Catalytic, asymmetric cyanohydrin synthesis in propylene carbonate

Article abstract of DOI:10.1016/j.tetlet.2009.05.052

Propylene carbonate can be used as a green solvent for asymmetric cyanohydrin synthesis catalyzed by VO(salen)NCS. A range of 10 aromatic and aliphatic aldehydes gave high enantioselectivities (up to 93%) and conversions (up to 100%) in reactions carried

Full text of DOI:10.1016/j.tetlet.2009.05.052

Tetrahedron Letters 50 (2009) 4452–4454
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Tetrahedron Letters
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Catalytic, asymmetric cyanohydrin synthesis in propylene carbonate
*
Michael North , Marta Omedes-Pujol
School of Chemistry and University Research Centre in Catalysis and Intensified Processing, Bedson Building, Newcastle University, Newcastle upon Tyne NE1 7RU, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
Propylene carbonate can be used as a green solvent for asymmetric cyanohydrin synthesis catalyzed by
VO(salen)NCS. A range of 10 aromatic and aliphatic aldehydes gave high enantioselectivities (up to 93%)
and conversions (up to 100%) in reactions carried out at or near room temperature with reaction times of
24 h or less.
Received 2 April 2009
Revised 6 May 2009
Accepted 15 May 2009
Available online 22 May 2009
Ó 2009 Elsevier Ltd. All rights reserved.
The asymmetric addition of trimethylsilyl cyanide to alde-
hydes1 is a 100% atom economical reaction2 which produces a
product which contains a stereocenter and two functional groups,
one of which is conveniently protected (Scheme 1). In recent years,
a large number of synthetic catalysts have been developed for this
reaction1 including bimetallic titanium(salen) complex3 1 and
vanadium(salen) complexes4 2a–c. Reactions catalyzed by com-
plexes 1 and 2 have been commercialized,5 and have a number
of green credentials including high substrate to catalyst ratios
(1000:1) and optimal activity at room temperature.6 However, cat-
alysts 1 and 2 (along with most other catalysts for this reaction7)
have only been found to be effective in chlorinated organic sol-
vents, preferably dichloromethane. Use of ethereal, alcoholic,
hydrocarbon, aromatic, or traditional polar aprotic solvents were
all found to be severely detrimental to the level of asymmetric
induction, though the use of ionic liquids did give good levels of
asymmetric induction at higher catalyst loadings.8
asymmetric
catalyst
O
OSiMe3
CN
+ Me3SiCN
R
H
R
tBu
tBu
tBu
tBu
N
N
O
O
O
O
N
N
O
O
Ti
Ti
tBu
tBu
Propylene carbonate 3 is starting to attract interest as a green
solvent for synthetic transformations.9 It can be prepared by the
100% atom economical reaction between carbon dioxide and pro-
pylene oxide (Scheme 2).10 The green credentials of propylene car-
bonate have recently been enhanced by the commercialization of a
low temperature route for the synthesis of propylene oxide from
propene and hydrogen peroxide;11 by the development of a green-
er synthesis of hydrogen peroxide12 and by the combination of
these processes into a one-pot synthesis of propylene oxide from
propene, hydrogen, and oxygen.13 In addition, it has recently been
demonstrated,14 that in the presence of an appropriate catalyst, the
reaction between propylene oxide and carbon dioxide can be
achieved at atmospheric pressure and room temperature, thus
facilitating the use of waste carbon dioxide in this process.
tBu
tBu
1
O
V
N
O
N
O
tBu
tBu
X
tBu
tBu
2a: X = EtOSO3
2b: X = Cl
2c: X = NCS
Scheme 1. Asymmetric cyanohydrin synthesis.
Therefore, we decided to investigate the use of propylene
carbonate as a replacement for dichloromethane in asymmetric
1
and 2c.15
A standard set of conditions were initially adopted in which all
reactions were carried out at room temperature for 2 h using
0.1 mol % of catalyst at a substrate concentration of 0.56 M in
either dichloromethane or propylene carbonate. The extent of con-
version of aldehyde into cyanohydrin trimethylsilyl ether was
cyanohydrin synthesis catalyzed by complexes
* Corresponding author. Tel.: +44 0 191 222 7128; fax: +44 0 191 6929.
