Supported 3,5-disubstituted chiral hydantoin: A practical catalyst for the asymmetric hydrocyanation of 3-phenoxybenzaldehyde

Article abstract of DOI:10.1081/SCC-120020198

A novel synthesis of six (R)-3,5-disubstituted chiral hydantoins in mixed solvent is reported. The catalysts were supported on a new polymeric resin afterwards and their enantioselectivities are examined via the asymmetric hydrocyanation of 3-phenoxybenzaldehyde.

Full text of DOI:10.1081/SCC-120020198

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Supported 3,5-Disubstituted Chiral Hydantoin: A
Practical Catalyst for the Asymmetric Hydrocyanation
of 3-Phenoxybenzaldehyde
Dr., Associate Professor Zhicai Zhai a b , Jinlong Chen a , Hailing Wang a & Quanxing Zhang a
a School of the Environment , Nanjing University , Nanjing, P.R. China
b Department of Chemical Engineering , Yancheng Institute of Technology , Yancheng,
Jiangsu, P.R. China
Published online: 17 Aug 2006.
To cite this article: Dr., Associate Professor Zhicai Zhai , Jinlong Chen , Hailing Wang & Quanxing Zhang (2003) Supported 3,5-
Disubstituted Chiral Hydantoin: A Practical Catalyst for the Asymmetric Hydrocyanation of 3-Phenoxybenzaldehyde, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry, 33:11, 1873-1883, DOI:
10.1081/SCC-120020198
To link to this article: http://dx.doi.org/10.1081/SCC-120020198
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SYNTHETIC COMMUNICATIONSÕ
Vol. 33, No. 11, pp. 1873–1883, 2003
Supported 3,5-Disubstituted Chiral Hydantoin:
A Practical Catalyst for the Asymmetric
Hydrocyanation of 3-Phenoxybenzaldehyde
1
1
Zhicai Zhai,1,2, Jinlong Chen, Hailing Wang,
*
and Quanxing Zhang1
1School of the Environment, Nanjing University,
Nanjing, P.R. China
2Department of Chemical Engineering,
Yancheng Institute of Technology, Yancheng,
Jiangsu, P.R. China
ABSTRACT
A novel synthesis of six (R)-3,5-disubstituted chiral hydantoins in
mixed solvent is reported. The catalysts were supported on a new
polymeric resin afterwards and their enantioselectivities are examined
via the asymmetric hydrocyanation of 3-phenoxybenzaldehyde.
*Correspondence: Dr., Associate Professor, Zhicai Zhai, School of the
Environment, Nanjing University, Hankou Road 20, Nanjing 210093, Jiangsu
Province, P.R. China; Department of Chemical Engineering, Yancheng Institute
of Technology, Yancheng 224003, Jiangsu, P.R. China; Fax: þ86-025-3596731;
E-mail: njuzzc0125@yahoo.com.cn.
1873
DOI: 10.1081/SCC-120020198
Copyright & 2003 by Marcel Dekker, Inc.
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com

