher enantiomeric excesses, though at lower
temperatures and using lower substrate to catalyst ratios.
Metal complexes of ligands 5 give especially good results
in the addition of trimethylsilyl cyanide to ketones.
The various problems associated with asymmetric cyanohy-
drin synthesis have now largely been solved by advances
made by a number of groups. The three most effective clas-
ses of catalysts for the asymmetric addition of trimethylsilyl
The availability of effective catalysts for asymmetric cyano-
hydrin synthesis along with a mechanistic understanding of
their mode of action has opened up the possibility of using
other, more convenient cyanide sources for asymmetric cya-
nohydrin synthesis as trimethylsilyl cyanide is both volatile
and expensive. Catalysts 1 and 2 (along with polymer sup-
ported versions of these complexes16) are unique in that
Keywords: Titanium; Salen; Cyanohydrin; Cyanoformate; Catalysis.
* Corresponding author. Tel.: +44 191 222 7128; fax: +44 870 131 3783;
e-mail: michael.north@ncl.ac.uk
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.07.016

Y. N. Belokon’ et al. / Tetrahedron 63 (2007) 9724–9740
9725
tBu
tBu
to aldehydes and ketones. Additionally, there is one report
of an enzymatic synthesis of cyanohydrin carbonates,30
and aluminium(salen) complexes have been used to catalyse
the asymmetric addition of cyanoformates to acylsilanes
with concomitant Brook rearrangement.31
tBu
tBu
N
N
O
O
O
N
N
O
Ti
Ti
O
O
In this manuscript, we give full details of our recently dis-
closed25 enantioselective and diastereoselective syntheses
of cyanohydrin carbonates using achiral and chiral cyanofor-
mates, respectively. The mechanism of these reactions has
been probed by studying the reaction kinetics. In addition,
an improved route for the synthesis of alkyl cyanoformates
is presented, and the relative stereochemistry of two of the
cyanohydrin carbonates is rigorously established by X-ray
crystallography.
tBu
tBu
tBu
tBu
X
1
O
V
N
N
tBu
O
H
O
H
tBu
O
tBu
tBu
2. Results and discussion
2
2.1. Synthesis of enantiomerically pure cyanoformates
NEt2
Al Cl
NEt2
POPh2
Al Cl
O
O
Cyanoformates can be synthesised from alcohols by two
main routes32 as shown in Scheme 1. Treatment of an alco-
hol with excess phosgene followed by potassium cyanide in
the presence of 18-crown-6 (route a) provides the most direct
route and has been used to prepare a range of aliphatic cya-
noformates.33 An alternative process was developed for the
synthesis of tert-butyl cyanoformate (route b).34 Thus, reac-
tion of tert-butanol with ethyl oxalyl chloride provides
a mixed oxalic diester. Ammonolysis of the less hindered
ethyl ester then provides an oxamide, which can be dehy-
drated to the desired cyanoformate.
O
O
POPh2
4
3
O
Ph
Ph
HO
X
OH
P
O
O
Y
5
O
O
they are compatible with potassium cyanide in the presence
of an anhydride, thus allowing the direct asymmetric synthe-
sis of cyanohydrin esters.17,18 Complex 1 can also be used
with acyl cyanides to achieve the same transformation under
homogeneous reaction conditions.19 Similarly, the titanium
analogue of complex 4 has been shown to catalyse the asym-
metric addition of benzoyl cyanide to aldehydes.20 Complex
4 has also been shown to accept diethyl cyanophosphonate
as a cyanide source,21,22 thus allowing the direct asymmetric
synthesis of cyanohydrin phosphonates.23
route b
OEt
OEt
R
OH
+
Cl
RO
O
COCl2
route a
O
NH3
O
(CF3CO)2O /
pyridine
O
O
NH2
KCN
RO
RO
Scheme 1.
Cl
RO
CN
O
However, the most popular alternatives to trimethylsilyl
cyanide are simple alkyl cyanoformates since cyanohydrin
carbonates are configurationally stable and significantly
less prone to hydrolysis than cyanohydrin trimethethylsilyl
ethers and the addition of cyanoformates to carbonyl com-
pounds is 100% atom economical. Complex 1 (but not vana-
dium based complex 2) will catalyse the asymmetric
addition of ethyl cyanoformate to aldehydes,18,19,24 and we
have demonstrated that this process is cocatalysed by cya-
nide ions, allowing a wider range of cyanoformates to be
utilised.25 Recently, an in situ prepared complex derived
from a salen ligand and titanium tetra-isopropoxide has
also been shown to catalyse the asymmetric addition of ethyl
cyanoformate to aldehydes in the presence of excess isopro-
panol.26 Complex 4 has been shown to accept methyl
cyanoformate22,27 as the cyanide source. A variety of other
chiral Lewis acids28 and Lewis bases29 have also been shown
to catalyse the asymmetric addition of alkyl cyanoformates
Initially, 1-phenylethanol was selected as a suitable chiral
alcohol as the racemate and both enantiomers are commer-
cially available and the phenyl and methyl groups have
significantly different steric and electronic properties, which
should be advantageous for subsequent diastereoselective
reactions with aldehydes. The corresponding cyanoformate
6 was not a known compound, and all attempts to prepare
it by route a shown in Scheme 1 were unsuccessful. The
intermediate 1-phenylethyl chloroformate was found to
rapidly decompose to 1-phenylethyl chloride, presumably by
an SN1 type process due to the relative stability of the sec-
ondary, benzylic carbenium ion. Therefore, the synthesis of
compound 6 by route b was investigated (Scheme 2). Reac-
tion between (R)- or (S)-1-phenylethanol 7a,b and ethyl
oxalyl chloride proceeded smoothly to give the desired mixed
diesters 8a,b in 97% yield. However, the subsequent reaction
between diesters 8a,b and ammonia was problematic. The
reaction appeared not to be as selective as observed for ethyl

9726
Y. N. Belokon’ et al. / Tetrahedron 63 (2007) 9724–9740
tert-butyl oxalate, and gave a mixture of the desired 1-phe-
nylethyl oxamides 9a,b, ethyl oxamide, oxamide and recov-
ered 1-phenylethanol. Whilst it was possible to isolate pure
samples of oxamides 9a,b from this reaction, this required
repeated slow recrystallisations and resulted in low and in-
consistent yields (20–37%) of oxamides 9a,b. Nevertheless,
gram quantities of oxamides 9a,b could be accessed by this
route, and the subsequent dehydration of these amides to the
desired cyanoformates 6a,b was straightforward. Cyanofor-
mates 6a,b were isolated as colourless oils in 71–85% yield.
due to the acid and thermal sensitivity of the acetonide
protecting group, combined with the hydrophilic nature of
compound 10d.
2.2. Cyanide ion cocatalysis in the asymmetric synthesis
of cyanohydrin carbonates from achiral cyanoformates
Catalyst 1 is capable of catalysing the asymmetric addition
of ethyl cyanoformate to aldehydes,18,19,24 giving non-
racemic cyanohydrin ethyl carbonates 13 as shown in
Scheme 4. However, this process requires a relatively large
amount of catalyst (5 mol %), and preliminary studies
showed that more hindered achiral or chiral cyanoformates
were not the substrates for this reaction. Therefore, we em-
barked on a study to optimise the reaction conditions for
complex 1 catalysed cyanohydrin carbonate synthesis so as
to allow the use of a wide variety of cyanoformates.
R2 R1
O
O
R2 R1
OH
pyridine
97%
OEt
OEt
+
Cl
O
Ph
Ph
7a,b
O
O
1) (COCl)2
2) NH3, THF
8a,b
6-9a: R1= Me; R2= H
6-9b: R1= H; R2= Me
20-37% NH3 (aq.)
98%
R2 R1
O
R2 R1
(CF3CO)2O /
pyridine
O
NH2
O
O
Ph
O
CN
O
6a,b
Ph
71-85%
1 (5 mol%), CH2Cl2, -40 °C
O
O
OEt
+ EtOCOCN
9a,b
R
H
R
CN
13a-g
Scheme 2.
a: R= Ph; b: R= 4-MeOC6H4; c: R= 4-CF3C6H4;
d: R= PhCH=CH; e: R= CH3(CH2)7; f: R= Cy;
g: R= tBu; h: R= 2-MeC6H4; i: R= 4-C6H4;
To avoid the problems associated with the ammonolysis of
diesters 8, an alternative synthesis of amides 9 was devel-
oped. Thus, treatment of alcohol 7b with 2 equiv of oxalyl
chloridegave (S)-1-phenylethyl oxalyl chloride,35 which was
immediately reacted with a solution of ammonia in THF to
provide amide 9b in 98% yield as shown in Scheme 2.
j: R= 2-MeOC6H4; k: R= 3-MeOC6H4; 1: R= 2-ClC6H4;
m: R= 4-ClC6H4; n: R= MeCH=CH; o: R= EtCH=CH;
p: R= MeCH=C(Me)
Scheme 4.
A study of the kinetics of this reaction (see Section 2.5)
showed that the reaction between benzaldehyde and ethyl
cyanoformate catalysed by complex 1 could not be fitted
to any simple reaction order (zero to third). This was in con-
trast to the reactions involving catalyst 1 and trimethylsilyl
cyanide, which always obey first order kinetics.5b,6 In view
of these kinetic results, it seemed likely that ethyl cyanofor-
mate may be hydrolysed to cyanide ion in situ and that cya-
nide was the actual cyanating agent in these reactions. The
concentration of cyanide would hence increase as the reac-
tion progressed, thus accounting for the non-linear kinetics
observed. Trapping of the so-formed cyanohydrin alkoxide
by another molecule of ethyl cyanoformate would then pro-
duce cyanohydrin ethyl carbonate 13 and regenerate cyanide
The optimised synthesis of cyanoformates shown in Scheme
2 was used to prepare four other enantiomerically pure
cyanoformates 10a,d derived from commercially available,
enantiomerically pure alcohols 11a,d as shown in Scheme 3.
For ethyl lactate 11a and ethyl mandelate 11b, high yields
of the oxamides 12a,b could only be obtained if the alcohol
was deprotonated with sodium hydride prior to the addition
of oxalyl chloride.36 In contrast, menthol and glycerol ace-
tonide were converted into oxamides 12c,d in good yields
without the need for prior deprotonation of the alcohol.37
Amides 12a–c were subsequently converted into cyanofor-
mates 10a–c in high yield.38 However, oxamide 12d gave
only a low yield of cyanoformate 10d, which is probably
OH
CO2Et
Me
Me
Me
1) (COCl)2
2) NH3
(CF3CO)2O /
pyridine
R
O
O
11a,b
NH2
O
OH 97%
O
96%
CN
CN
1) NaH / (COCl)2
2) NH3
O
27-97%
O
11c
12c
10c
O
NH2
OH
O
O
O
R
1) (COCl)2
2) NH3
(CF3CO)2O /
pyridine
O
O
O
O
O
O
O
O
O
CO2Et
12a,b
NH2
72%
21%
Me
Me
Me
Me
11d
Me Me
10d
12d
(CF3CO)2O / pyridine
O
78-87%
O
CN
10-12a: R = Me
10-12b: R = Ph
CO2Et
10a,b
R
Scheme 3.

Y. N. Belokon’ et al. / Tetrahedron 63 (2007) 9724–9740
9727
ion. Therefore, it was felt that adding additional cyanide ions
to these reactions might increase the rate of reaction, and
thus allow the amount of catalyst 1 to be reduced and/or
allow other less reactive cyanoformates to be used.
methyl cyanoformate,27,29,40 benzyl cyanoformate27,29 and
tert-butyl cyanoformate32,34 to these aldehydes was investi-
gated (Scheme 5). The results of this study are shown in
Table 2. The cyanohydrin benzyl carbonates 14b,e and the
tert-butyl carbonate 14c were too non-volatile to analyse
by chiral GC, though they were formed in quantitative yields
(Table 2; entries 3,4 and 7). However, comparison of the
enantiomeric excesses obtained for cyanohydrin carbonates
14a and 13a (Table 2: entries 1 and 2) and of cyanohydrin
carbonates 13g, 14d and 14f (Table 2: entries 5, 6 and 8)
revealed that the structure of the cyanoformate did not
have a significant influence on the enantioselectivity of the
formation of cyanohydrin carbonates.
An initial reaction using benzaldehyde, complex
1
(2 mol %) and tetrabutylammonium cyanide (5 mol %) as
cocatalyst was not encouraging since mandelonitrile ethyl
carbonate (13, R¼Ph) was obtained with just 4% enantio-
meric excess. However, this reaction had gone to completion
after 24 h, despite the reduced amount of complex 1 used.
Fortunately, changing the cyanide source to potassium
cyanide restored the enantioselectivity, whilst retaining the
accelerated rate of reaction.39 Selected results for the addi-
tion of ethyl cyanoformate (1.2 equiv) to benzaldehyde in
dichloromethane catalysed by complex 1 and potassium
cyanide are summarised in Table 1.
O
1 (2 mol%), KCN (10 mol%),
O
CH2Cl2, -40 °C
O
+ R'OCOCN
OR'
R
H
a: R= Ph, R'= Me; b: R= Ph, R'= Bn; c, R= Ph, R'= tBu;
R
CN
14a-f
Entries 1 and 2 of Table 1 confirm that in the absence of
potassium cyanide, complete conversion of benzaldehyde
to mandelonitrile ethyl carbonate 13 requires 5 mol % of
catalyst 1, with negligible reaction occurring when just
1 mol % of catalyst was used even at room temperature
over an extended reaction time. Comparison of entries 2
and 3 of Table 1 clearly demonstrates the catalytic effect
of potassium cyanide on this reaction, though at room tem-
perature the asymmetric induction is rather low. Increasing
the amount of potassium cyanide catalyst at room tempera-
ture (Table 1: entry 4) did increase the enantioselectivity of
the reaction, but did not increase the rate of reaction. The
enantioselectivity could be further increased by reducing
the reaction temperature to ꢀ40 ꢁC (Table 1: entry 5), and
both the conversion and enantioselectivity could be restored
to the previously reported values by use of 2 mol % of
complex 1 in conjunction with 10 mol % of potassium cya-
nide (Table 1: compare entries 1 and 6). However, further
reduction of the reaction temperature to ꢀ70 ꢁC completely
suppressed the formation of compound 13, even when
5 mol % of catalyst 1 was used with 10 mol % of potassium
cyanide (Table 1: entry 7).
d: R= tBu, R'= Me; e: R= tBu, R'= Bn; f: R= tBu, R'= tBu
Scheme 5.
Having determined the optimal reaction conditions and that
varying the structure of the cyanoformate was not beneficial,
the asymmetric addition of ethyl cyanoformate to six other
aldehydes was investigated. The results are shown in Table
3. Electron rich aromatic aldehydes (Table 3: entries 1 and
2) and cinnamaldehyde (Table 3: entry 4) are excellent
Table 2. The asymmetric addition of cyanoformates to aldehydes catalysed
by complex 1 and potassium cyanidea
Entry Substrate Product Cyanoformate Yield (%) eeb (%)
1
2
3
4
5
6
7
8
PhCHO
PhCHO
PhCHO
PhCHO
tBuCHO
tBuCHO
tBuCHO
tBuCHO
14a
13a
14b
14c
14d
13g
14e
14f
MeOCOCN
EtOCOCN
BnOCOCN
tBuOCOCN
MeOCOCN
EtOCOCN
BnOCOCN
tBuOCOCN
92
100
100
100
85
79
100
100
95
95
c
c
62
68
c
65
a
Reactions were conducted at ꢀ40 ꢁC for 24 h in dichloromethane using
1.2 equiv of the cyanoformate with complex 1 (2 mol %) and KCN
(10 mol %) as catalysts.
Enantiomeric excesses were determined by chiral GC.
Could not be determined, but the product was optically active.
Under the optimal conditions developed for the addition of
ethyl cyanoformate to benzaldehyde (Table 1: entry 6),
a range of other cyanoformates were found to add to alde-
hydes to form cyanohydrin carbonates. Thus, benzaldehyde
and pivaldehyde were selected as representative aromatic
and aliphatic aldehydes and the asymmetric addition of
b
c
Table 3. The asymmetric addition of ethyl cyanoformate to aldehydes cata-
lysed by complex 1 and potassium cyanidea
Table 1. The asymmetric addition of ethyl cyanoformate to benzaldehyde
catalysed by complex 1 and potassium cyanidea
Entry Substrate
1 (mol %) Product Yield (%) eeb (%)
1
2
3
4
5
6
7
PhCHO
2
2
1
2
2
1
2
13a
13b
13c
13d
13e
13f
100
98
100
94
90
86
79
95 (95)
97 (95)
69 (76)
95 (94)
79 (84)
74 (79)
68 (76)
Entry
1
KCN
Temp Time Completion eeb
4-MeOC6H4CHO
4-(CF3)C6H4CHO
PhCH]CHCHO
CH3(CH2)7CHO
CyCHO
(mol %) (mol %) (ꢁC)
(h)
(%)
(%)
1c
2
3
4
5
6
7
5
1
1
1
1
2
5
0
0
1
10
10
10
10
ꢀ40
25
25
25
ꢀ40
ꢀ40
ꢀ70
18
90
48
48
19
26
24
100
5
95 (S)
89 (S)
51 (S)
68 (S)
81 (S)
95 (S)
100
98
87
100
0
tBuCHO
13g
a
Reactions were conducted at ꢀ40 ꢁC for 24 h in dichloromethane using
1.2 equiv of EtOCOCN with complex
(10 mol %) as catalysts.
1 (2 mol %) and KCN
a
b
Reactions were carried out in dichloromethane using 1.2 equiv of
EtOCOCN unless otherwise stated.
Enantiomeric excesses were determined by chiral GC.
Result taken from Ref. 24 and using 2 equiv of ethyl cyanoformate.
Enantiomeric excesses were determined by chiral GC. The value in
brackets is that reported in Ref. 24 for the use of catalyst 1 (5 mol %) in
the absence of KCN. In each case, the (S)-enantiomer of the cyanohydrin
carbonate was formed from (R,R)-1.
b
c

