Enantioselective synthesis of 3,5-disubstituted thiohydantoins and hydantoins

Article abstract of DOI:10.1016/j.tet.2015.10.041

A mild method to convert optically pure amino acid thiourea and urea derivatives to thiohydantoins and hydantoins, respectively, is described. It provides an efficient way to realize enantioselective synthesis of thiohydantoins and hydantoins with good to high isolated yields and enantiomeric purities. We found that the enantiomeric purities were highly dependent on the reaction conditions including bases, solvents, and temperature.

Full text of DOI:10.1016/j.tet.2015.10.041

Accepted Manuscript
Enantioselective synthesis of 3,5-disubstituted thiohydantoins and hydantoins
Yu Chen, Li Su, Xinying Yang, Wenyan Pan, Prof. Hao Fang
PII:
S0040-4020(15)30141-1
10.1016/j.tet.2015.10.041
TET 27213
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 2 September 2015
Revised Date: 14 October 2015
Accepted Date: 15 October 2015
Please cite this article as: Chen Y, Su L, Yang X, Pan W, Fang H, Enantioselective synthesis of 3,5-
disubstituted thiohydantoins and hydantoins, Tetrahedron (2015), doi: 10.1016/j.tet.2015.10.041.
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Graphical Abstract

ACCEPTED MANUSCRIPT
Enantioselective synthesis of 3,5-disubstituted thiohydantoins and hydantoins
Yu Chen a,†, Li Su b,†, Xinying Yang a, Wenyan Pan a, and Hao Fang a,*
a
Department of Medicinal Chemistry, Key Laboratory of Chemical Biology
(Ministry of Education), School of Pharmacy, Shandong University, 44 West
Wenhua Rd., Ji’nan 250012, China.
b
Department of Medicinal Chemistry, Qingdao University School of Pharmacy,
Qingdao University, 38 Dengzhou Rd., Qingdao 266021, China.
† Yu Chen and Li Su contributed equally to this work.
Address correspondence to this author:
Prof. Hao Fang*, Department of Medicinal Chemistry, School of Pharmacy,
Shandong University, 44 West Wenhua Rd., Ji’nan 250012, China.
Email: haofangcn@sdu.edu.cn
Tel: 86-531-88382731
Fax: 86-531-88382548
1