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1874
Zhai et al.
Key Words: Chiral hydantoin; Catalyst; 3-Phenoxybenzaldehyde;
Polymeric resin; Hydrocyanation; Enantioselectivity.
Chiral hydantoin (1) is a highly efficient catalyst for the asymmetric
synthesis of optically active cyanohydrins. (S)-2-Hydroxy-2-(3-phenoxy-
phenyl)acetonitrile ((S)-2), being one of them, is an important alcohol
moiety of optically active pyrethroid insecticides.[1] With respect to the
enantioselective addition of hydrogen cyanide to 3-phenoxybenzaldehyde
(m-PBA), there have been few literatures concerning the enantioselectiv-
ity inthe presence of a chiral catalyst. Mori et al. have reported that the
chiral cyclic dipeptide containing a (S)-histidine residue, demonstrated
high enantioselectivities in the asymmetric hydrocyanation of alde-
hydes.[2] Danda has prepared several kinds of (R)-chiral hydantoins,
which possess a structure similar to that of cyclo[(S)-phenylalanyl-(S)-
histidyl], and reported that the highest enantiomeric excess (ee) of (S)-2
was 37% inhydrocyanationof
m-PBA.[3] Ina published UK patent,
a chiral cyclic dipeptide, adsorbed ona solid support comprisign a
non-ionic polymeric resin, XAD-4, was made for asymmetric synthesis
of (S)-2.[4] All these methods, however, suffer from different drawbacks,
and they are somewhat impractical from the industrial point of view.
It is therefore anobject of the present study to provide aneasily-
made catalyst via reactionof ( R)-histidine and aromatic isocyanate,
in which mixed solvent was used instead of water. In our research, six
kinds of 3,5-disubstituted chiral hydantoins have been prepared and
supported on NDA-99, one of our newly-developed hypercrosslinked
polymeric adsorptionresisn, which has better adsorptioncapacity
compared with Amberlite XAD-4 (Rohm and Haas Company). In
addition, the catalytic activities of the supported catalysts were investi-
gated by means of asymmetric hydrocyanation of m-PBA ona similar
industrial scale.
In mixed solvent, the chiral catalysts were prepared firstly by coupling
of the specific amino acid with a series of isocyanates, some of which were
obtained from reaction of the corresponding amine with phosgene, and
then followed by cyclization under acidic condition to give 1 (Sch. 1).
The mixed solvent is a mixture of water and 1,4-dioxane, THF or
acetonitrile, in which 1,4-dioxane being the best choice for the coupling
reaction. We found that the by-product, diphenylurea, derived from
hydrolysis of isocyanate, could be easily separated after the reaction,
pure product thus being obtained.
The asymmetric hydrocyanation of m-PBA was carried out inthe
presence of 1.0–2.5 mol% of 1 (based on m-PBA), supported ona resin

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Supported 3,5-Disubstituted Chiral Hydantoin
1875
Scheme 1. 1a (R ¼ 5-imidazolylmethyl, R0 ¼ Ph); 1b (5-imidazolylmethyl,
R0 ¼ benzyl); 1c (5-imidazolylmethyl, R0 ¼ 4-fluorobenzyl); 1d (R ¼ benzyl,
R0 ¼ Ph); 1e (R ¼ benzyl, R0 ¼ benzyl); 1f (R ¼ benzyl, R0 ¼ 4-fluorobenzyl).
Scheme 2.
adsorbent, to give (S)-2 with reasonable optical yield, as well as high
conversion of m-PBA (Sch. 2).
In an attempt to examine the catalytic activities of different chiral
hydantoins, addition of HCN to m-PBA, catalyzed by 1 directly and sup-
ported ones, was carried out in a similar procedure respectively. Some
properties of the catalysts, conversions and ee values are listed in Table 1.
As canbe seenfrom Table 1, the suspended catalysts resulted ina
low ee value inthe reactioncompared with the supported ones, attributed
to their poor solubility inthe reactionmixture. Moreover, it was surpris-
ingly found that catalyst supported on NDA-99 resulted in higher
conversion and ee value than that on XAD-4. This may be due to its
higher surface area and partial polarity of the novel structure with the
residual chloromethyl, carbonyl, and hydroxyl groups. Table 2 lists some
characteristics of the two polymeric adsorbents. It is believed that the
catalyst adsorbed onNDA-99, provides anactivated monomolecular
layer of the chiral catalyst, which is responsible for the high efficiency
and selectivity of the supported catalyst. Among all the catalysts, 1b and
1c immobilized onNDA-99 exhibited satisfactory catalytic activities with
conversion of 96.1%, 94.8%, and ee of 49.7%, 64.0%, respectively.
The most important factor to practically use the supported catalysts,
onthe other hand, is the stability of them. Inanattempt to test the
stabilities of the catalysts onpolymeric adsorbents, the procedure for
asymmetric hydrocyanation of m-PBA was thus repeated consecutively,