9728
Y. N. Belokon’ et al. / Tetrahedron 63 (2007) 9724–9740
substrates for the reaction under these conditions, giving
cyanohydrin ethyl carbonates 13a,b,d in high yields and
with high enantiomeric excesses. In contrast, para-trifluoro-
methylbenzaldehyde gave cyanohydrin ethyl carbonate 13c
with much lower enantiomeric purity, though still in high
yield (Table 3: entry 3). The apparently lower asymmetric
induction obtained using this substrate may be due to its in-
herently high reactivity (as a result of which only 1 mol % of
catalyst 1 was required to obtain quantitative conversion into
product 13c) towards nucleophilic addition enhancing the
rate of the racemic background reaction. However, product
13c was also found to racemise on standing, so it may be
that the enantiomeric excess of the product is not truly
representative of the asymmetric induction in this case.
a total reaction time of 72 h. In contrast, pivaldehyde was
found to be converted quantitatively into products 15–18b
after a reaction time of 24 h.
O
Me
O
Me
O
O
Ph
O
O
Ph
R
CN
R
CN
18a,b (minor)
17a,b (major)
1 (2 mol%), KCN (10 mol%),
6b (1.2 eq.), CH2Cl2, -40 °C
15-18a: R = Ph
15-18b: R = tBu
RCHO
1 (2 mol%), KCN (10 mol%),
6a (1.2 eq.), CH2Cl2, -40 °C
All the three aliphatic aldehydes studied gave products with
lower enantiomeric excesses than the electron rich aromatic
aldehydes, as is generally observed for the asymmetric syn-
thesis of cyanohydrin derivatives. However, the reaction
appears to be sensitive to the steric environment of the alde-
hyde as both the chemical yield and the enantiomeric excess
of the product decreased as the carbonyl became more steri-
cally hindered (Table 3: entries 5–7). Attempts were also
made to use ketones as substrates, but no reaction occurred
with either acetophenone or heptan-2-one, even when
5 mol % of catalyst 1 was used along with 10 mol % of
potassium cyanide at room temperature.
O
Me
O
Me
O
O
Ph
O
O
Ph
R
CN
R
CN
15a,b (major)
16a,b (minor)
Scheme 6.
Table 4. Diastereoselective synthesis of cyanohydrin carbonates derived
from chiral cyanoformates 6a,b
Entry Aldehyde Cyanoformate
Conversion Diastereomeric
ratioc
2.3. Cyanide ion cocatalysis in the diastereoselective
synthesis of cyanohydrin carbonates from chiral
cyanoformates
(major product) (%)
1a,b
2a,b
3a
PhCHO
PhCHO
tBuCHO
tBuCHO
6a (15a)
6b (17a)
6a (15b)
6b (17b)
88
66
100
100
28:1 (93% de)
18:1 (89% de)
5.3:1 (68% de)
3.6:1 (57% de)
4a
Previous studies on the asymmetric synthesis of cyanohy-
drin carbonates have always employed simple achiral cya-
noformates, usually the methyl22,27,29 or ethyl18,19,24,28,29
derivatives. However, in view of the compatibility of the
catalyst 1/potassium cyanide system with a wide range of
cyanoformates (Table 2), we felt that it was worthwhile
investigating the use of more complex cyanoformates, and
in particular those which are themselves chiral so as to
achieve a diastereomeric cyanohydrin synthesis. This was
particularly attractive as there were no previous reports on
the synthesis of cyanohydrin derivatives using chiral cya-
nide sources.
a
Reactions were conducted at ꢀ40 ꢁC for 24 h in dichloromethane using
1.2 equiv of cyanoformate 6a or 6b with complex 1 (2 mol %) and
KCN (4 mol %) as catalysts.
After 24 h, additional complex 1 (2 mol %) and KCN (4 mol %) were
added and the reaction mixture was stirred for a further 48 h at ꢀ40 ꢁC.
Diastereomeric ratios were determined by 1H NMR spectroscopy.
b
c
In each case, the NMR spectra of the product mixture indi-
cated that the major product obtained using cyanoformate
6a was enantiomeric with the minor product obtained using
cyanoformate 6b. This indicated that it was the stereochem-
istry of catalyst 1 rather than that of the cyanoformates 6a,b
was the dominant factor in determining the stereochemistry
of compounds 15–18. On this basis, the stereochemistry of
the products was expected to be as shown in Scheme 6, since
in every case studied to date the (R,R)-enantiomer of catalyst
1 induces the addition of a cyanide source to the re-face of an
aldehyde to give a cyanohydrin derivative with (S)-configu-
ration (except in few cases where the Cahn–Ingold–Prelog
priority rules result in the cyanohydrin derivative having
(R)-configuration). This stereochemical assignment was
confirmed by crystal structures (Figs. 1 and 2) of the major
diastereomer obtained from the reaction between benzalde-
hyde or pivaldehyde and cyanoformate 6a, which showed
that in each case the two stereocentres had opposite config-
urations and hence confirmed the assignment of structures
15a,b to these compounds. The very small crystals of 15a
were twinned and gave weak diffraction data, limiting the
precision of the derived structure, but the relative stereo-
chemistry is unambiguous. There are two molecules in the
For the initial studies, (R)- and (S)-1-phenylethyl cyanofor-
mates 6a,b were selected as the chiral cyanoformates since
both enantiomers of the precursor alcohol 7a,b are available
and this would allow any matched/mismatched pairs with
(R,R)-catalyst 1 to be identified. Benzaldehyde and pivalde-
hyde were again selected as representative aromatic and
aliphatic aldehydes. Control experiments confirmed that
even at room temperature, neither potassium cyanide
(2 mol %) nor complex 1 (2 mol %) alone would induce
any reaction between cyanoformates 6a,b and benzalde-
hyde. However, under the optimal conditions developed
for use of ethyl cyanoformate (Table 1: entry 6), cyanofor-
mates 6a,b did react with both benzaldehyde and pivalde-
hyde to give a mixture of cyanohydrin carbonates 15a,b,
16a,b and 17a,b, 18a,b, respectively, as shown in Scheme
6 and detailed in Table 4. Reactions involving benzaldehyde
as substrate did not go to completion even after the addition
of a second batch of catalyst 1 and potassium cyanide and at

Y. N. Belokon’ et al. / Tetrahedron 63 (2007) 9724–9740
9729
as shown in Scheme 7. The results of this study are shown
in Table 5. In each case, H NMR analysis of the product
1
mixture showed that the major product obtained using cata-
lyst (R,R)-1 was diastereomeric with the major product
obtained using catalyst (S,S)-1, consistent with predominant
catalyst control of the stereochemistry as observed using
cyanoformates 6a,b. In this case, the reactions did not
show a significant double asymmetric induction effect, and
when pivaldehyde was used as substrate, the use of the
(S,S)-enantiomer of catalyst 1 actually gave a slightly higher
diastereoselectivity than the use of the (R,R)-enantiomer of
the catalyst (Table 5: entries 3 and 4).
Figure 1. The structure of one of the two independent molecules of cyano-
hydrin carbonate 15a; the other molecule is almost identical.
1 (2 mol%),
CO2Et
Me
CO2Et
Me
O
O
KCN (4 mol%),
10a (1.2 eq.),
CH2Cl2, -40 °C
O
O
O
O
+
asymmetric unit. For these and the unique molecule of 15b,
geometrical parameters are unexceptional. There are no sig-
nificant direction-specific intermolecular interactions in ei-
ther of the crystal structures. Full details are given in the
supplementary material.
RCHO
19: R = Ph
20: R = tBu
R
CN
19b, 20b
R
CN
19a, 20a
Scheme 7.
It is apparent from Table 4 that the combination of (R,R)-1
with cyanoformate 6a constitutes a matched pair, whilst
the combination of (R,R)-1 and 6b forms a mismatched
pair (compare Table 4: entries 1,2 and 3,4). Notably, the dia-
stereomeric excesses obtained for the matched pair were
comparable with the enantiomeric excesses obtained when
the same aldehyde was reacted with ethyl cyanoformate
(compare Table 3: entry 1 with Table 4: entry 1 and Table
3: entry 7 with Table 4: entry 3).
Table 5. Diastereoselective synthesis of cyanohydrin carbonates derived
from chiral cyanoformate 10aa
Entry Aldehyde Catalyst Conversion (%) Diastereomeric ratiob
1
2
3
4
PhCHO (R,R)-1 32
PhCHO (S,S)-1 54
tBuCHO (R,R)-1 28
tBuCHO (S,S)-1 46
19a/19b¼12.3:1 (85% de)
19b/19a¼9:1 (80% de)
20a/20b¼10.8:1 (83% de)
20b/20a¼13.3:1 (86% de)
a
Reactions were conducted at ꢀ40 ꢁC for 24 h in dichloromethane using
1.2 equiv of cyanoformate 10a with complex 1 (2 mol %) and KCN
(4 mol %) as catalysts.
Diastereomeric ratios were determined by 1H NMR spectroscopy.
b
The reaction of cyanoformates 10a–d with benzaldehyde
and pivaldehyde in the presence of complex 1 and potassium
cyanide was also investigated. However, only in the case of
lactate derived cyanoformate 10a did any reaction occur
under the conditions shown in Scheme 6, and in this case
the conversions (28–54%) were significantly lower than
those observed using cyanoformates 6a,b. Cyanoformates
10b–d also failed to react when the reactions were left for
2 weeks at room temperature.
2.4. A homogeneous system for the asymmetric synthesis
of cyanohydrin carbonates
Whilst the addition of solid potassium cyanide to reactions
between aldehydes and cyanoformates did allow the amount
of chiral catalyst used to be reduced to just 1–2 mol %, the
heterogeneous nature of these reactions was a concern, espe-
cially for larger scale reactions and also meant that the reac-
tion kinetics could not be analysed. The complex formed
between potassium cyanide and 18-crown-6 is known to be
soluble in dichloromethane,41 so the use of this complex to
catalyse the asymmetric addition of ethyl cyanoformate to
aldehydes under homogeneous reaction conditions was in-
vestigated.42
Since only one enantiomer of cyanoformate 10a had been
prepared, reactions were carried out using both enantiomers
of catalyst 1 and either benzaldehyde or pivaldehyde as sub-
strate to give cyanoformates 19a,b and 20a,b, respectively,
When benzaldehyde was used as the substrate, it was found
that the potassium cyanide/18-crown-6 complex would
indeed cocatalyse the synthesis of mandelonitrile ethyl
carbonate at ꢀ40 ꢁC, and that the amount of catalyst 1
required could be further reduced to 1.5 mol %. However,
the amount of the potassium cyanide/18-crown-6 complex
used was found to be critical. Use of 3 mol % of potassium
cyanide/18-crown-6 complex gave mandelonitrile ethyl
carbonate with just 17% enantiomeric excess presumably
due to a facile uncatalysed addition of cyanide to the alde-
hyde in the presence of high concentrations of soluble cya-
nide. In contrast, use of less than 1 mol % of potassium
Figure 2. The molecular structure of cyanohydrin carbonate 15b.