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ABSTRACT: A mild method to convert optically pure amino acid thiourea and urea
derivatives to thiohydantoins and hydantoins, respectively, is described. It provides
an efficient way to realize enantioselective synthesis of thiohydantoins and
hydantoins with good to high isolated yields and enantiomeric purities. We found
that the enantiomeric purities were highly dependent on the reaction conditions
including bases, solvents, and temperature.
Keyword: thiohydantoins; hydantoins; enantioselective synthesis
1. Introduction
Thiohydantoins and hydantoins are important structural motifs found in many
natural products and drugs with various pharmacological activities, including
anti-androgen, anti-bacterial, anti-diabetic, anti-seizure and anti-convulsant (Figure
1).1-4 Some hydantoin derivatives, such as phenytoin5 and nilutamide,6 have been
used to treat convulsant and prostate cancer, respectively. Recently, thiohydantoin
enzalutamide was proved as androgen receptor antagonist for the treatment of
castration-resistant prostate cancer.7 In addition, necrostatin-1 has been used as
promising receptor-interacting protein (RIP1) kinase inhibitor.8, 9 Furthermore,
optically pure thiohydantoins and hydantoins have been widely used as chiral
auxiliaries10 and metal ligands11 in asymmetric catalysis. Some thiohydantoins and
hydantoins are also valuable intermediates for the synthesis of optically pure amino
acids through dynamic kinetic resolution.12
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Figure 1. Thiohydantoins and hydantoins with a wide range of applications
A variety of methods have been reported in the literatures for the synthesis of
14
3,5-disubstituted hydantoins13,
(Scheme 1) and thiohydantoins.15-21 As for
3,5-disubstituted thiohydantoins, they were generally prepared from the
isothiocyanate and α-amino acid methyl ester under basic conditions. These methods
20
include alkaline-mediated synthesis,16,
one-pot three-component synthesis,19
17, 21
ionic-liquid-supported synthesis,18 and microwave-mediated synthesis.15,
However, only racemic products could be obtained by the above methods, the
enantioselective synthesis of 3,5-disubstituted thiohydantoins was proved to be very
challenging.22 In 2011, Catherine Foulon et al investigated the mechanism for the
racemization of 3,5-disubstituted thiohydantoins and found that these compounds
were configurationally not stable under many reaction conditions.22 Herein, we
demonstrate a three-step synthesis of 3,5-disubstituted enantiopure thiohydantoins
through isothiocyanate intermediates.
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Scheme 1. Previous studies13, 14 and our work
2. Results and discussion
According to results from the Foulon’ group, the bases, temperature and solvents
are associated with the racemization of hydantoins and thiohydantoins.22 Kinetic
studies for racemization of typical hydantoins at room temperature (25 °C, t1/2 = 2.5
h) and higher temperature (60 °C, t1/2 = 0.1 h) showed greatly different half life of
racemization,22 which suggested that lower temperature could improve the
enantiomeric purities. Therefore, we tested different reaction conditions at low
temperature (-60 °C) to solve the issue of racemization (Table 1). In our initial study,
a simple base sodium methoxide was employed but we obtained racemic products
(entry 1). As we suspected that the basicity might be responsible for the
racemization,22 we employed weaker bases instead. However, these weak bases,
including triethylamine (TEA), diisopropylethylamine (DIEA), K2CO3 and NaHCO3,
still gave racemic products (entries 2-5). The sterically hindered bases such as
t-BuOK, LDA and NaHMDS also led to absolute racemization (entries 6-8). Finally,
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NaH in THF yielded a product (2a) with high enantiomeric purity (81% ee) (entry 9).
Further studies showed the solvents also proved to be critical. For example, CH2Cl2
and dimethylformamide (DMF) gave products with low enantiomeric purity or a
racemic mixture (27% ee, entry 10, and 0% ee, entry 11).
Table 1. Effects of bases and solvents on the formation of chiral thiohydantoins
isolated
entry
solvent
base
time (h)
ee (%)
yield (%)
56
1
THF
THF
THF
THF
THF
THF
THF
THF
THF
DCM
DMF
NaOMe
Et3N
2
0a
2
4
53
0a
3
DIEA
4
49
0a
4
K2CO3
NaHCO3
t-BuOK
LDA
6
55
0a
5
24
0.5
0.5
0.5
2
25
0a
6
51
0a
7
53
0a
8
NaHMDS
NaH
66
0a
9
63
81b
27b
0a
10
11
NaH
2
45
NaH
2
42
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a ee determined by specific rotation. b ee determined by chiral HPLC.
We further investigated the effects of the reaction temperature on the enantiomeric
purities. Firstly, lower temperature (-78 °C) was tested in our studies and products
with high enantiomeric purities were obtained (entries 1, 7 and 9). We also found
that one of the substrates (1b) could not react at -78 °C (entry 4), but it could cyclize
at -60 °C, with 90% ee of the product (2b, entry 5). In contrast, all of these products
were obtained with lower ee values when the temperature was raised to -20 °C
(entries 3, 6 and 11) and -60 °C (entries 2, 5, 8 and 10). These results indicated that
lower reaction temperature was an important factor in influencing enantioselectivity
(Table 2).
Table 2. Effects of temperature on the formation of thiohydantoins
S
R2
N
NH
S
NaH
O
H3CO
R2
N
N
THF/temp.
H
H
O
1
2
entry R2
temp.(°C) time(h) product isolated
yield(%)
ee(%)a
1
2
3
4
4-OCH3-Ph- - 78
4-OCH3-Ph- - 60
4-OCH3-Ph- - 20
6
40
63
66
-
94
81
69
-
2a
2a
2a
-
2
0.5
-
-Ph
-78
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5
-Ph
- 60
- 20
- 78
- 60
- 78
- 60
- 20
8
81
85
66
70
54
55
62
90
14
92
72
98
62
2
2b
2b
2c
2c
2d
2d
2d
6
-Ph
1
7
n-Bu-
6
8
n-Bu-
2
9
4-Cl-Ph-
4-Cl-Ph-
4-Cl-Ph-
6
10
11
2
0.5
a ee determined by chiral HPLC.
Therefore, the conditions of the transformation from α-amino acid thioureas to
corresponding enantiopure thiohydantoins were established as follows: employing
NaH as the base and anhydrous THF as the solvent, in addition, cyclization reactions
should be operated at a temperature as low as possible. And then, we investigated the
scope of this method (Table 3). Some substrates (1a and 1c-1f) could cyclize at
-78 °C, with good to high enantiomeric purities of the products (2a and 2c-2f, entries
1 and 3-6). However, others (1b and 1g-1l) could cyclize only when the temperature
was raised to -60 °C, with relatively poor enantiomeric purities of the products (2b
and 2g-2l, entries 2 and 7-12). In summary, enantiopure thiohydantoins could be
obtained by direct enantioselective synthesis, with good isolated yields and
enantiomeric purities of the products.
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Table 3. Synthesis of 3,5-disubstituted enantiopure thiohydantoins
time
(h)
6
isolated
entry R1
R2
temp.(°C)d
product
ee(%)f
yield(%)e
52
1
-CH2Ph
4-OCH3-Ph- -78
-Ph -60
-(CH2)3CH3 -78
94
90
92
98
83
86
66
61
84
68
83
89
2a
2b
2c
2d
2e
2f
2
-CH2Ph
-CH2Ph
-CH2Ph
-CH2Ph
-CH2Ph
-CH3
8
71
3
6
58
4
4-Cl-Ph-
-CH2Ph
-78
-78
-78
-60
6
39
5
6
64
6
-(CH2)4Ph
-CH2Ph
6
65
7
10
8
59
2g
2h
2i
8
-CH3
4-OCH3-Ph- -60
4-F-Ph-CH2- -60
24
9
-CH3
4
76
10
11
12
-CH3
-(CH2)4Ph
-60
-60
6
45
2j
-CH2CH(CH3)2 -(CH2)4Ph
3-methylene
6
49
2k
2l
-(CH2)3CH3 -60
8
36
-indole
b
a prepared according to the literature,23 and intermediates (6a-6l) are used to the next step directly.
prepared according to the literature,24 and intermediates (1a-1l) are used to the next step directly. c reaction
conditions: ureas (1 mmol), NaH (6 mmol), THF anhydrous. d as low as possible for the cyclization
8