E-mail address: Michael.north@ncl.ac.uk (M. North).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.05.052

M. North, M. Omedes-Pujol / Tetrahedron Letters 50 (2009) 4452–4454
4453
determined by 1H NMR spectroscopy, and the asymmetric induc-
tion was determined by chiral GC after conversion of the cyanohy-
drin trimethylsilyl ether into the corresponding cyanohydrin
acetate as previously reported.16 Initial results using catalyst 1
were not encouraging as detailed in Table 1. In each case, use of
propylene carbonate as solvent significantly lowered the enanti-
oselectivity of the reaction, and for aromatic substrates the conver-
sion was also reduced substantially. Interestingly however,
nonanal gave a higher conversion in propylene carbonate than in
dichloromethane. The reason for the generally lower reactivity
and enantioselectivity observed in propylene carbonate is probably
related to the dissociation of bimetallic catalyst 1 into monometal-
lic units in the more polar solvent.3
In contrast, reactions catalyzed by vanadium-based catalyst 2c
were far less affected by the change in solvent. Table 2 details
the results obtained with 10 different aldehydes. Whilst aromatic
aldehydes again gave lower conversions in propylene carbonate,
the decrease was nowhere near as dramatic as that observed for
catalyst 1. Aliphatic aldehydes in contrast gave conversions in pro-
pylene carbonate which were comparable to, or higher than those
obtained in dichloromethane. The enantioselectivities obtained in
propylene carbonate were in the range of 62–93%, which, whilst
lower than those obtained using catalyst 2 in dichloromethane,
were much higher than those obtained using catalyst 1 in propyl-
ene carbonate.
The kinetics of the addition of trimethylsilyl cyanide to benzal-
dehyde catalyzed by complex 2c (0.2 mol %) were determined at
0 °C as previously described.3,4 The reaction was shown to follow
overall second-order kinetics (first order in both benzaldehyde
and trimethylsilyl cyanide) to at least 74% conversion (Fig. 1). This
is the same kinetic profile as previously determined in dichloro-
methane4 which suggests that the mechanism of catalysis is the
same in both solvents. In addition, the kinetics showed no evidence
of catalyst deactivation which indicates that the lower conversions
observed in propylene carbonate are due to an intrinsically slower
reaction rather than to catalyst decomposition. This was also sup-
ported by the kinetics analysis which showed that the second-or-
der rate constant in dichloromethane was five times greater than
that in propylene carbonate.
To optimize the reaction conditions for the use of catalyst 2c in
propylene carbonate, the effects of varying the reaction tempera-
ture, reaction time and amount of catalyst were determined. As
the results shown in Table 3 illustrate, for benzaldehyde, increas-
ing the reaction time to 24 h at room temperature increased the
conversion to >90% whilst retaining a high level of asymmetric
induction. Increasing the amount of catalyst to 0.2 mol % had a
O
8
O
TS1
catalyst
7
O
O
+ H2O2
+ CO2
y = 0.2031x + 0.2854
R2= 0.9957
6
Me
Me
Me
TS1 = titanium silicate-1
5
4
3
Scheme 2. Synthesis of propylene carbonate.
3
2
1
0
y = 0.0433x + 0.1258
R2= 0.996
Table 1
Synthesis of cyanohydrin trimethylsilyl ethers using catalyst 1
Aldehyde
Propylene carbonate
Dichloromethane
0
50
100
150
Conversiona
eeb
Conversiona
eeb
Time (mins)
PhCHO
33
24
20
47
30
16
98
100
40 (S)
35 (S)
25 (S)
43 (S)
61 (S)
49 (S)
45 (S)
10 (S)
95
40
98
76
95
82
71
93
80 (S)
78 (S)
83 (S)
76 (S)
97 (S)
69 (S)
73 (S)
47 (S)
Figure 1. Second-order kinetics plot for the addition of trimethylsilyl cyanide to
benzaldehyde at 0 °C catalyzed by complex 2c (0.2 mol %) in dichloromethane
(triangles) and propylene carbonate (diamonds). The units for the vertical scale are:
ln[(BoAt)/(BtAo)]/(Ao À Bo) where: A = [PhCHO], B = [Me3SiCN] and the subscripts o
and t refer to initial concentrations and concentrations at time t, respectively.