9730
Y. N. Belokon’ et al. / Tetrahedron 63 (2007) 9724–9740
cyanide/18-crown-6 complex was ineffective as no reaction
occurred. Thus, the use of 1 mol % of potassium cyanide/18-
crown-6 complex and 1.5 mol % of catalyst 1 was adopted as
the standard conditions, and under these conditions benz-
aldehyde was completely converted into (S)-mandelonitrile
ethyl carbonate with 91% enantiomeric excess. Under these
conditions, the reaction between a range of aldehydes and
ethyl cyanoformate was studied and the results are
presented in Table 6.
To illustrate the utility of b,g-unsaturated cyanohydrin car-
bonates, compound 13n was treated with sodium azide in
the presence of tetrakis(triphenylphosphine)palladium(0)
under conditions previously reported by Deardorff et al.43b
to give g-azido-a,b-unsatured nitrile 21 as shown in Scheme
8. Compound 21 was formed as a 4:1 ratio of E- and
Z-isomer.43b Subsequent hydrogenation of compound 21
resulted in the formation of g-amino nitrile 22, which was
converted into N-benzoyl derivative 23 for characterisation.
Chiral GC analysis showed that compound 23 had an enan-
tiomeric excess of 80%, a result, which is consistent with the
findings of Deardorff et al. on the partial racemisation of
cyanohydrin derivatives during palladium catalysed allylic
substitution.43a
Table 6. Potassium cyanide/18-crown-6 induced synthesis of cyanohydrin
ethyl carbonatesa
Entry Aldehyde
Product Conversion (%) eec (%)
1
2
3
4
5
6
7
8
PhCHO
13a
13h
13i
100
100
100
100
100
100
100
100
100b
100
100
100b
98
91 (S)
97 (S)
99 (S)
100 (S)
97 (S)
90 (S)
93 (S)
100 (S)
90 (S)
93 (S)
91 (S)
89 (S)
81 (S)
78 (S)
71 (S)
2-MeC6H4CHO
4-MeC6H4CHO
2-MeOC6H4CHO
3-MeOC6H4CHO
4-MeOC6H4CHO
2-ClC6H4CHO
4-ClC6H4CHO
PhCH]CHCHO
MeCH]CHCHO
EtCH]CHCHO
OCO2Et
CN
N3
NaN3 (2 equiv.) /
Pd(PPh3)4 (2 mol%)
13j
CN
25-81%
13k
13b
13l
13m
13d
13n
13o
21
13n
H2 / Pd,C 17%
PhCOCl /
Et3N
81%
CN
NH2
NHCOPh
9
10
11
12
13
14
15
CN
22
23
MeCH]C(Me)CHO 13p
Scheme 8.
CH3(CH2)7CHO
CyCHO
Me3CCHO
13e
13f
13g
100
100
2.5. Reaction kinetics for the asymmetric addition of
ethyl cyanoformate to benzaldehyde in the presence of
potassium cyanide/18-crown-6
a
Reactions were conducted at ꢀ40 ꢁC for 24 h (unless stated otherwise) in
dichloromethane using 1.2 equiv of ethyl cyanoformate with complex 1
(1.5 mol %) and KCN/18-crown-6 (1 mol %) as catalysts.
Reaction required 48 h to go to completion.
b
c
To obtain a better understanding of the processes occurring
during the potassium cyanide/18-crown-6 complex cata-
lysed processes, the reaction kinetics were monitored. These
reactions were conducted at 22 ꢁC using benzaldehyde as
substrate, and at appropriate intervals samples were with-
drawn and analysed by 1H NMR spectroscopy to determine
the ratio of benzaldehyde to mandelonitrile ethyl carbonate.
Under these conditions, no side reactions occurred to inter-
fere with the kinetic data.
ee values were determined by chiral GC and are accurate to ꢂ4%.
The enantioselectivities reported in Table 6 are comparable
to those obtained in the absence of cyanide,24 and to those
obtained using potassium cyanide under heterogeneous
conditions (Table 3). In every case, the (S)-cyanohydrin car-
bonate was obtained from the (R,R)-enantiomer of catalyst 1.
Thus, electron rich aromatic aldehydes (Table 6: entries 1–6)
were found to be excellent substrates as were chlorinated
benzaldehydes (Table 6: entries 7 and 8). In the case of the
products derived from 2-methoxybenzaldehyde and 4-
chlorobenzaldehyde, only one enantiomer could be detected
by chiral GC. Four a,b-unsaturated aldehydes were investi-
gated as the b,g-unsaturated cyanohydrin carbonates derived
from these substrates are known to be substrates for palla-
dium catalysed allylic substitution chemistry,22,43 thus en-
hancing the range of chiral products available from chiral
cyanohydrins. In each case, the a,b-unsaturated aldehydes
gave a cyanohydrin ethyl carbonate with around 90% enan-
tiomeric excess (Table 6: entries 9–12), though two of these
reactions (Table 6: entries 9 and 12) were slow, requiring
48 h to go to completion. Finally, three representative
aliphatic aldehydes were investigated (Table 6: entries 13–
15) and gave products with 71–81% enantiomeric excess,
which in each case is comparable to the enantioselectivity
obtained in the absence of any cyanide and to that obtained
in the presence of solid potassium cyanide (Table 3: entries
5–7). Hence, the combination of complex 1 (1.5 mol %) and
the potassium cyanide/18-crown-6 complex (1 mol %) con-
stitutes a highly effective catalytic system for the asymmet-
ric synthesis of a variety of cyanohydrin carbonates.
Figure 3 shows the first order kinetic plots for reactions car-
ried out in the absence of any potassium cyanide/18-crown-6
complex (using 5 mol % of catalyst 1) and in the presence of
increasing amounts of the potassium cyanide/18-crown-6
complex (using 2 mol % of catalyst 1). Reactions carried
out with no potassium cyanide/18-crown-6 complex or
with 0.5–1.0 mol % of the potassium cyanide/18-crown-6
complex are clearly not first order (and also do not fit second
or third order), whilst reactions carried out in the presence of
2–4 mol % of the potassium cyanide/18-crown-6 complex
show an increasingly good fit to first order kinetics, as
expected based on the previous work using trimethylsilyl
cyanide as the cyanide source.5b,6
We have previously proposed a mechanism for the asymmet-
ric synthesis of cyanohydrin carbonates using catalyst 1, in
which complex 1 is proposed to react with the cyanoformate
to form species 24 (Scheme 9).18 Complex 24 then decom-
poses to bis-cyanide complex 25, which is a key intermedi-
ate needed to start the catalytic cycle. The kinetic results
presented above suggest that in the absence of potassium
cyanide/18-crown-6, the conversion of complex 24 into
bis-cyanide 25 occurs at a rate, which is comparable to or

Y. N. Belokon’ et al. / Tetrahedron 63 (2007) 9724–9740
9731
-1.84
-1.86
-1.88
-1.9
-1.5
-2
0
40
80
120
160
0
50
100
150
-2.5
-3
-3.5
-4
-1.92
-1.94
-1.96
-1.98
-4.5
-5
2 mol% 1 and 0.5 mol% KCN/18-crown-6
5 mol% catalyst 1 and no KCN/18-crown-6
-5.5
Time (min)
Time (min)
-1
-1.5
-2
-1.5
-2
0
5
10
15
20
25
30
0
50
100
150
-2.5
-3
-2.5
-3
R2 = 0.98
-3.5
-4
-3.5
-4
-4.5
-5
2 mol% 1 and 1 mol% KCN/18-crown-6
2 mol% 1 and 2 mol% KCN/18-crown-6
Time (min)
Time (min)
-1.5
0
2
4
6
8
-2.5
-3.5
-4.5
-5.5
-6.5
-7.5
-8.5
R2 = 0.9935
2 mol% 1 and 4 mol% KCN/18-crown-6
Time (min)
Figure 3. First order kinetic plots for the addition of ethyl cyanoformate to benzaldehyde in the presence of varying amounts of the potassium cyanide/18-crown-
6 complex.
slower than the release of the titanium bound cyanohydrin
26, which is the rate determining step when trimethylsilyl
cyanide is used as the cyanating agent.5b,6 Increasing the
concentration of cyanide ions would then increase the rate
at which 24 was converted into 25, resulting in the release
of titanium bound cyanohydrin 26 again becoming the rate
determining step in the catalytic cycle, and thus restoring
the overall first order kinetics.
9. Complex 26 can then react either with ethyl cyanoformate
(which will regenerate the cyanide catalyst directly) or with
the more reactive ammonium salt 27 (which regenerates the
tertiary amine, which can then react with another molecule
of the ethyl cyanoformate or acetyl cyanide to regenerate
the cyanide cocatalyst) to form the cyanohydrin ethyl car-
bonate (or acetate) product.
However, Moberg recently reported19c that when H13CN
was added to the reaction mixture, no 13C incorporation
into the cyanohydrin occurred. This appeared to rule out
the presence of cyanide ions in the reaction mixture, and
on this basis Moberg proposed the alternative transition state
shown in Figure 4. Whilst the transition state structure
shown in Figure 4 appears to neatly explain Moberg’s find-
ings, it suffers from two difficulties. Firstly, it is not easily
extendable to cyanide sources such as trimethylsilyl cyanide,
which does not contain a carbonyl bond. Since trimethylsilyl
cyanide is known to be an excellent substrate5,6 for catalyst
1, this is a major limitation. Secondly, both the titanium ions
in the structure given in Figure 4 are in the +3 oxidation state
2.6. Relationship to other work on the asymmetric
addition of ethyl cyanoformate to aldehydes using
titanium(salen) complexes
Moberg has reported that the asymmetric addition of ethyl
cyanoformate (or acetyl cyanide) to aldehydes catalysed
by complex 1 is accelerated in the presence of a tertiary
amine.19 In view of the results we have obtained on cyanide
catalysis, Moberg’s results could be explained by the reac-
tion of tertiary amine with the ethyl cyanoformate (or acetyl
cyanide) to generate cyanide ions (Scheme 10). These then
catalyse the formation of complex 26 as shown in Scheme

9732
Y. N. Belokon’ et al. / Tetrahedron 63 (2007) 9724–9740
[(salen)TiO]2
2 x (salen)Ti=O
RCHO
were accelerated by the presence of excess isopropanol,
and Feng interpreted this on the basis of catalysis by a mono-
meric titanium complex, which is only formed in the pres-
ence of excess isopropanol to inhibit the formation of
bimetallic complex 1. However, we have previously shown
that monomeric titanium(salen) complexes are catalytically
inactive in asymmetric cyanohydrin synthesis and demon-
strated that any catalysis observed is due to adventitious
moisture in the reactions resulting in the formation of cata-
lytically active bimetallic complex 1.5 An alternative expla-
nation of Feng’s results, therefore, is that the isopropoxide
reacts with ethyl cyanoformate to form isopropyl ethyl car-
bonate and cyanide. The latter then catalyses the asymmetric
addition of ethyl cyanoformate to the aldehyde as shown in
Scheme 9.
1
2 x R'OCOCN
COOR'
O
R
O
2 CN
Ti(salen)
(salen)Ti
(salen)Ti
O
O
COOR'
24
slow in absence of
added cyanide
OCOOR' CN
Ti(salen) + Ti(salen)
OCOOR'
CN
25
R
(salen)Ti CN
O
(salen)Ti
O
O
H
RCHO
CN
3. Conclusions
(salen)Ti CN
(salen)Ti CN
By studying the reaction kinetics, it has been shown that cya-
nide ion acts as a cocatalyst in the asymmetric synthesis of
cyanohydrin carbonates catalysed by Ti(salen) complex 1.
This knowledge has allowed the development of reaction
conditions under which the amount of catalyst 1 required to
accomplish this transformation can be reduced to just 1.5–
2 mol % by use of either solid potassium cyanide or the potas-
sium cyanide/18-crown-6 complex as cocatalysts. Under
these optimised conditions, both achiral and chiral cyanofor-
mates were found to undergo enantio- and diastereoselective
additions to a range of aldehydes to form highly enantio-
and diastereomerically enriched cyanoformates. The stereo-
chemistry of the major diastereomer of the cyanohydrin
carbonate formed from (R)-1-phenylethyl cyanoformate 6a
and both benzaldehyde and pivaldehyde was unambiguously
determined by X-ray crystallography and the results indicate
that the stereochemistry of catalyst 1 rather than that of the
cyanoformate is the dominant factor in determining the ste-
reochemistry of the cyanoformate derivatives.
R'OCOCN
rate
determining
step
R
H
OCO2R'
CN
(salen)Ti
O
CN
O
R
(salen)Ti CN
26
Scheme 9.
O
O
R
R'3N
CN
NR'3
CN
R
27
R = Me or OEt
Scheme 10.
(salen)Ti
O
Ti (salen)
O
O
N
The reaction kinetics indicate that provided at least 2 mol %
of the potassium cyanide/18-crown-6 complex is employed,
the reactions display first order kinetics consistent with the
mechanistic cycle previously proposed for related reactions
employing trimethylsilyl cyanide as the cyanide source. This
mechanistic cycle and cyanide ion catalysis also provide
a single, unified explanation of previous results on the
asymmetric addition of ethyl cyanoformate to aldehydes
catalysed by titanium(salen) complexes in the presence of
tertiary amines or alcohols as cocatalysts.
R'
CN
R
Figure 4. Moberg’s mechanism for addition of acyl cyanides to aldehydes in
the presence of triethylamine.19c
and there is no precedent for the formation of Ti(III)(salen)
complexes, and no indication was given on how complex 1
could be reduced under the reaction conditions. Monitoring
1
of our reactions involving complex 1 by H NMR spectro-
scopy gave no evidence for the formation of paramagnetic
species in situ. Thus, the transition state shown in Figure 4
appears non-viable, and the mechanistic explanation given
in Scheme 9 and involving species 27 is more likely. The
lack of 13C incorporation may be due to slow exchange be-
tween the titanium associated cyanide counterions (which
will come exclusively from acetyl cyanide) and free hydro-
gen cyanide present in the solution.
4. Experimental
4.1. General methods
1H and 13C NMR spectra were recorded on Bruker Avance
300 or 360 spectrometer (1H 300/360 MHz, 13C 75/
90 MHz). The solvent for a particular spectrum is given in
parentheses. Spectra were referenced to TMS and chemi-
cal-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.
Feng has recently reported the asymmetric addition of ethyl
cyanoformate to aldehydes catalysed by a titanium complex
generated in situ from a salen ligand (optimally the same li-
gand used for the synthesis of complexes 1 and 2) and tita-
nium tetra-isopropoxide.26 It was found that the reactions