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1876
Zhai et al.
Table 1. Experimental results of asymmetric addition of hydrogen cyanide to
m-PBA catalyzed by suspended and supported chiral catalysts.
Catalyst adsorbed/
solid support (%)
Conversion
(%)
ee
(%)
Chiral hydantoin
Solid support
1a
1b
1c
1d
1e
1f
89.2
96.1
94.8
90.0
91.5
88.3
86.0
92.4
95.5
80.9
86.0
87.2
96.1
94.8
86.5
90.2
86.4
9.3
12.7
17.6
10.4
8.3
13.0
21.8
35.3
42.1
17.3
20.4
35.5
49.7
64.0
21.7
45.8
32.1
1a
1b
1c
1d
1e
1a
1b
1c
1d
1e
1f
XAD-4
XAD-4
XAD-4
XAD-4
XAD-4
NDA-99
NDA-99
NDA-99
NDA-99
NDA-99
NDA-99
4.12
4.50
5.06
4.52
5.30
4.64
5.38
6.31
6.05
5.10
5.42
Table 2. Typical characteristics of XAD-4 and NDA-99 adsorbents.
Property
Structure
XAD-4
NDA-99
Polystyrene, aromatic
Amine modified
polystyrene
Polarity
BET surface area (m2/g)
Porosity (cm3/g)
Nonpolar
750a
1.02
Moderate polar
950
0.52
2.5
Average pore diameter (nm)
Average particle size (mm)
Residual chloride content (%)
Oxygen content (%)
4.0
0.5
0.3–0.4
3.5
5.95
aValue according to reference.[5]
using 1c supported both on XAD-4 and NDA-99. The results of 6 runs
for each solid support are detailed inTable 3.
As showninTable 3, the catalytic activity of 1c onXAD-4 substan-
tially reduces with time, and the column thus needs to be recharged

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Supported 3,5-Disubstituted Chiral Hydantoin
1877
Table 3. Repeated reactions of asymmetric hydrocyanation of m-PBA catalyzed
by 1c ondifferent solids.
Cat./
m-PBA
m-PBA Reaction Reaction
conc.
temp.
(ꢀC)
time
(h)
Conversion ee
(%)
Entry Support (mole %)a (%)b
(%)c
1
2
XAD-4
XAD-4
XAD-4
XAD-4
XAD-4
XAD-4
NDA-99
NDA-99
NDA-99
NDA-99
NDA-99
NDA-99
2.0
21.75
21.75
21.75
25.8
5
5
5
5
5
5
5
5
5
5
5
5
3.0
3.0
3.0
3.5
4.0
4.0
3.0
3.0
3.0
3.5
4.0
4.0
94.1
85.4
87.0
74.9
82.9
78.1
95.0
96.3
94.1
97.0
93.6
94.7
39.4
33.5
18.2
12.2
10.3
12.7
66.3
62.4
61.2
63.9
57.0
59.4
1.04
0.79
0.36
0.40
0.38
2.0
3
4
5
25.8
25.8
6
7
21.75
21.75
21.75
21.75
25.8
8
1.85
1.68
1.53
1.50
1.46
9
10
11
12
25.8
aThe ratio is calculated according to the initial concentration and the amount
recycled.
bThe m-PBA concentration is defined as: (m-PBA volume/total volume of
solution) ꢀ 100.
cAll reactions are carried out under similar conditions.
before each performance, which is in correspondence with the literature
reported.[4] Incontrast, 1c on NDA-99 provides a consistent performance
with favorable conversions of 94–96% and ee of around 62%, and does
not undergo appreciable physical changes after 5 runs. It is attributed to
the fine pore structures of the latter and interactions of polar groups
between the catalyst and the adsorbent, resulting in a tight immobiliza-
tion of the chiral hydantoin. Therefore, the process introduced herein is
practical.
When carrying out asymmetric synthesis, it is generally believed that
the enantioselectivity results from the spatial blocking effect of the chiral
catalyst.[6] We may discuss the catalytic mechanism of asymmetric hydro-
cyanation of aldehyde catalyzed by the chiral hydantoin, 1c for example,
based onthe postulationwhich Tanaka et al. made for the asymmetric
hydrocyanation by a cyclic dipeptide.[7] It is postulated, according to
Prelog rule,[8] that the molecule of the aldehyde forms a stereo structure
with si-face and re-face (Sch. 3).
As illustrated inSch. 3, the carbonyl oxygeninthe substrate is con-
sidered firstly to combine with the catalyst 1c (R ¼ 5-imidazolylmethyl,