4-FC6H4CHO
4-ClC6H4CHO
2-MeC6H4CHO
3-MeC6H4CHO
4-MeC6H4CHO
Me(CH2)7CHO
Me3CCHO
Table 3
a
Conversions were determined by 1H NMR spectroscopy.
Enantioselectivities were determined by chiral GC analysis after conversion of
Optimization of the synthesis of cyanohydrin trimethylsilyl ethers using catalyst 2c in
propylene carbonate
b
the cyanohydrin trimethylsilyl ethers into the corresponding cyanohydrin acetates.
Aldehyde
Temperature
Time
Catalyst mol %
Conversiona
eeb
PhCHO
PhCHO
PhCHO
PhCHO
4-MeC6H4CHO
Me(CH2)7CHO
CyCHO
Me3CCHO
Me(CH2)7CHO
CyCHO
rt
rt
rt
4 h
24 h
2 h
0.1
0.1
0.2
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
83
92
86
73
63
100
92
100
98
88
100
88
89
86
100
93
90
83 (S)
85 (S)
85 (S)
86 (S)
91 (S)
72 (S)
78 (S)
80 (S)
79 (S)
81 (S)
82 (S)
88 (S)
80 (S)
83 (S)
86 (S)
90 (S)
85 (S)
Table 2
Synthesis of cyanohydrin trimethylsilyl ethers using catalyst 2c
0 °C
0 °C
0 °C
0 °C
0 °C
À20 °C
À20 °C
À20 °C
0 °C
0 °C
0 °C
rt
18 h
18 h
18 h
18 h
18 h
24 h
24 h
24 h
24 h
24 h
24 h
24 h
24 h
24 h
Aldehyde
Propylene carbonate
Dichloromethane
Conversiona
eeb
Conversiona
eeb
PhCHO
73
67
56
73
78
67
56
96
97
99
81 (S)
77 (S)
64 (S)
76 (S)
62 (S)
93 (S)
86 (S)
66 (S)
67 (S)
72 (S)
100
81
83
90
81
100
86
88
100
100
86 (S)
91 (S)
89 (S)
93 (S)
97 (S)
98 (S)
87 (S)
92 (S)
88 (S)
86 (S)
4-FC6H4CHO
3-ClC6H4CHO
4-ClC6H4CHO
2-MeC6H4CHO
3-MeC6H4CHO
4-MeC6H4CHO
Me(CH2)7CHO
CyCHO
Me3CCHO
4-FC6H4CHO
3-ClC6H4CHO
4-ClC6H4CHO
2-MeC6H4CHO
3-MeC6H4CHO
4-MeC6H4CHO
rt
rt
Me3CCHO
a
a
Conversions were determined by 1H NMR spectroscopy.
Conversions were determined by 1H NMR spectroscopy.
b
b
Enantioselectivities were determined by chiral GC analysis after conversion of
the cyanohydrin trimethylsilyl ethers into the corresponding cyanohydrin acetates.
Enantioselectivities were determined by chiral GC analysis after conversion of
the cyanohydrin trimethylsilyl ethers into the corresponding cyanohydrin acetates.

4454
M. North, M. Omedes-Pujol / Tetrahedron Letters 50 (2009) 4452–4454
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Harrington, R. W.; Maleev, V. I.; North, M.; Omedes Pujol, M.; Usanov, D. L.;
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similar effect after a reaction time of just 2 h. For a range of five
aldehydes, reducing the reaction temperature to 0 °C enhanced
the enantioselectivities, in the case of aromatic aldehydes, to a le-
vel comparable with or better than those obtained in dichloro-
methane at room temperature. However, these reactions did
require an extended reaction time (18 h) to give conversions which
were comparable to those obtained in 2 h at room temperature.