Y. N. Belokon’ et al. / Tetrahedron 63 (2007) 9724–9740
9733
For 13C NMR spectra, the peak assignments were made with
the assistance of DEPT experiments.
(9 mL) was added 0.88 ammonia (5.4 mL) in 4–5 portions
with swirling over 3–5 min. The solution was allowed to
stand at room temperature for 3 days and then diluted with
CH2Cl2 (34 mL). The organic layer was separated and the
aqueous layer extracted with CH2Cl2 (25 mL). The com-
bined organic layers were dried (MgSO4) and evaporated
in vacuo to leave an oil, which solidified on standing. The
solid was washed with 40–60 petroleum ether, recrystallised
from toluene (50 mL) and washed again with 40–60 petro-
leum ether. Further recrystallisation from toluene/methanol
(9:1) gave compound 9a (3.0 g, 20%) as white crystals.
Mp 89.5–90.5 ꢁC (from benzene/60–90 petroleum ether);
[a]2D0 +109.1 (c 0.5, CHCl3); nmax (neat) 3403 s, 3234 s,
1736 s and 1688 s cmꢀ1; dH (CDCl3) 1.68 (3H, d, J 6.6 Hz,
CH3), 5.99 (1H, q, J 6.6 Hz, CH), 6.61 (1H, br, NH), 6.98
(1H, br, NH), 7.3–7.4 (5H, m, ArH); dC (CDCl3) 159.9
(C]O), 159.1 (C]O), 140.4 (ArC), 129.1 (ArCH), 128.9
(ArCH), 126.7 (ArCH), 76.4 (OCH), 22.3 (CH3); m/z (CI)
211 (M+NH+4, 100). Found (ESI) 216.0628; C10H11NO3Na
(M+Na)+ requires 216.0631.
Infrared spectra were recorded on a Perkin–Elmer FTIR Par-
agon 1000 spectrometer, as a thin film between NaCl plates
or on the pure solid using ATR. 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 AX505 W
spectrometer within the Chemistry Department at King’s
College. The sample was ionised by electron ionisation
(EI), chemical ionisation (CI), fast atom bombardment
(FAB) or electrospray ionisation (ESI). The major fragment
ions are reported and only the molecular ions are assigned.
Optical rotations were recorded on a Perkin–Elmer 343
polarimeter or a Polaar 2001 Optical Activity automatic
polarimeter in a thermostated cell of length 1 dm at 20 ꢁC
using the sodium D-line, and a suitable solvent that is
reported along with the concentration (in g/100 mL). Melt-
ing points are uncorrected and were recorded on a Barnstead
Electrothermal 9100 melting point apparatus.
4.2.4. (S)-1-Phenylethyl oxamide 9b from diester 8b.
Prepared from compound 8b (9.0 g, 40.7 mmol) as de-
scribed for the (R)-enantiomer 9a (Section 4.2.3) to give
compound 9b (2.9 g, 37%) as white crystals. [a]2D0 ꢀ109.3
(c 0.45, CHCl3). Other analytical data as reported for the
(R)-enantiomer 9a.
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 mꢃ0.25 mm) and hydro-
gen as the carrier gas.
4.2.5. (S)-1-Phenylethyl oxamide 9b from alcohol 7b. A
solution of (S)-phenylethanol 7b (1.0 g, 8.2 mmol) in
CH2Cl2 (10 mL) was stirred and cooled in an ice bath. Ox-
alyl chloride (2.1 g, 16.4 mmol) was added dropwise and
the resulting mixture was stirred for 1 h at room temperature.
The solvent and excess oxalyl chloride were removed in
vacuo. The residue was dissolved in CH2Cl2 (50 mL) and
cooled to 0 ꢁC in an ice bath. A saturated solution of ammo-
nia in THF (0.2 mL, excess) was added dropwise, and the
resulting mixture was stirred for 15 min. The reaction mix-
ture was washed with water (40 mL), the aqueous layer
was extracted with CH2Cl2 (40 mL) and the combined
organic layers were washed with water (40 mL). The organic
layer was dried (MgSO4) and evaporated in vacuo. The
residue was recrystallised from a toluene/hexane mixture
to give oxamide 9b (0.90 g, 98%) as a white solid.
4.2. Synthesis of chiral cyanoformates
4.2.1. Ethyl (R)-1-phenylethyl oxalate 8a. A stirred solu-
tion of (R)-1-phenylethanol 7a (6.9 g, 56.5 mmol) and pyr-
idine (4.5 g, 57.0 mmol) in CH2Cl2 (24 mL) was cooled in
an ice bath and ethyl oxalyl chloride (7.8 g, 57.0 mmol)
was added over 1 h. The mixture was stirred in an ice bath
for 4 h, then at room temperature overnight. The reaction
mixture was washed with water (2ꢃ6 mL), dried (MgSO4)
and solvent evaporated in vacuo to leave diester 8a
(12.2 g, 97%) as a colourless liquid. [a]2D0 +60.0 (c 1.25,
CHCl3); nmax (neat) 2985 s and 1740 s cmꢀ1; dH (CDCl3)
1.38 (3H, t, J 7.1 Hz, CH3), 1.68 (3H, d, J 6.6 Hz, CH3),
4.35 (2H, q, J 7.1 Hz, CH2), 6.03 (1H, q, J 6.6 Hz, CH),
7.3–7.4 (5H, m, ArH); dC (CDCl3) 158.3 (C]O), 157.7
(C]O), 140.4 (ArC), 128.9 (ArCH), 128.8 (ArCH), 126.6
(ArCH), 75.9 (OCH), 63.4 (OCH2), 22.2 (CH3), 14.2
(CH3); m/z (CI) 223 (MH+, 24), 209 (52), 131 (35), 106
(67), 105 (100), 104 (46), 77 (48), 51 (15). Found (ESI)
245.0783; C12H14O4Na (M+Na)+ requires 245.0784.
4.2.6. (R)-1-Phenylethyl cyanoformate 6a. To a stirred
mixture of oxamide 9a (2.9 g, 15.0 mmol) and pyridine
(4.6 g, 57.8 mmol) in CH2Cl2 (27 mL), in an ice bath, TFAA
(3.8 g, 17.9 mmol) was added dropwise over 10 min. The ice
bath was removed and the thick reaction mixture was al-
lowed to stir at room temperature for 2 h. Water (58 mL)
was added, the organic layer was separated, washed with
water (43 mL) and the aqueous layer extracted with
CH2Cl2 (2ꢃ30 mL). The combined CH2Cl2 layers were
again washed with water (50 mL), dried (MgSO4) and evap-
orated in vacuo to leave an oil, which was subjected to bulb-
to-bulb distillation (120–170 ꢁC at 150 mmHg) to give
compound 6a (1.9 g, 71%) as a colourless oil. [a]2D0 +95.6
(c 1.65, CHCl3); nmax (neat) 2244 s and 1744 s cmꢀ1; dH
(CDCl3) 1.71 (3H, d, J 6.5 Hz, CH3), 6.06 (1H, q, J
6.5 Hz, CH), 7.3–7.4 (5H, m, ArH); dC (CDCl3) 144.0
(C]O), 138.8 (ArC), 129.6 (ArCH), 129.3 (ArCH), 126.8
(ArCH), 109.8 (CN), 78.8 (OCH), 21.9 (CH3); m/z (EI)
4.2.2. Ethyl (S)-1-phenylethyl oxalate 8b. Prepared from
(S)-1-phenylethanol 7b (5.0 g, 40.9 mmol) as described for
the (R)-enantiomer 8a (Section 4.2.1) to give compound
8b (9.0 g, 97%) as a colourless liquid. [a]2D0 ꢀ60.0 (c 1.1,
CHCl3). Other analytical data as reported for the (R)-enan-
tiomer 8a.
4.2.3. (R)-1-Phenylethyl oxamide 9a from diester 8a. To
a solution of compound 8a (17.3 g, 78.2 mmol) in ethanol

9734
Y. N. Belokon’ et al. / Tetrahedron 63 (2007) 9724–9740
175 (M+, 38), 159 (12), 132 (11), 121 (11), 105 (100), 77
(24). Found (ESI) 293.1147; C17H18O3Na (2MꢀCO(CN)2+
Na)+ requires 293.1148. Compound reacts with water under
electrospray mass spectrometric conditions to form
(PhCHMeO)2CO in situ.
4.2.10. (D)-Menthyl oxamide 12c. To a stirred solution of
(+)-menthol (1.0 g, 7.7 mmol) in CH2Cl2 (20 mL) at 0 ꢁC,
oxalyl chloride (1.95 g, 15.4 mmol) was added dropwise.
The ice bath was removed and the mixture was stirred for
1 h at room temperature. The solvent was then removed in
vacuo, and the residue was dried on a vacuum line. The crude
oxalic ester was redissolved in CH2Cl2 (50 mL), and concen-
trated aqueous ammonia (0.46 mL excess) was added at
0 ꢁC. The mixture was stirred for 30 min, then water was
added and the two layers were separated. The aqueous layer
was extracted with CH2Cl2 (2ꢃ20 mL) and the combined or-
ganic layers were washed with water. The organic layer was
dried (MgSO4) and the solvent was removed in vacuo. The
residue was recrystallised from CH2Cl2 to give compound
12c (1.7 g, 97%) as a white solid. Mp 148–148.5 ꢁC; [a]D20
+87.4 (c 0.95, CHCl3); nmax (ATR) 3404 m, 3234 m, 2957
m, 2921 m, 2872 m, 1733 s, 1682 s and 1651 m cmꢀ1; dH
(CDCl3) 0.76 (3H, d, J 7.0 Hz, CH3), 0.90 (3H, d, J
7.0 Hz, CH3), 0.92 (3H, d, J 6.5 Hz, CH3), 1.0–1.3 (1H, m,
CH), 1.4–2.1 (8H, m, 3ꢃCH2, 2ꢃCH), 4.84 (1H, td, J 11.0
and 4.5 Hz, CHO), 5.84 (1H, br, NH2), 6.95 (1H, br, NH2);
dC (CDCl3) 160.0 (C]O), 158.9 (C]O), 78.5 (CHO),
47.2 (CH), 40.7 (CH2), 34.4 (CH2), 31.9 (CH), 26.7 (CH),
24.0 (CH2), 22.1 (CH3), 20.9 (CH3), 16.6 (CH3); m/z (ESI)
245 (M+NH+4, 30), 139 (20), 122 (18). Found (ESI)
245.1864; C12H25N2O3 (M+NH+4) requires 245.1864.
4.2.7. (S)-1-Phenylethyl cyanoformate 6b. Prepared from
compound 9b (1.1 g, 5.7 mmol) as described for the (R)-
enantiomer 6a (Section 4.2.6) to give compound 6b
(0.85 g, 85%) as a colourless oil. [a]2D0 ꢀ95.6 (c 1.35,
CHCl3). Other analytical data as reported for the (R)-enan-
tiomer 6a.
4.2.8. (R)-1-(Carboxyethyl)ethyl oxamide 12a. To a stirred
solution of ethyl lactate (1.0 g, 7.7 mmol) in CH2Cl2
(20 mL) at 0 ꢁC, oxalyl chloride (2.0 g, 15.4 mmol) was
added dropwise. The ice bath was removed and the mixture
was stirred for 1 h, after which the solvent was removed in
vacuo and the residue dried on a vacuum line. The resulting
crude mono-ester was redissolved in CH2Cl2, cooled to 0 ꢁC
and concentrated aqueous ammonia (0.46 mL, 1.2 equiv)
was added. The mixture was stirred for 30 min, then water
was added and the two layers were separated. The aqueous
layer was extracted with CH2Cl2 (2ꢃ20 mL) and the com-
bined organic layers were washed with water. The organic
layer was dried (MgSO4) and evaporated in vacuo. The resi-
due was recrystallised from CH2Cl2 to give oxamide 12a
(0.44 g, 27%) as a white solid. Mp 77–79 ꢁC; [a]D20 ꢀ36.5
(c 0.26, CHCl3); nmax (CH2Cl2) 3349 w, 3239 w, 3222 w,
1733 s, 1676 s and 1667 s cmꢀ1; dH (CDCl3) 1.26 (3H, t, J
7.1 Hz, CH3CH2), 1.61 (3H, d, J 7.0 Hz, CH3CH), 4.21
(2H, q, J 7.1 Hz, OCH2), 5.18 (1H, q, J 7.0 Hz, CH3CHO),
6.00 (1H, br, NH2), 6.92 (1H, br, NH2); dC (CDCl3) 169.5
(C]O), 159.6 (C]O), 157.8 (C]O), 71.5 (OCH), 62.1
(OCH2), 17.0 (CH3), 14.3 (CH3); m/z (ESI) 207 (M+NH+4,
80%), 180 (100). Found (ESI) 207.0978; C7H15N2O5
(M+NH+4) requires 207.0975.
4.2.11. (S)-Glycerol acetonide oxamide 12d. To a stirred
mixture of sodium hydride in mineral oil (0.02 g,
0.56 mmol) and (S)-glycerol acetonide (0.10 g, 0.56 mmol)
in THF (20 mL) at 0 ꢁC, oxalyl chloride (0.14 g,
1.12 mmol) was added dropwise. The ice bath was removed
and the mixture was stirred at room temperature for 16 h.
The solvent was removed in vacuo, and the residue dried
on a vacuum line. The crude oxalic ester was redissolved
in CH2Cl2 (2 mL), and concentrated aqueous ammonia
(0.20 mL excess) was added at 0 ꢁC. The mixture was stirred
for 30 min, then water was added and the two layers were
separated. The aqueous layer was extracted with CH2Cl2
(2ꢃ20 mL) and the combined organic layers were washed
with water. The organic layer was dried (MgSO4) and the
solvent was removed in vacuo to give compound 12d
(82 mg, 72%) as a white solid. Mp 184–186 ꢁC (decomp.);
[a]2D0 ꢀ18.0 (c 0.05, CHCl3); nmax (ATR) 3391 m, 3131 s,
3043 s, 1737 m, 1690 s and 1607 m cmꢀ1; dH (CDCl3)
1.33 (3H, s, CH3), 1.41 (3H, s, CH3), 3.80 (1H, dd, J 8.7
and 5.4 Hz, OCH2), 4.08 (1H, dd, J 8.7 and 6.4 Hz,
OCH2), 4.2–4.5 (3H, m, OCH), 6.32 (1H, br, NH2) 7.00
(1H, br, NH2); dC (CDCl3) 160.0 (C]O), 158.3 (C]O),
110.2 (OCMe2), 73.0 (OCH), 67.0 (OCH2), 66.3 (OCH2),
26.7 (CH3), 25.3 (CH3); m/z (ESI) 221 (M+NH+4, 30), 204
(MH+, 100), 163 (70), 146 (50), 101 (95). Found (ESI)
221.1133; C8H17N2O5 (M+NH+4) requires 221.1132.
4.2.9. (R)-1-(Carboxyethyl)benzyl oxamide 12b. Sodium
hydride (22 mg of a 60% dispersion in mineral oil) was
washed with petrol, suspended in THF (20 mL) and cooled
in an ice bath. Ethyl mandelate (0.10 g, 0.56 mmol) was
added, followed by dropwise addition of oxalyl chloride
(0.14 g, 1.12 mmol). The ice bath was removed and the mix-
ture was stirred for 16 h. The solvent was removed in vacuo,
and the residue was dried on a vacuum line. The crude mono-
ester was redissolved in CH2Cl2, and concentrated aqueous
ammonia (0.20 mL, excess) was added at 0 ꢁC. The mixture
was stirred for 30 min, then water was added, and the two
layers were separated. The aqueous layer was extracted
with CH2Cl2 (2ꢃ20 mL) and the combined organic layers
were washed with water (20 mL). The organic layer was
dried (MgSO4) and evaporated in vacuo to give compound
12b (0.15 g, 97%) as a white solid. Mp 190–200 ꢁC (de-
comp.); [a]2D0 +4.7 (c 0.3, CHCl3); nmax (ATR) 3445 br,
2983 m, 1748 s and 1601 m cmꢀ1; dH (CDCl3) 1.12 (3H, t,
J 7.1 Hz, CH3CH2), 4.0–4.3 (2H, m, OCH2CH3), 5.91 (1H, s,
PhCHO), 6.5–6.6 (1H, br, NH), 7.0–7.1 (1H, br, NH), 7.2–7.5
(5H, m, ArCH); dC (CDCl3) 167.8 (C]O), 159.6 (C]O),
157.7 (C]O), 133.2 (ArC), 129.9 (ArCH), 129.2 (ArCH),
128.1 (ArCH), 73.4 (OCH), 62.4 (OCH2), 14.2 (CH3); m/z
(CI) 269 (M+NH+4, 30%), 198 (70), 182 (100). Found (ESI)
269.1130; C12H17N2O5 (M+NH+4) requires 269.1132.
4.2.12. (R)-1-(Carboxyethyl)ethyl cyanoformate 10a. To
a solution of oxamide 12a (0.8 g, 4.2 mmol) and pyridine
(1.4 mL, 16.9 mmol) in CH2Cl2 (15 mL), TFAA (0.7 mL,
5.0 mmol) was added dropwise at 0 ꢁC. The ice bath was re-
moved and the solution was stirred for 2 h at room tempera-
ture. Water was added and the layers were separated. The
organic layer was washed with water (20 mL) and then
with dilute hydrochloric acid (20 mL). The organic layer
was dried (MgSO4) and the solvent was removed in vacuo