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1878
Zhai et al.
Scheme 3.
R0 ¼ 4-fluorobenzyl), via hydrogen bond, to form the intermediate I. It is
also believed that hydrogen cyanide interacts with the imidazolyl moiety
of the histidine residue to form a cyanide ion, which subsequently attacks
the re-face of the activated carbonyl group to form the intermediate II,
while the si-face is blocked by the aromatic ring of 4-fluorobenzyl
isocyanate residual group (R0), inwhich the substituted fluoro-group
reinforces the blocking effect to some extent. However, the blocking
caused by the aromatic ring would be too loose to give (S)-2 with a
satisfactory enantioselectivity.[9]
For addition of hydrocyanic acid to aldehyde, some important
factors which should be considered are: (a) the molar ratio of the catalyst
to m-PBA, (b) the concentration of m-PBA, and (c) the temperature at
which the reactiontakes place.
The quantity of the catalyst should be in the range of 1.0–2.5%.
The molar ratio below 1.0% does not afford high ee value, but high
conversions are obtained both at low and high catalyst concentrations.
Higher catalyst concentration, on the other hand, may adversely affect ee
value, due to competing racemization.
The concentration of m-PBA inthe reactionmixture affects the rate
of reaction, as well as conversion and ee. With concentrations of m-PBA
between 20–25%, high conversions of 92–96% and ee of 60–65% are
obtained.

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Supported 3,5-Disubstituted Chiral Hydantoin
1879
The reactiontemperature is usually around 0 ꢀC. From À5ꢀC to
25ꢀC, conversion proceeds in the reaction. However, the lower the
temperature, the higher the ee, the temperature of 5ꢀC is thus suitable
for the reaction.
Other factors of importance are the excess of HCN and solvent of the
reaction. In our study, two molar times of HCN relative to m-PBA were
used. With respect to the solvent, toluene is recommended. However,
other solvents can be employed as well, such as benzene, disopropyl
ether, and hydrocarbon solvents. But they mostly result in unsatisfactory
conversions and ee.
In conclusion, chiral hydantoin 1c was found to be an excellent
optically active catalyst for asymmetric synthesis of (S)-cyanohydrins,
owing to its catalytic groups in the structure. While the hypercrosslinked
polymeric adsorbent NDA-99, which possesses a favorable pore structure
and functional groups, demonstrated fine properties for supporting
the catalyst 1c. The supported chiral hydantoin, 1c onNDA-99,
therefore, has beenevaluated as a suitable catalyst for asymmetric
synthesis of (S)-2.
EXPERIMENTAL
General
X-4 Microscopic melting point meter and WXG-4 polarimeter
(Shanghai Optic Instrument Plant, Shanghai, China), were used to
1
detect the data of m.p. and optical rotations of 1 respectively. H NMR
spectra were obtained at 300 MHz on a Bruker AM-300; IR spectra were
obtained on a Neclet FTR-360; Carleerbea EA-1106 was used for
elementary analysis; Waters HPLC-660 was employed, YWG-18 being
used as columnfor determinationof the conversionof
OA-4100 (Sumitomo Chemical Co. Ltd., Japan) as chiral column for
m-PBA, Sumipax
determination of the optical yield of (S)-2.
Preparation of (5R)-5-(5-Imidazolylmethyl)-3-phenyl-2,4-imidazolidine-
dione (1a)
To a mixture of 3.1 g (20 mmol) of (R)-histidine in 150 mL of mixed
solvent (H2O/1,4-dioxane ¼ 1/3, V/V), was added 30% aqueous NaOH
under mechanical stirring, until the solution showed pH 9 and the solid
disappeared. Three point six grams (30 mmol) of phenyl isocyanate was