On the basis of the above results, the aldehydes were grouped
into three classes each of which had its own optimal reaction tem-
perature to obtain high conversions and enantioselectivities after a
reaction time of 24 h. Aliphatic aldehydes gave high conversions
even at reduced reaction temperatures, so the optimal conditions
involved carrying out reactions at À20 °C to maximize the asym-
metric induction (Table 3), though these were only slightly better
than the enantioselectivities obtained at 0 °C. For electron-defi-
cient aromatic aldehydes, the optimal reaction temperature was
0 °C, whilst electron-rich aromatic aldehydes only gave high con-
versions at room temperature (Table 3).
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J.; Verevkin, S. P.; Börner, A. Tetrahedron Lett. 2008, 49, 768–771.
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Catal. 2006, 242, 142–152.
It was not possible to directly isolate the cyanohydrin trimeth-
ylsilyl ether from reactions carried out in propylene carbonate as
they codistilled with the solvent and decomposed when purifica-
tion was attempted by chromatography. However, one of the main
applications of cyanohydrins is in the preparation of
a-hydroxy
acids5 and it was possible to obtain (S)-mandelic acid in 60% iso-
lated yield simply by refluxing the mixture of propylene carbonate
and mandelonitrile trimethylsilyl ether (81% ee) with 12 N hydro-
chloric acid for 6 h followed by crystallization from ether/hexane.
That no racemization occurred during this process was demon-
strated by conversion of the mandelic acid into methyl mandelate
followed by chiral HPLC (Chirasil OD column; 80% hexane, 20% pro-
pan-2-ol; flow rate 1 mL per minute) which gave an enantiomeric
excess of 87%.
In conclusion, we have shown that vanadium complex 2c is an
active catalyst for asymmetric cyanohydrin synthesis in propylene
carbonate using low catalyst loadings at or near to room
temperature.
12. Chen, Q.; Beckman, E. J. Green Chem. 2007, 9, 802–808.
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Sheldon, R. A. Chem. Commun. 2008, 3352–3365.
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(b) North, M.; Pasquale, R. Angew. Chem., Int. Ed. 2009, 48, 2946–2948; (c)
Meléndez, J.; North, M.; Villuendas, P. Chem. Commun. 2009, 2577–2579.
15. Typical experimental procedure: The aldehyde (0.98 mmol) was added to a
Acknowledgements
The authors thank the EPSRC for financial support and a stu-
dentship (to M.O.P.).
solution of catalyst 1 or 2c (0.98
lmol, 0.1 mol %) in propylene carbonate
(1.75 mL) at the specified temperature. Trimethylsilyl cyanide (1.12 mmol,
0.15 mL) was then added and the reaction mixture was stirred for the specified
time. The solution was then passed through a short silica plug eluting with
CH2Cl2. The eluent was evaporated in vacuo to remove the CH2Cl2, and the
residue was analyzed by 1H NMR spectroscopy to determine the conversion. To
determine the enantiomeric excess, acetic anhydride (2.0 mmol, 0.15 mL) and
Sc(OTf)3 (5 mg, 0.01 mmol) were added to the stirred residue. After 20 min, the
reaction mixture was passed through a short silica plug eluting with MeCN.
The resulting solution was analyzed by chiral GC using a Supelco Gamma DEX
120 fused silica capillary column (30 m  0.25 mm) with hydrogen as a carrier
gas. Synthesis of mandelic acid: To a solution of mandelonitrile trimethylsilyl
ether in propylene carbonate obtained as above, was added 12 N HCl (10 mL).
The mixture was heated at reflux for 6 h, cooled to rt and made basic using 10%
aqueous NaOH solution. The aqueous solution was extracted with ether
(3 Â 10 mL), acidified with 12 N HCl, and extracted again with ether
(3 Â 10 mL). The last three ethereal extracts were combined, dried (Na2CO3),
and evaporated in vacuo to give a yellow solid which was recrystallized at 4 °C
from ether/hexane and the resulting solid was washed with hexane to give
mandelic acid (91 mg, 60%) as white crystals.
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