Y. N. Belokon’ et al. / Tetrahedron 63 (2007) 9724–9740
9735
to leave compound 10a (0.57 g, 78%) as a yellow oil. [a]D20
ꢀ40.3 (c 1.2, CHCl3); nmax (CH2Cl2) 2989 s, 2945 m,
2249 m and 1748 s cmꢀ1; dH (CDCl3) 1.27 (3H, t, J
7.1 Hz, CH3CH2), 1.58 (3H, d, J 7.1 Hz, CH3CH), 4.21
(2H, q, J 7.1 Hz, OCH2), 5.20 (1H, q, J 7.1 Hz, CH3CHO);
dC (CDCl3) 168.1 (C]O), 143.8 (C]O), 109.3 (CN),
73.0 (OCH), 62.6 (OCH2), 16.8 (CH3), 14.3 (CH3); m/z
(EI) 171 (M+, 55%), 98 (50), 73 (60), 54 (90), 43 (100).
Found (ESI) 285.0948 and 263.1111; C11H18O7Na
(2Mꢀ2CNꢀCO+Na)+ requires 285.0950 and C11H19O7
(2Mꢀ2CNꢀCO+H)+ requires 263.1131.
layer was dried (MgSO4) and the solvent was removed
in vacuo to leave compound 10d (0.16 g, 21%) as a yellow
oil. [a]2D0 +1.4 (c 1.15, CHCl3); nmax (neat) 2991 w, 2248
w, 1791 m and 1755 s cmꢀ1; dH (CDCl3) 1.34 (3H, s,
CH3), 1.41 (3H, s, CH3), 3.76 (1H, dd, J 8.6 and 4.9 Hz,
OCH2), 4.08 (1H, dd, J 8.6 and 6.1 Hz, OCH2), 4.2–4.4
(3H, m, OCH+OCH2); dC (CDCl3) 144.3 (CO2), 110.8
(CMe2), 109.3 (CN), 73.1 (OCH), 68.7 (OCH2), 64.8
(OCH2), 26.9 (CH3), 25.5 (CH3); m/z (CI) 336
(2Mꢀ2CN+NH+4, 20), 294 (100), 277 (50), 232 (70). Found
(ESI) 336.1651; C14H26NO8 (2Mꢀ2CN+NH+4) requires
336.1653.
4.2.13. (R)-1-(Carboxyethyl)benzyl cyanoformate 10b. To
a solution of oxamide 12b (1.1 g, 4.2 mmol) and pyridine
(1.4 mL, 16.9 mmol) in CH2Cl2 (15 mL), TFAA (0.7 mL,
5.0 mmol) was added dropwise at 0 ꢁC. The ice bath was
removed and the solution was stirred for 2 h at room temper-
ature. Water was added and the layers were separated. The
organic layer was washed with water (20 mL) and then
with dilute hydrochloric acid (20 mL). The organic layer
was dried (MgSO4) and the solvent was removed in vacuo
to leave compound 10b (0.87 g, 87%) as a yellow oil.
[a]2D0 ꢀ8.4 (c 0.5, CHCl3); nmax (neat) 3069 s, 3038 w,
2986 m, 2943 m, 2908 w, 2249 m, 1791 s and 1748
s cmꢀ1; dH (CDCl3) 1.23 (3H, t, J 7.1 Hz, CH3CH2), 4.1–
4.3 (2H, m, OCH2), 6.05 (1H, s, PhCHO), 7.3–7.5 (5H, m,
ArH); dC (CDCl3) 166.6 (C]O), 143.8 (C]O), 138.8
(ArC), 129.6 (ArCH), 128.1 (ArCH), 126.9 (ArCH), 109.1
(CN), 78.3 (OCH), 62.8 (OCH2), 14.2 (CH3); m/z (EI) 233
(M+, 1%), 160 (90), 105 (100). Found (EI) 233.0685;
C12H11NO4 (M+) requires 233.0683.
4.3. Asymmetric addition of achiral cyanoformates to
aldehydes in the presence of potassium cyanide
To a stirred solution of aldehyde (9.4 mmol) and catalyst 1
(229 mg, 0.2 mmol) in CH2Cl2 (25 mL) was added KCN
(61 mg, 0.9 mmol). The mixture was cooled to ꢀ40 ꢁC,
then the cyanoformate (11.3 mmol) was added and the reac-
tion mixture was stirred vigorously at ꢀ40 ꢁC for 24 h. The
reaction mixture was warmed to room temperature and
passed through a plug of silica gel, eluting with CH2Cl2.
The solvent was removed in vacuo to give the cyanohydrin
carbonates 13a–g or 14a–f as a yellow oil.
4.3.1. O-Ethoxycarbonyl (S)-2-hydroxy-2-phenyl-aceto-
nitrile 13a.10b,18,28a Compound 13a was obtained in quanti-
tative yield. [a]D20 ꢀ16.5 (c 1.0, CHCl3) [lit.28a [a]D20 +16.2 (c
2.8, CHCl3) for (R)-enantiomer with 94% ee]. Chiral GC
conditions: flow rate 1 mL/min, initial temperature 100 ꢁC,
held at initial temperature for 2 min, then ramp rate
0.2 ꢁC/min; tR¼117.2 and 119.5 min.
4.2.14. (D)-Menthyl cyanoformate 10c.38 To a solution of
oxamide 12c (0.5 g, 2.2 mmol) and pyridine (0.7 g,
8.8 mmol) in CH2Cl2 (8 mL), TFAA (0.55 g, 2.6 mmol)
was added dropwise at 0 ꢁC. The ice bath was removed,
and the solution was stirred for 2 h at room temperature.
Water was added and the layers were separated. The organic
layer was washed with water (20 mL), then with dilute
hydrochloric acid (20 mL). The organic layer was dried
(MgSO4), and the solvent was removed in vacuo to leave
compound 10c (0.44 g, 96%) as a yellow oil. [a]2D0 +78.5
(c 1.0, CHCl3); nmax (neat) 2960 s, 2873 s, 2244 m and
1744 s cmꢀ1; dH (CDCl3) 0.70 (3H, d, J 7.0 Hz, CH3),
0.86 (3H, d, J 7.0 Hz, CH3), 0.87 (3H, d, J 6.5 Hz, CH3),
0.9–1.2 (3H, m, 3ꢃCyCH), 1.3–1.5 (2H, m, 2ꢃCyCH),
1.6–1.7 (2H, m, 2ꢃCyCH), 1.7–1.9 (1H, m, CyCH), 1.9–
2.0 (1H, m, CyCH), 4.80 (1H, td, J 11.0 and 4.5 Hz,
CHO); dC (CDCl3) 144.3 (CO), 109.9 (CN), 81.2 (OCH),
47.1 (CH), 40.6 (CH2), 34.4 (CH2), 31.9 (CH), 26.8 (CH),
23.9 (CH2), 22.0 (CH3), 20.8 (CH3), 16.5 (CH3); m/z (CI)
232 (MꢀCN+OMe+NH+4, 30), 172 (100), 155 (40), 137
(50), 95 (60). Found (ESI) 384.3110; C22H42NO4
(2Mꢀ2CN+NH+4) requires 384.3108.
4.3.2. O-Ethoxycarbonyl (S)-2-hydroxy-2-(4-methoxy-
phenyl)acetonitrile 13b.18 Compound 13b was obtained
in 98% yield. [a]D20 +1.8 (c 1.35, CHCl3) [lit.18 [a]2D0 +1.8
(c 1.8, CHCl3) for (S)-enantiomer with 95% ee]. Chiral
GC conditions: flow rate 1 mL/min, initial temperature
100 ꢁC, held at initial temperature for 2 min, then ramp
rate 0.2 ꢁC/min; tR¼242.2 and 245.7 min.
4.3.3. O-Ethoxycarbonyl (S)-2-hydroxy-2-(4-trifluoro-
methylphenyl)acetonitrile 13c.18 Compound 13c was
obtained in quantitative yield. [a]2D0 ꢀ9.9 (c 1.4, CHCl3).
Chiral GC conditions: flow rate 1 mL/min, initial tempera-
ture 100 ꢁC, held at initial temperature for 2 min, then
ramp rate 0.4 ꢁC/min; tR¼79.4 and 82.6 min.
4.3.4. O-Ethoxycarbonyl (S)-2-hydroxy-4-phenyl-but-
3-enonitrile 13d.18,28b,c Compound 13d was obtained in
94% yield. [a]D20 +21.9 (c 1.1, CHCl3) [lit.18 [a]D20 ꢀ23.4
(c 1.9, CHCl3) for (S)-enantiomer with 94% ee. Chiral GC
conditions: flow rate 1 mL/min, initial temperature 100 ꢁC,
held at initial temperature for 2 min, then ramp rate
0.2 ꢁC/min; tR¼250.1 and 254.2 min.
4.2.15. (S)-Glycerol acetonide cyanoformate 10d. To a
solution of oxamide 12d (0.86 g, 4.2 mmol) and pyridine
(1.4 mL, 16.9 mmol) in CH2Cl2 (15 mL), TFAA (0.7 mL,
5.0 mmol) was added dropwise at 0 ꢁC. The ice bath was
removed and the solution was stirred for 2 h at room temp-
erature. Water was added and the layers were separated.
The organic layer was washed with water (20 mL) and
then with dilute hydrochloric acid (20 mL). The organic
4.3.5. O-Ethoxycarbonyl (S)-2-hydroxy-decanonitrile
13e.18 Compound 13e was obtained in 90% yield. [a]2D0
ꢀ42.8 (c 1.05, CHCl3). Chiral GC conditions: flow rate
1 mL/min, initial temperature 100 ꢁC, held at initial temper-
ature for 2 min, then ramp rate 0.2 ꢁC/min; tR¼140.6 and
143.3 min.