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1880
Zhai et al.
thenadded to the solutionat 35–40 ꢀC, meanwhile, 30% aqueous NaOH
was added drop-wise to adjust pH 8.5–9ꢀ. After the pH was unchangeable,
the reactionmixture was stirred at 40 C for 1.5 h, and distilled under
vacuum to remove 1,4-dioxane. After being cooled to ambient tempera-
ture, the mixture was filtered as to separate the by-product derived from
hydrolysis of isocyanate.
The filtrate was adjusted to pH 1 with 36% hydrochloric acid and
kept under reflux for 3 h. Finally, the mixture was cooled to 5ꢀC an d
neutralized to pH 6 with 30% aqueous NaOH. After being allowed to
stand at 5ꢀC for 2 h, the precipitate was filtered, washed with cold water
and then recrystallized from anhydrous ethanol to give 3.9 g of 1a as
25
white crystals: yield (76%), m.p. 187–188ꢀC. ½ꢀꢁD 158.2ꢀ (MeOH). IR
1
(KBr): 3192, 1765, 1711, 1595, 1500 (cmÀ1). H NMR (TMS, DMSO-
d6), ꢁ: 3.0 (m, 2H, CH2), 4.5 (t, 1H, CH), 6.9 (s, 1H, CONH), 7.2–7.5 (m,
5H, ArH), 7.6 (s, 1H, CH), 8.4 (s, 1H, NH). Calcd. for C13H12N4O2 (1a):
C, 60.93; H, 4.72; N, 21.86. Found: C, 60.60; H, 4.84; N, 21.79%.
Preparation of (5R)-3-Benzyl-5-(5-imidazolylmethyl)-2,4-imidazolidine-
dione (1b)
To a solution of 5.32 g (40 mmol) of benzylamine in 40 mL of toluene
was added 12 g (120 mmol) of phosgene at 100ꢀC, stirring for 1 h. After
removal of the solvent and surplus phosgene under vacuum, the residual
crude oil of benzyl isocyanate was directly subjected to the following
procedure.
The procedure givenfor 1a was thencarried out inthe same way with
benzyl isocyanate obtained above to give 4.43 g of 1b as white crystals:
25
yield (82%), m.p. 212–214ꢀC. ½ꢀꢁD 16.8ꢀ (MeOH). IR (KBr): 3245, 1762,
1
1709, 1599, 1500, 1425 (cmÀ1). H NMR (TMS, DMSO-d6), ꢁ: 3.0 (m,
2H, CH2), 4.4 (m, 2H, CH2), 4.5 (t, 1H, CH), 6.9 (s, 1H, CONH), 7.2–7.5
(m, 5H, ArH), 7.6 (s, 1H, CH), 8.4 (s, 1H, NH). Calcd. for C14H14N4O2
(1b): C, 62.21; H, 5.22; N, 20.73. Found: C, 62.21; H, 5.38; N, 19.67%.
Preparationof (5R)-3-(4-Fluorobeznyl)-5-(5-imidazolylmethyl)-2,4-imi-
dazolidinedione (1c)
The procedure givenfor 1b was performed onthe same scale, using
4-fluorobenzylamine instead of benzylamine, to give 4.6 g of 1c as white
solids: yield (79%), m.p. 207–208ꢀC. ½ꢀꢁD25 24.2ꢀ (MeOH). IR (KBr): 3300,
1
2924, 1752, 1695, 1571, 1502, 1430 (cmÀ1). H NMR (TMS, DMSO-d6),