9736
Y. N. Belokon’ et al. / Tetrahedron 63 (2007) 9724–9740
4.3.6. O-Ethoxycarbonyl (S)-2-hydroxy-2-cyclohexyl-
acetonitrile 13f.18,28c Compound 13f was obtained in 86%
yield. [a]2D0 ꢀ42.1 (c 1.05, CHCl3) [lit.28c [a]2D0 +53.4 (c
2.0, CHCl3) for (R)-enantiomer with 96% ee]. Chiral GC
conditions: flow rate 1 mL/min, initial temperature 100 ꢁC,
held at initial temperature for 2 min, then ramp rate
0.2 ꢁC/min; tR¼97.8 and 99.1 min.
(CH3)3), 1.44 (9H, s, (CH3)3), 4.81 (1H, s, CHO); dC
(CDCl3) 152.5 (CO3), 116.4 (CN), 84.5 (OCH), 72.7
(OCMe3), 35.2 (CMe3), 28.0 ((CH3)3), 25.5 ((CH3)3); m/z
(CI) 214 (MH+, 100%), 196 (23), 113 (59), 96 (93), 59 (82),
41 (53). Found (ESI) 236.1256; C11H19NO3Na (M+Na)+ re-
quires 236.1257. Chiral GC conditions: flow rate 1 mL/min,
initial temperature 70 ꢁC, held at initial temperature for
2 min, then ramp rate 0.1 ꢁC/min; tR¼73.4 and 74.9 min.
4.3.7. O-Ethoxycarbonyl (S)-2-hydroxy-3,3-dimethyl-bu-
tanonitrile 13g.18,28c Compound 13g was obtained in 79%
yield. [a]2D0 ꢀ68.0 (c 1.35, CHCl3) [lit.28c [a]2D0 +75.6 (c
2.2, CHCl3) for (R)-enantiomer with 87% ee]. Chiral GC
conditions: flow rate 1 mL/min, initial temperature 50 ꢁC,
held at initial temperature for 2 min, then ramp rate
0.1 ꢁC/min; tR¼150.7 and 157.7 min.
4.4. Diastereoselective synthesis of cyanoformates
derived from chiral cyanoformates 6a,b
To a stirred solution of aldehyde (benzaldehyde or pivalde-
hyde) (2.4 mmol) and catalyst 1 (57.8 mg, 0.05 mmol) in
CH2Cl2 (6 mL) was added KCN (7.7 mg, 0.1 mmol). The
mixture was cooled to ꢀ78 ꢁC, then cyanoformate 6a or
6b (0.5 g, 2.9 mmol) was added and the reaction mixture
was stirred vigorously at ꢀ40 ꢁC for 24 h. If after this
time, the reaction had not reached completion an additional
batch of KCN (7.7 mg, 0.1 mmol) and catalyst 1 (57.8 mg,
0.05 mmol) was added and the reaction mixture was stirred
at ꢀ40 ꢁC for a further 48 h. The reaction mixture was
warmed to room temperature and passed through a plug of
silica gel, eluting with CH2Cl2. The solvent was removed
in vacuo to give the product.
4.3.8. O-Methoxycarbonyl (S)-2-hydroxy-2-phenyl-ace-
tonitrile 14a.27a,40,44 Compound 14a was obtained in 92%
yield. [a]2D0 ꢀ15.7 (c 1.15, CHCl3). Chiral GC conditions:
flow rate 1 mL/min, initial temperature 100 ꢁC, held at
initial temperature for 2 min, then ramp rate 0.2 ꢁC/min;
tR¼99.7 and 103.0 min.
4.3.9. O-Benzyloxycarbonyl (S)-2-hydroxy-2-phenyl-ace-
tonitrile 14b.27a Compound 14b was obtained in 100%
yield. [a]2D0 ꢀ17.4 (c 1.2, CHCl3); nmax (neat) 2985 s, 2245
m and 1756 s cmꢀ1; dH (CDCl3) 5.0–5.3 (2H, m, OCH2),
6.18 (1H, s, CHCN), 7.2–7.5 (10H, m, ArH); dC (CDCl3)
153.8 (CO3), 131.1 (ArC), 130.0 (ArC), 129.7 (ArCH),
129.5 (ArCH), 129.4 (ArCH), 129.2 (ArCH), 129.0
(ArCH), 128.3 (ArCH), 116.1 (CN), 71.5 (OCH), 67.0
(OCH2); m/z (EI) 267 (M+, 3%), 191 (5), 117 (100). Found
(ESI) 290.07807; C16H13NO3Na (M+Na+) requires
290.07876.
4.4.1. Compounds 15a (major) and 16a (minor). Com-
pounds 15a and 16a were obtained as a colourless, crystal-
line solid (0.48 g, 88% conversion from benzaldehyde). To
obtain crystals suitable for X-ray analysis, the white solid
was first further purified by flash chromatography (CH2Cl2)
and then recrystallised from CH2Cl2. [a]2D0 +36.8 (c 1.45,
CHCl3); nmax (neat) 2985 m, 2346 w and 1762 s cmꢀ1; dH
(CDCl3) 15a: 1.51 (3H, d, J 6.7 Hz, CH3), 5.68 (1H, q, J
6.7 Hz, CHMe), 6.15 (1H, s, CHCN), 7.2–7.8 (10H, m,
ArH); 16a (not all peaks visible): 6.10 (1H, s, CH); dC
(CDCl3) 15a: 153.3 (CO3), 140.5 (ArC), 131.8 (ArC),
131.1 (ArCH), 129.7 (ArCH), 129.2 (ArCH), 129.0
(ArCH), 128.4 (ArCH), 126.5 (ArCH), 116.23 (CN), 78.9
(PhCHCN), 66.9 (PhCHO), 22.6 (CH3); m/z (CI) 282
(MH+, 2%), 238 (7), 193 (10), 105 (100). Found (ESI)
304.0945; C17H15NO3Na (M+Na)+ requires 304.0944.
4.3.10. O-tert-Butyloxycarbonyl (S)-2-hydroxy-2-phenyl-
acetonitrile 14c.32b Compound 14c was obtained in 100%
yield. [a]2D0 ꢀ14.2 (c 1.25, CHCl3); m/z (EI) 233 (M+,
6%), 177 (60), 133 (15), 116 (100), 77 (10), 57 (96).
4.3.11. O-Methoxycarbonyl (S)-2-hydroxy-3,3-dimethyl-
butanonitrile 14d.40 Compound 14d was obtained in 85%
yield. [a]2D0 ꢀ74.1 (c 1.2, CHCl3); m/z (EI) 171 (M+, 3%),
156 (10), 112 (15), 96 (20), 57 (100). Chiral GC conditions:
flow rate 1 mL/min, initial temperature 70 ꢁC, held at initial
temperature for 2 min, then ramp rate 0.1 ꢁC/min; tR¼35.4
and 36.7 min.
4.4.2. Compounds 15b (major) and 16b (minor). Com-
pounds 15b and 16b were obtained as a white solid
(0.59 g, 100% conversion from pivaldehyde). To obtain
crystals suitable for X-ray analysis, the white solid was first
further purified by flash chromatography (CH2Cl2) and then
recrystallised from CH2Cl2. [a]2D0 +33.3 (c 1.15, CHCl3);
nmax (KBr) 2973 s, 2244 w and 1754 s cmꢀ1; dH (CDCl3)
15b: 1.02 (9H, s, (CH3)3), 1.55 (3H, d, J 6.6 Hz, CH3),
4.85 (1H, s, CHCN), 5.69 (1H, q, J 6.6 Hz, CHMe), 7.2–
7.4 (5H, m, ArH); 16b (not all peaks visible): 4.79 (1H, s,
CH); dC (CDCl3) 153.8 (CO3), 140.4 (ArC), 129.1
(ArCH), 128.9 (ArCH), 126.4 (ArCH), 115.9 (CN), 78.5
(CHCN), 73.6 (CHMe), 35.4 (CMe3), 25.5 ((CH3)3), 22.5
(CH3); m/z (EI) 261 (M+, 27%), 121 (41), 105 (100). Found
(ESI) 284.1257; C15H19NO3Na (M+Na)+ requires 284.1257.
4.3.12. O-Benzyloxycarbonyl (S)-2-hydroxy-3,3-di-
methyl-butanonitrile 14e. Compound 14e was obtained
in 100% yield. [a]D20 ꢀ40.9 (c 1.1, CHCl3); nmax (neat)
2970 s, 2245 w and 1755 s cmꢀ1; dH (CDCl3) 1.12 (9H, s,
(CH3)3), 4.94 (1H, s, CHCN), 5.2–5.3 (2H, m, CH2O),
7.3–7.5 (5H, m, ArH); dC (CDCl3) 154.4 (CO3), 134.7
(ArC), 129.4 (ArCH), 129.2 (ArCH), 129.0 (ArCH), 116.1
(CN), 73.9 (CHO), 71.3 (CH2O), 35.3 (CMe3), 25.5
((CH3)3); m/z (EI) 247 (M+, 43%), 161 (100). Found (CI)
265.1546; C14H21N2O3 (M+NH4)+ requires 265.1547.
4.3.13. O-tert-Butyloxycarbonyl (S)-2-hydroxy-3,3-di-
methyl-butanonitrile 14f. Compound 14f was obtained in
100% yield. [a]D20 ꢀ55.3 (c 1.1, CHCl3); nmax (neat) 2975
s, 2242 w and 1752 s cmꢀ1; dH (CDCl3) 1.03 (9H, s,
4.4.3. Compounds 17a (major) and 18a (minor). Com-
pounds 17a and 18a were obtained as a yellow oil (0.53 g,
66% conversion from benzaldehyde). [a]2D0 ꢀ40.1 (c 2.75,
CHCl3); nmax (neat) 2986 m, 2348 w and 1761 s cmꢀ1; dH

Y. N. Belokon’ et al. / Tetrahedron 63 (2007) 9724–9740
9737
(CDCl3) 17a: 1.52 (3H, d, J 6.5 Hz, CH3), 5.70 (1H, q, J
6.5 Hz, CHMe), 6.11 (1H, s, CHCN), 7.2–7.8 (10H, m,
ArH); 18a (not all peaks visible): 6.15 (1H, s, CH); dC
(CDCl3) 153.3 (CO3), 140.4 (ArC), 131.5 (ArC), 131.0
(ArCH), 129.6 (ArCH), 129.1 (ArCH), 129.0 (ArCH),
128.2 (ArCH), 126.5 (ArCH), 116.2 (CN), 78.9 (CHCN),
66.8 (CHPh), 22.6 (CH3); m/z (CI) 282 (MH+, 4%), 105
(100). Found (ESI) 304.0956; C17H15NO3Na (M+Na)+ re-
quires 304.0944.
+100 (c 0.05, CHCl3); nmax (ATR) 2988 m, 1761 m, 1744 and
1633 s cmꢀ1; dH (CDCl3) 20a: 1.13 (9H, s, (CH3)3), 1.26 (3H,
t, J 7.1 Hz, CH3CH2), 1.54 (3H, d, J 7.1 Hz, CH3CH), 4.19
(2H, q, J 7.1 Hz, CH3CH2O), 4.98 (1H, s, CHCN), 5.02
(1H, q, J 7.1 Hz, CH3CHO); 20b: 1.12 (9H, s, (CH3)3),
1.30 (3H, t, J 7.1 Hz, CH3CH2), 1.57 (3H, d, J 7.1 Hz,
CH3CH), 4.1–4.3 (2H, m, CH3CH2O), 4.92 (1H, s, CHCN),
5.05 (1H, q, J 7.1 Hz, CH3CHO); dC (CDCl3) 20a: 169.7
(CO2), 153.5 (CO3), 115.4 (CN), 73.8 (CHO), 73.1 (CHO),
62.0 (OCH2), 35.1 (CMe3), 25.2 (CH3), 17.0 (CH3), 14.1
(CH3); 20b: 169.4 (CO2), 153.4 (CO3), 115.3 (CN), 73.9
(CHO), 73.2 (CHO), 61.8 (OCH2), 35.0 (CMe3), 25.1
(CH3), 16.8 (CH3), 14.0 (CH3); m/z (ESI) 280 (M+Na+,
80%), 275 (M+NH+4, 100), 258 (MH+, 10), 241 (20). Found
(ESI) 275.1600; C12H23N2O5 (M+NH4)+ requires 275.1601.
4.4.4. Compounds 17b (major) and 18b (minor). Com-
pounds 17b and 18b were obtained as a yellow oil (0.37 g,
100% conversion from pivaldehyde). [a]2D0 ꢀ115.2 (c 1.25,
CHCl3); nmax (neat) 2972 s, 2227 w and 1753 s cmꢀ1; dH
(CDCl3) 17b: 1.10 (9H, s, (CH3)3), 1.65 (3H, d, J 6.6 Hz,
CH3), 4.89 (1H, s, CHCN), 5.79 (1H, q, J 6.6 Hz, CHMe),
7.3–7.4 (5H, m, ArH); 18b: 4.96 (1H, s, CH); dC (CDCl3)
153.8 (CO3), 140.8 (ArC), 129.1 (ArCH), 128.9 (ArCH),
126.4 (ArCH), 116.2 (CN), 78.5 (CHCN), 73.6 (CHMe),
25.5 ((CH3)3), 22.6 (CH3); m/z (EI) 261 (M+, 16%), 121
(33), 105 (100). Found (ESI) 284.1251; C15H19NO3Na
(M+Na)+ requires 284.1257.
4.6. Asymmetric addition of ethyl cyanoformate to
aldehydes in the presence of potassium cyanide/
18-crown-6 complex
KCN/18-crown-6 complex41 (6.6 mg, 0.02 mmol) and
catalyst 1 (36 mg, 0.03 mmol) were dissolved in CH2Cl2
(5 mL). The solution was cooled to ꢀ40 ꢁC, then aldehyde
(2.0 mmol) and ethyl cyanoformate (0.24 mL, 2.4 mmol)
were added. The resulting solution was allowed to stir for
24 h (or 48 h when specified) at ꢀ40 ꢁC. The reaction mix-
ture was warmed to room temperature and passed through
a plug of silica gel, eluting with CH2Cl2. The solvent was
removed in vacuo to give the product as a yellow oil.
4.5. Diastereoselective synthesis of cyanoformates
derived from chiral cyanoformates 10a–d
To a stirred solution of KCN (3.3 mg, 0.06 mmol) and cata-
lyst 1 (31.2 mg, 0.027 mmol) at ꢀ40 ꢁC were added alde-
hyde (1.28 mmol) and cyanoformate 10a–d (1.54 mmol).
The reaction mixture was stirred at ꢀ40 ꢁC for 24 h and if
no reaction occurred, the mixture was allowed to warm to
room temperature and stirred for an additional two weeks.
The reaction mixture was passed through a plug of silica
gel, eluting with CH2Cl2. The sample was purified by flash
chromatography (CH2Cl2) to give compounds 19a,b or
20a,b as white solids.
4.6.1. O-Ethoxycarbonyl (S)-2-hydroxy-2-phenyl-aceto-
nitrile 13a.10b,18,28a Compound 13a was obtained in quanti-
tative yield. Analytical data as reported in Section 4.3.1.
4.6.2. O-Ethoxycarbonyl (S)-2-hydroxy-2-(4-methoxy-
phenyl)acetonitrile 13b.18 Compound 13b was obtained
in quantitative yield. Analytical data as reported in Section
4.3.2.
4.5.1. Compounds 19a and 19b. Compounds 19a and 19b
were obtained in a 12.3:1 ratio in favour of 19a using the
(R,R)-enantiomer of catalyst 1 and in a 9:1 ratio in favour
of 19b using the (S,S)-enantiomer of catalyst 1. [a]2D0 19a:
+112 (c 0.05, CHCl3), 19b: ꢀ12.5 (c 0.8, CHCl3); nmax
(neat) 2988 m and 1748 s cmꢀ1; dH (CDCl3) 19a: 1.22 (3H,
t, J 7.1 Hz, CH3CH2), 1.56 (3H, d, J 7.2 Hz, CH3CH), 4.19
(2H, q, J 7.1 Hz, CH3CH2O), 5.07 (1H, q, J 7.2 Hz,
CH3CHO), 6.28 (1H, s, CHCN), 7.4–7.7 (5H, m, ArH);
19b: 1.27 (3H, t, J 7.1 Hz, CH3CH2), 1.51 (3H, d, J 7.1 Hz,
CH3CH), 4.1–4.3 (2H, m, CH3CH2O), 5.01 (1H, q, J
7.1 Hz, CH3CHO), 6.25 (1H, s, CHCN), 7.4–7.6 (5H, m,
ArH); dC (CDCl3) 19a: 169.5 (CO2), 153.1 (CO3), 131.5
(ArC), 130.7 (ArCH), 129.5 (ArCH), 125.9 (ArCH), 115.4
(CN), 73.2 (OCH), 66.9 (OCH), 61.7 (OCH2), 16.8 (CH3),
13.9 (CH3); 19b: 169.4 (CO2), 152.9 (CO3), 131.6 (ArC),
130.8 (ArCH), 129.6 (ArCH), 126.1 (ArCH), 115.3 (CN),
73.3 (OCH), 67.0 (OCH), 61.8 (OCH2), 16.8 (CH3), 14.0
(CH3); m/z (CI) 295 (M+NH4+, 40), 136 (100). Found (ESI)
295.1292; C14H19N2O5 (M+NH4)+ requires 295.1288.
4.6.3. O-Ethoxycarbonyl (S)-2-hydroxy-4-phenyl-but-
3-enonitrile 13d.18,28b,c Compound 13d was obtained in
quantitative yield after a reaction time of 48 h. Analytical
data as reported in Section 4.3.4.
4.6.4. O-Ethoxycarbonyl (S)-2-hydroxy-decanonitrile
13e.18 Compound 13e was obtained in 98% yield. Analytical
data as reported in Section 4.3.5.
4.6.5. O-Ethoxycarbonyl (S)-2-hydroxy-2-cyclohexyl-
acetonitrile 13f.18,28c Compound 13f was obtained in quan-
titative yield. Analytical data as reported in Section 4.3.6.
4.6.6. O-Ethoxycarbonyl (S)-2-hydroxy-3,3-dimethyl-bu-
tanonitrile 13g.18,28c Compound 13g was obtained in quan-
titative yield. Analytical data as reported in Section 4.3.7.
4.6.7. O-Ethoxycarbonyl (S)-2-hydroxy-2-(2-methylphe-
nyl)acetonitrile 13h.45 Compound 13h was obtained in
quantitative yield. [a]2D0 ꢀ21.5 (c 1.0, CHCl3); nmax (neat)
2986 m, 1756 s and 1697 w cmꢀ1; dH (CDCl3) 1.34 (3H, t,
J 7.1 Hz, CH3CH2), 2.44 (3H, s, ArCH3), 4.2–4.4 (2H, m,
OCH2), 6.38 (1H, s, CHCN), 7.2–7.4 (3H, m, ArH), 7.56
(1H, dd, J 7.5 and 1.3 Hz, ArH); dC (CDCl3) 153.8 (CO3),
4.5.2. Compounds 20a and 20b. Compounds 20a and 20b
were obtained in a 10.8:1 ratio in favour of 20a using the
(R,R)-enantiomer of catalyst 1 and in a 13.3:1 ratio in favour
of 20b using the (S,S)-enantiomer of catalyst 1. Mp 20a: 82–
84 ꢁC, 20b: 89–91 ꢁC; [a]D20 20a: +34.0 (c 0.1, CHCl3), 20b:

9738
Y. N. Belokon’ et al. / Tetrahedron 63 (2007) 9724–9740
137.1 (ArC), 131.7 (ArCH), 130.9 (ArCH), 130.1 (ArC),
128.9 (ArCH), 127.1 (ArCH), 115.9 (CN), 65.8 (CHCN),
65.0 (CH2O), 19.1 (CH3), 14.4 (CH3); m/z (EI) 219 (M+,
5%), 130 (40), 129 (100). Found (EI) 219.0813;
C12H13NO3 (M+) requires 219.0890. Chiral GC conditions:
flow rate 1.6 mL/min, initial temperature 100 ꢁC, held at
initial temperature for 2 min, then ramp rate 0.2 ꢁC/min;
tR¼146.7 and 147.0 min.
4.6.14. O-Ethoxycarbonyl (S,E)-2-hydroxy-hex-3-enoni-
trile 13o. Compound 13o was obtained in quantitative yield.
[a]2D0 +8.6 (c 4.5, CHCl3); nmax (neat) 2971 w, 2879 w and
1758 s cmꢀ1; dH (CDCl3) 1.06 (3H, t, J 7.4 Hz, CH3CH2),
1.27 (3H, t, J 7.3 Hz, CH3CH2O), 2.0–2.2 (2H, m,
CH3CH2CH]), 4.19 (2H, q, J 7.3 Hz, OCH2), 5.4–5.6
(2H, m, ]CHCHCN), 6.18 (1H, dt, J 15.3 and 6.3 Hz,
]CHCH2); dC (CDCl3) 152.5 (CO3), 141.4 (]CH), 118.3
(]CH), 114.4 (CN), 64.3 (OCH2), 64.0 (OCH), 24.1
(]CHCH2), 13.1 (CH3), 11.5 (CH3); m/z (CI) 201
(M+NH+4, 60%), 113 (100), 102 (50). Found (ESI)
206.0789; C9H13NO3Na (M+Na)+ requires 206.0787. Chiral
GC conditions: flow rate 1.6 mL/min, initial temperature
100 ꢁC, held at initial temperature for 2 min, then ramp
rate 0.2 ꢁC/min; tR¼36.2 and 37.4 min.
4.6.8. O-Ethoxycarbonyl (S)-2-hydroxy-2-(4-methylphe-
nyl)acetonitrile 13i.18 Compound 13i was obtained in quan-
titative yield. [a]D20 ꢀ1.9 (c 1.55, CHCl3). Chiral GC
conditions: flow rate 1.6 mL/min, initial temperature
100 ꢁC, held at initial temperature for 2 min, then ramp
rate 0.2 ꢁC/min; tR¼118.7 and 121.3 min.
4.6.9. O-Ethoxycarbonyl (S)-2-hydroxy-2-(2-methoxy-
phenyl)acetonitrile 13j.18 Compound 13j was obtained in
quantitative yield. [a]D20 +2.8 (c 1.0, CHCl3). Chiral GC con-
ditions: flow rate 1.6 mL/min, initial temperature 100 ꢁC,
held at initial temperature for 2 min, then ramp rate
0.2 ꢁC/min; tR¼207.6 and 224.9 min.
4.6.15. O-Ethoxycarbonyl (S,E)-2-hydroxy-3-methyl-
pent-3-enonitrile 13p. Compound 13p was obtained in
quantitative yield after a 48 h reaction. [a]2D0 +7.7 (c 1.8,
CHCl3); nmax (neat) 2986 s, 2950 s, 2921 s, 2484 w, 1756 s
and 1670 s cmꢀ1; dH (CDCl3) 1.29 (3H, t, J 7.1 Hz,
CH3CH2), 1.66 (3H, d, J 7.0 Hz, CH3CH]), 1.76 (3H, s,
CH3C]), 4.1–4.3 (2H, m, OCH2), 5.55 (1H, s, CHCN),
5.87 (1H, q, J 7.0 Hz, ]CHCH3); dC (CDCl3) 153.6 (CO3),
130.2 (]CH), 127.1 (]C), 115.6 (CN), 70.1 (CHCN),
64.5 (OCH2), 14.2 (CH3), 13.7 (CH3), 12.3 (CH3); m/z (CI)
201 (M+NH+4, 70%), 113 (100). Found (CI) 201.1233;
C9H17N2O3 (M+NH4)+ requires 201.1234. Chiral GC condi-
tions: flow rate 1.6 mL/min, initial temperature 100 ꢁC, held
at initial temperature for 2 min, then ramp rate 0.2 ꢁC/min;
tR¼32.2 and 33.6 min.
4.6.10. O-Ethoxycarbonyl (S)-2-hydroxy-2-(3-methoxy-
phenyl)acetonitrile 13k.18 Compound 13k was obtained
in quantitative yield. [a]2D0 ꢀ4.9 (c 1.65, CHCl3). Chiral
GC conditions: flow rate 1.6 mL/min, initial temperature
100 ꢁC, held at initial temperature for 2 min, then ramp
rate 0.2 ꢁC/min; tR¼223.4 and 227.9 min.
4.6.11. O-Ethoxycarbonyl (S)-2-hydroxy-2-(2-chlorophe-
nyl)acetonitrile 13l.46 Compound 13l was obtained in quan-
titativeyield. [a]D20 ꢀ10.1 (c 1.05, CHCl3); nmax (neat) 3074 s,
2986 s, 2941 s, 2868 sand 1763 s cmꢀ1; dH (CDCl3) 1.35(3H,
t, J 7.2 Hz, CH3CH2), 4.2–4.4 (2H, m, OCH2), 6.62 (1H, s,
CHCN), 7.3–7.5 (3H, m, ArH), 7.7–7.8 (1H, m, ArH); dC
(CDCl3) 153.5 (CO3), 133.9 (ArC), 132.1 (ArCH), 130.6
(ArCH), 129.9 (ArCH), 129.8 (ArC), 128.0 (ArCH), 115.3
(CN), 66.0 (OCH2), 64.0 (CHO), 14.4 (CH3); m/z (CI) 259
((37Cl)M+NH4+, 35%), 257 ((35Cl)M+NH+4, 100%), 171
(20), 169 (60). Found (CI) 257.0687; C11H14N2O3(35Cl)
(M+NH4)+ requires 257.0687. Chiral GC conditions: flow
rate 1.6 mL/min, initial temperature 100 ꢁC, held at initial
temperature for 2 min, then ramp rate 2 ꢁC/min; tR¼41.0
and 42.0 min.
4.7. Conversion of (S)-cyanohydrin carbonates into
g-substituted nitriles
4.7.1. (S)-4-Azido-pent-2-enonitrile 21.43 A solution of
cyanohydrin carbonate 13n (2.0 g, 11.8 mmol) and sodium
azide (1.54 g, 23.6 mmol) in THF (30 mL) and water
(30 mL) was cooled in an ice bath and stirred under a nitro-
gen atmosphere. Tetrakis(triphenylphosphine)palladium(0)
(0.28 g, 0.28 mmol) was added, the solution was allowed
to warm to room temperature and stirred for 16 h. Et2O
(100 mL) was added, the organic layer was separated
and the aqueous layer was extracted with Et2O
(2ꢃ100 mL). The combined organic layers were dried
(MgSO4) and the solvent was evaporated in vacuo. The
residue was passed through a plug of silica topped with
MgSO4, eluting with Et2O. The eluent was evaporated
in vacuo and the residue was purified by silica gel chro-
matography (CHCl3) to give compound 21 (1.17 g, 81%)
as a colourless oil. [a]2D0 ꢀ38.5 (c 1.05, CHCl3) [lit.43a
[a]2D0 ꢀ38.7 (c 1.9, CHCl3) for (R)-enantiomer with
81% ee].
4.6.12. O-Ethoxycarbonyl (S)-2-hydroxy-2-(4-chlorophe-
nyl)acetonitrile 13m.18 Compound 13m was obtained in
quantitative yield. [a]2D0 ꢀ2.6 (c 0.94, CHCl3) [lit.18 [a]2D0
ꢀ2.9 (c 1.3, CHCl3)]. Chiral GC conditions: flow rate
1.6 mL/min, initial temperature 100 ꢁC, held at initial tem-
perature for 2 min, then ramp rate 0.2 ꢁC/min; tR¼123.4
and 124.2 min.
4.6.13. O-Ethoxycarbonyl (S,E)-2-hydroxy-pent-3-eno-
nitrile 13n.43 Compound 13n was obtained in quantitative
yield. [a]2D0 +6.6 (c 1.0, CHCl3) [lit.43a [a]2D5 ꢀ12.8 (c 1.4,
CHCl3) for (R)-enantiomer]; m/z (CI) 187 (M+NH+4,
100%). Found (CI) 187.1077; C8H15N2O3 (M+NH4)+
requires 187.1077. Chiral GC conditions: flow rate
1.6 mL/min, initial temperature 100 ꢁC, held at initial
temperature for 2 min, then ramp rate 0.2 ꢁC/min; tR¼22.6
and 24.4 min.
4.7.2. (S)-4-Amino-pentanonitrile 22. Azide 21 (0.25 g,
2.0 mmol) was dissolved in dry methanol (150 mL) and
10% Pd/C (0.04 g) was added. The reaction mixture was
stirred under a hydrogen atmosphere for 4 days, then filtered
through a plug of silica and the solvent evaporated in vacuo.
The residue was purified by silica gel chromatography
(MeOH) to give compound 22 (50 mg, 17%) as a colourless
oil. Compound 22 was found to be unstable and so was
characterised as its N-benzoyl derivative.

Y. N. Belokon’ et al. / Tetrahedron 63 (2007) 9724–9740
9739
Sukumaran, J.; Hanefeld, U. Chem. Soc. Rev. 2005, 34, 530–
542.
4.7.3. N-Benzoyl (S)-4-amino-pentanonitrile 23. To
a stirred solution of amine 22 (50 mg, 0.6 mmol) in CH2Cl2
(10 mL) was added triethylamine (0.12 g, 1.2 mmol) and
benzoyl chloride (0.17 g, 1.2 mmol). The reaction mixture
was stirred at room temperature for 16 h, then the solvent
was evaporated invacuo and the residuewas purified by silica
gel chromatography (CHCl3) to give compound 23 (0.09 g,
81%) as a yellow oil. dH (CDCl3) 1.42 (3H, d, J 6.7 Hz,
CH3CH), 1.8–1.9 (2H, m, CH2CH2CN), 2.39 (2H, t, J
7.5 Hz, CH2CN), 4.1–4.3 (1H, m, CHNH), 6.67 (1H, br,
NH), 7.3–7.8 (5H, m, ArH). Chiral GC conditions: flow
rate 1.6 mL/min, initial temperature 100 ꢁC, ramp rate
2 ꢁC/min; tR¼9.6 and 12.3 min.
5. (a) 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; (b) 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; (c) Belokon’, Y. N.; Green,
B.; Ikonnikov, N. S.; North, M.; Tararov, V. I. Tetrahedron
Lett. 1999, 40, 8147–8150.
6. Belokon’, Y. N.; Green, B.; Ikonnikov, N. S.; North, M.;
Parsons, T.; Tararov, V. I. Tetrahedron 2001, 57, 771–779.
7. (a) Belokon’, Y. N.; North, M.; Parsons, T. Org. Lett. 2000, 2,
1617–1619; (b) Belokon’, Y. N.; Maleev, V. I.; North, M.;
Usanov, D. L. Chem. Commun. 2006, 4614–4616.
4.8. Kinetics of the addition of ethyl cyanoformate to
benzaldehyde catalysed by complex 1 and potassium
cyanide/18-crown-6
8. Blacker, J.; Clutterbuck, L. A.; Crampton, M. R.; Grosjean, C.;
North, M. Tetrahedron: Asymmetry 2006, 17, 1449–1456.
9. Belokon’, Y. N.; North, M.; Maleev, V. I.; Voskoboev, N. V.;
Moskalenko, M. A.; Peregudov, A. S.; Dmitriev, A. V.;
Ikonnikov, N. S.; Kagan, H. B. Angew. Chem., Int. Ed. 2004,
43, 4085–4089.
10. (a) Hamashima, Y.; Sawada, D.; Kanai, M.; Shibasaki, M.
J. Am. Chem. Soc. 1999, 121, 2641–2642; (b) Hamashima,
Y.; Sawada, D.; Nogami, H.; Kanai, M.; Shibasaki, M.
Tetrahedron 2001, 57, 805–814; (c) Yabu, K.; Masumoto, S.;
Yamasaki, S.; Hamashima, Y.; Kanai, M.; Du, W.; Curan,
D. P.; Shibasaki, M. J. Am. Chem. Soc. 2001, 123, 9908–9909.
To a stirred solution of catalyst 1, KCN/18-crown-6 complex
and ethyl cyanoformate (0.2 g, 2.0 mmol) in CH2Cl2 at
20 ꢁC, benzaldehyde (0.106 g, 1.0 mmol) was added. Sam-
ples (0.5 mL) were taken at regular intervals and passed
through a plug of silica. The solvent was evaporated invacuo,
and the residue was redissolved in CDCl3 and analysed by
1H NMR spectroscopy. The extent of reaction was deter-
mined from the relative integrals of the PhCHO signals of
unreacted benzaldehyde and mandelonitrile ethyl carbonate.
4.9. Supplementary information
ꢀ
11. Casas, J.; Najera, C.; Sansano, J. M.; Saa, J. M. Org. Lett. 2002,
4, 2589–2592; Casas, J.; Najera, C.; Sansano, J. M.; Saa, J. M.
ꢀ
ꢀ
ꢀ
Crystallographic data (excluding structural factors) for the
structures in this paper have been deposited at the Cam-
bridge Crystallographic Data Centre as supplementary pub-
lication nos. CCDC 624637 and 624638. Copies of the data
can be obtained, free of charge, on application to CCDC, 12
Union Road, Cambridge CB2 1EZ, UK (fax: +44 (0) 1223
336033 or e-mail: deposit@ccdc.cam.ac.uk).
Tetrahedron 2004, 60, 10487–10496.
12. (a) Hamashima, Y.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc.
2000, 122, 7412–7413; (b) Hamashima, Y.; Kanai, M.;
Shibasaki, M. Tetrahedron Lett. 2001, 42, 691–694; (c) Yabu,
K.; Masumoto, S.; Kanai, M.; Curran, D. P.; Shibasaki, M.
Tetrahedron Lett. 2002, 43, 2923–2926; (d) Masumoto, S.;
Suzuki, M.; Kanai, M.; Shibasaki, M. Tetrahedron Lett. 2002,
43, 8647–8651; (e) Masumoto, S.; Suzuki, M.; Kanai, M.;
Shibasaki, M. Tetrahedron 2004, 60, 10497–10504; (f)
Suzuki, M.; Kato, N.; Kanai, M.; Shibasaki, M. Org. Lett.
2005, 7, 2527–2530.
13. (a) 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; (b) Dong, L.-C.; Crowe, M.; West, J.;
Ammann, J. R. Tetrahedron Lett. 2004, 45, 2731–2733.
14. Complexes 1 and 2 have also been commercialized by NPIL
under the tradename CACHyÔ. For discussions on commercial
applications of these catalysts, see: (a) Stinson, S. C. Chem.
Eng. News 2001, 79, 35–38; (b) Blacker, A. J.; North, M.
Chem. Ind. 2005, 22–25.
Acknowledgements
The authors thank the EPSRC for a studentship (to E.I.) and
partial postdoctoral funding (for R.W.H.) and the EPSRC
National Mass Spectrometry Service at the University of
Wales, Swansea for low- and high-resolution mass spectra.
Use of the EPSRC’s Chemical Database Service at Dares-
bury is also gratefully acknowledged.
References and notes
~
15. Baleizao, C.; Gigante, B.; Garcia, H.; Corma, A. Green Chem.
2002, 4, 272–274.
16. (a) Kim, G.-J.; Shin, J. H. Catal. Lett. 1999, 63, 83–90; (b)
1. For reviews on these developments, see: (a) North, M.
Tetrahedron: Asymmetry 2003, 14, 147–176; (b) Brunel, J.-M.;
Holmes, I. P. Angew. Chem., Int. Ed. 2004, 43, 2752–2778.
2. For leading articles on asymmetric cyanohydrin synthesis, see:
North, M., Ed.; Tetrahedron 2004, 60, 10383–10568.
3. For a review on this early work, see: North, M. Synlett 1993,
807–820.
4. For reviews on the chemistry and biochemistry of oxynitrilase
enzymes, see: (a) Gregory, R. J. H. Chem. Rev. 1999, 99, 3649–
3682; (b) Effenberger, F.; Forster, S.; Wajant, H. Curr. Opin.
Biotechnol. 2000, 11, 532–539; (c) Griengl, H.; Schwab, H.;
Fechter, M. Trends Biotechnol. 2000, 18, 252–256; (d)
~
Baleizao, C.; Gigante, B.; Garcia, H.; Corma, A. J. Catal.
2003, 215, 199–207; (c) Baleizao, C.; Gigante, B.; Das, D.;
Alvaro, M.; Garcia, H.; Corma, A. Chem. Commun. 2003,
~
1860–1861; (d) Baleizao, C.; Gigante, B.; Garcia, H.; Corma,
A. Tetrahedron Lett. 2003, 44, 6813–6816; (e) Baleizao, C.;
Gigante, B.; Garcia, H.; Corma, A. Tetrahedron 2004, 60,
10461–10468; (f) Huang, W.; Song, Y.; Wang, J.; Cao, G.;
~
~
~
Zheng, Z. Tetrahedron 2004, 60, 10469–10477; (g) Baleizao,
C.; Gigante, B.; Garcia, H.; Corma, A. J. Catal. 2004, 221,

9740
Y. N. Belokon’ et al. / Tetrahedron 63 (2007) 9724–9740
ꢀ
~
77–84; (h) Baleizao, C.; Gigante, B.; Das, D.; Alvaro, M.;
Garcia, H.; Corma, A. J. Catal. 2004, 223, 106–113; (i) Kim,
J. H.; Kim, G. J. Catal. Lett. 2004, 92, 123–130; (j) Huang,
W.; Song, Y.; Bai, C.; Cao, G.; Zheng, Z. Tetrahedron Lett.
2004, 45, 4763–4767; (k) Khan, N. H.; Agrawal, S.; Kureshy,
R. I.; Abdi, S. H. R.; Mayani, V. J.; Jasra, R. V. Eur. J. Org.
Chem. 2006, 3175–3180; (l) Khan, N. H.; Agrawal, S.;
Kureshy, R. I.; Abdi, S. H. R.; Mayani, V. J.; Jasra, R. V.
Tetrahedron: Asymmetry 2006, 17, 2659–2666.
Shibasaki, M. J. Am. Chem. Soc. 2005, 127, 3413–3422; (d)
Li, Q.; Chang, L.; Liu, X.; Feng, X. Synlett 2006, 1675–1678.
29. Tian, S.-K.; Deng, L. J. Am. Chem. Soc. 2001, 123, 6195–6196.
30. Purkarthofer, T.; Skranc, W.; Weber, H.; Griengl, H.;
€
Wubbolts, M.; Scholz, G.; Pochlauer, P. Tetrahedron 2004,
60, 735–739.
31. (a) Nicewicz, D. A.; Yates, C. M.; Johnson, J. S. Angew. Chem.,
Int. Ed. 2004, 43, 2652–2655; (b) Nicewicz, D. A.; Yates,
C. M.; Johnson, J. S. J. Org. Chem. 2004, 69, 6548–6555.
32. For other syntheses of cyanoformates, see: (a) Carpino, L. A.
J. Org. Chem. 1964, 29, 2820–2824; (b) Nii, Y.; Okano, K.;
Kobayashi, S.; Ohno, M. Tetrahedron Lett. 1979, 20, 2517–
2520; (c) Thomas, H. G.; Greyn, H. D. Synthesis 1990,
129–130.
33. (a) Childs, M. E.; Weber, W. P. J. Org. Chem. 1976, 41, 3486–
3487; (b) Donnelly, D. M. X.; Finet, J.-P.; Rattigan, B. A.
J. Chem. Soc., Perkin Trans. 1 1993, 1729–1735.
34. Carpino, L. A. J. Am. Chem. Soc. 1960, 82, 2725–2727.
35. Rhoads, S. J.; Michael, R. E. J. Am. Chem. Soc. 1963, 85,
585–591.
17. (a) 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; (b)
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; (c) Belokon’, Y. N.; Carta, P.;
North, M. Lett. Org. Chem. 2004, 1, 81–83; (d) North, M.;
Parkins, A. W.; Shariff, A. N. Tetrahedron Lett. 2004, 45,
7625–7627; (e) Belokon’, Y. N.; Carta, P.; North, M.
Tetrahedron Lett. 2005, 46, 4483–4486.
18. Belokon’, Y. N.; Blacker, A. J.; Carta, P.; Clutterbuck, L. A.;
North, M. Tetrahedron 2004, 60, 10433–10447.
36. For a previous report on the synthesis of the ethyl lactate mono-
ester of oxalyl chloride, see: Togo, H.; Fujii, M.; Yokoyama, M.
Bull. Chem. Soc. Jpn. 1991, 64, 57–67.
37. For previous reports on the synthesis of the menthol mono-ester
of oxalyl chloride, see: (a) Hub, L.; Mosher, H. S. J. Org. Chem.
1970, 35, 3691–3694; (b) Tietze, L.-F.; Meier, H.; Voß, E.
Synthesis 1988, 274–277; (c) Blanco, J. M.; Caaman˜o, O.;
19. (a) Lundgren, S.; Wingstrand, E.; Penhoat, M.; Moberg, C.
J. Am. Chem. Soc. 2005, 127, 11592–11593; (b) Wingstrand,
E.; Lundgren, S.; Penhoat, M.; Moberg, C. Pure Appl. Chem.
2006, 78, 409–411; (c) Lundgren, S.; Wingstrand, E.;
Moberg, C. Adv. Synth. Catal. 2007, 349, 364–372.
ꢀ
ꢀ
20. Baeza, A.; Najera, C.; Sansano, J. M.; Saa, J. M. Tetrahedron:
ꢀ
ꢀ
ꢀ
ꢀ
Fernandez, F.; Garcıa-Mera, X.; Lopez, C.; Rodrıguez-
Borges, J. E.; Hergueta, A. R. Synthesis 1998, 1590–1592.
38. Menthol cyanoformate has also been prepared by treating
menthol with phosgene and potassium cyanide. See:
Kunisch, F.; Hobert, K.; Welzel, P. Tetrahedron Lett. 1985,
26, 5433–5436.
Asymmetry 2005, 16, 2385–2389.
ꢀ
21. (a) Baeza, A.; Casas, J.; Najera, C.; Sansano, J. M.; Saa, J. M.
Angew. Chem., Int. Ed. 2003, 42, 3143–3146; (b) Baeza, A.;
ꢀ
ꢀ
Najera, C.; Sansano, J. M.; Saa, J. M. Chem.—Eur. J. 2005,
11, 3849–3862; (c) Baeza, A.; Najera, C.; Sansano, J. M.
ꢀ
ꢀ
Eur. J. Org. Chem. 2007, 1101–1112.
ꢀ
22. Baeza, A.; Casas, J.; Najera, C.; Sansano, J. M. J. Org. Chem.
2006, 71, 3837–3848.
23. For an alternative catalyst for the asymmetric synthesis of
cyanohydrin phosphonates, see: (a) Abiko, Y.; Yamagiwa, N.;
Sugita, M.; Tian, J.; Matsunaga, S.; Shibasaki, M. Synlett
2004, 2434–2436; (b) Yamagiwa, N.; Abiko, Y.; Sugita, M.;
Tian, J.; Matsunaga, S.; Shibasaki, M. Tetrahedron:
Asymmetry 2006, 17, 566–573.
24. Belokon’, Y. N.; Blacker, J.; Clutterbuck, L. A.; North, M. Org.
Lett. 2003, 5, 4505–4507.
25. Belokon’, Y. N.; Ishibashi, E.; Nomura, H.; North, M. Chem.
Commun. 2006, 1775–1777.
26. Chen, S.-K.; Peng, D.; Zhou, H.; Wang, L.-W.; Chen, F.-X.;
Feng, X.-M. Eur. J. Org. Chem. 2007, 639–644.
ꢀ
27. (a) Casas, J.; Baeza, A.; Sansano, J. M.; Najera, C.; Saa, J. M.
Tetrahedron: Asymmetry 2003, 14, 197–200; (b) Baeza, A.;
39. Potassium cyanide has been reported to catalyse the racemic
synthesis of various cyanohydrin derivatives. See: North, M.
Comprehensive Organic Functional Group Transformations,
1st ed.; Katritzky, A. R., Meth-Cohn, O., Rees, C. W.,
Pattenden, G., Eds.; Pergamon: Oxford, UK, 1995; Vol. 3,
Chapter 18.
40. Scholl, M.; Lim, C.-K.; Fu, G. C. J. Org. Chem. 1995, 60,
6229–6231.
41. Livinghouse, T. Org. Synth. 1981, 60, 126–130.
42. For the use of potassium cyanide/18-crown-6 in related
chemistry of acyl silanes, see: Linghu, X.; Nicewicz, D. A.;
Johnson, J. S. Org. Lett. 2002, 4, 2957–2960.
43. (a) Deardorff, D. R.; Taniguchi, C. M.; Nelson, A. C.; Pace,
A. P.; Kim, A. J.; Pace, A. K.; Jones, R. A.; Tafti, S. A.;
Nguyen, C.; O’Connor, C.; Tang, J.; Chen, J. Tetrahedron:
Asymmetry 2005, 16, 1655–1661; (b) 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.
ꢀ
ꢀ
Casas, J.; Najera, C.; Sansano, J. M.; Saa, J. M. Eur. J. Org.
Chem. 2006, 1949–1958.
ꢀ
28. (a) Tian, J.; Yamagiwa, N.; Matsunaga, S.; Shibasaki, M.
Angew. Chem., Int. Ed. 2002, 41, 3636–3638; (b) Tian, J.;
Yamagiwa, N.; Matsunaga, S.; Shibasaki, M. Org. Lett. 2003,
5, 3021–3024; (c) Yamagiwa, N.; Tian, J.; Matsunaga, S.;
44. Okimoto, M.; Chiba, T. Synthesis 1996, 1188–1190.
45. Thasana, N.; Prachyawarakorn, V.; Tontoolarug, S.;
Ruchirawat, S. Tetrahedron Lett. 2003, 44, 1019–1021.
46. Buck, J. S. J. Am. Chem. Soc. 1933, 55, 2593–2597.