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Supported 3,5-Disubstituted Chiral Hydantoin
1881
ꢁ: 3.0 (m, 2H, CH2), 4.4–4.44 (m, 2H, CH2), 4.5 (t, 1H, CH), 6.9 (s, 1H,
CONH), 7.2–7.4 (m, 4H, ArH), 7.5 (s, 1H, CH), 8.3 (s, 1H, NH). Calcd.
for C14H13FN4O2 (1c): C, 58.33; H, 4.55; N, 19.43. Found: C, 58.10; H,
5.63; N, 19.31%.
Preparation of (5R)-5-Benzyl-3-phenyl-2,4-imidazolidinedione (1d)
With (R)-phenylalanine replacing (R)-histidine, the procedure given
for 1a was carried out onthe same scale to give 3.35 g of 1d as white
25
crystals: yield (63%), m.p. 167–168ꢀC. ½ꢀꢁD 161.1ꢀ (MeOH). IR (KBr):
1
3245, 3110, 1774, 1715, 1600, 1500, 1428, 1348 (cmÀ1). H NMR (TMS,
CDCl3), ꢁ: 3.0–3.1 (m, 2H, CH2), 4.4 (m, 1H, CH), 6.5 (s, 1H, CONH),
7.2–7.5 (m, 10H, ArH). Calcd. for C16H14N2O2 (1d): C, 72.17; H, 5.30; N,
10.52. Found: C, 72.02; H, 5.31; N, 10.26%.
Preparation of (5R)-3,5-Dibenzyl-2,4-imidazolidinedione (1e)
Using phenylalanine, the procedure for 1b was performed onthe
same scale resulting in 4.1 g of 1e as white solids: yield (74%), m.p.
25
141–142ꢀC. ½ꢀꢁD 41.8ꢀ (MeOH). IR (KBr): 3260, 1765, 1694, 1598,
1500, 1425 (cmÀ1). 1H NMR (TMS, CDCl3), ꢁ: 3.0 (m, 2H, CH2),
4.2–4.5 (m, 2H, CH2), 4.6 (m, 1H, CH), 6.7–7.3 (m, 10H, ArH), 8.3 (s,
1H, CONH). Calcd. for C17H16N2O2 (1e): C, 72.84; H, 5.75; N, 9.99.
Found: C, 72.56; H, 5.81; N, 9.87%.
Preparation of (5R)-5-Benzyl-3-(4-fluorobenzyl)-2,4-imidazolidinedione
(1f )
With phenylalanine and 4-fluorobenzylamine, the procedure given
for 1b was repeated ina similar way to give 4.9 g of 1f as white crystals:
25
yield (82%), m.p. 152–153.5ꢀC. ½ꢀꢁD 18.6ꢀ (MeOH). IR (KBr): 3252,
1
1759, 1690, 1603, 1498, 1420, 1340 (cmÀ1). H NMR (TMS, CDCl3), ꢁ:
3.1 (m, 2H, CH2), 4.3–4.5 (m, 2H, CH2), 4.7 (m, 1H, CH), 7.0–7.4 (m,
9H, ArH), 8.4 (s, 1H, CONH). Calcd. for C17H15FN2O2 (1f ): C, 68.45;
H, 5.07; N, 9.39. Found: C, 68.29; H, 5.14; N, 9.14%.
Asymmetric Hydrocyanation of m-PBA
A reasonable amount of XAD-4 and NDA-99, after a pretreatment
process of the resins,[10] were immobilized inthe columns. The supported

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1882
Zhai et al.
catalysts were prepared by passing a solution of 1 inwater (0.1–0.2%)
through the columnat a rate of 3BV/h. After the prescribed amount of 1
was charged onto the support, the column was washed with water to
remove any traces of non-adsorbed material, and dried in vacuum
ꢀ
ovenat 50 C.
The columnpacked with 10 g of supported catalyst (about 0.6 g
(2.5 mmol) of chiral hydantoin adsorbed), was connected to a three-
neck flask containing 25 g (125 mmol) of m-PBA in100 mL of toluene,
and the mixture was circulated through the top of the column by a
metering pump. After the system was cooled to 5ꢀC inice/water bath,
6.8 mL (250 mmol) of hydrogencyanide was added drop-wise to the
circulationfrom the top of the columnover 1 h. The reactionmixture
was recycled at a rate of 20 mL minÀ1 through the columnat 5 ꢀC for 2 h.
Finally, the mixture was extracted with 50 mL of dilute phosphoric acid
to remove the damaged catalyst if necessary. After evaporation of toluene
under vacuum, the residue gave (S)-2 with an optimal conversion and ee
value, of which ee was determined by HPLC analysis (column, Sumipax
OA-4100; eluent, acetonitrile/petroleum ether¼15/85(V/V); flow rate,
1.0 mL minÀ1; detection, 254 nm) and the conversion of m-PBA was
also determined by HPLC analysis (column, YWG-18; eluent,
THF/petroleum ether ¼2/98(V/V); flow rate, 1.0 mL minÀ1; detection,
25
254 nm). Found: ½ꢀꢁD À22.3ꢀ (DMSO). IR (KBr): 3308 (OH), 3059
(ArH), 2931, 2874 (CH), 2242 (CN), 1582, 1497, 1448 (Ar) (cmÀ1).
ACKNOWLEDGMENTS
We are gratefully to Jiangsu Kuaida Agrochemical Co. Ltd. for the
assistance in carrying out some of the experiments and HPLC analysis.
Thanks also go to the Analytical Center of China Pharmaceutical
University for the elementary analysis.
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Received inJapanJune 16, 2002

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