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reactions, compound (1b) and (1g-1l) are not reacted in -78 °C. e overall isolated yields of three steps. f ee
determined by chiral HPLC.
Having demonstrated the protocol as a general approach for the synthesis of
enantiopure thiohydantoins, we extended it to the enantioselective preparation of
3,5-disubstituted hydantoins. We found that all of the enantiopure hydantoins (4)
could be smoothly formed at -60 °C, with good to high isolated yields of the
products, and the enantiomeric purities of the majority of products (4a-4d and 4h-4l)
were determined to be > 97% by chiral HPLC analysis (Table 4).
Table 4. Synthesis of 3,5-disubstituted enantiopure hydantoins
Time
(min)
15
isolated
entry
R1
R2
product
ee(%)d
yield(%)c
1
2
3
4
5
-CH2Ph
-CH2Ph
-CH2Ph
4-OCH3-Ph-
4-F-Ph-CH2-
-(CH2)3CH3
68
77
54
86
68
98
97
98
97
90
4a
4b
4c
4d
4e
15
60
-CH2CH(CH3)2 -CH2Ph
-CH2Ph -CH2Ph
90
30
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6
-CH2Ph
-CH2Ph
-CH2Ph
-CH2Ph
-CH2Ph
-CH2Ph
-CH2Ph
-(CH2)5CH3
-Ph
30
30
60
90
5
74
79
56
81
66
74
81
95
4f
4g
4h
4i
7
94
2-methylene
-furan
8
> 99
98
9
-(CH2)4Ph
4-F-Ph-
10
11
12
> 99
97
4j
4k
4l
2-methylene
-thiophene
4-OCH3-Ph
-CH2-
15
60
98
a prepared according to the literature,25 intermediates (7a-7l) and (3a-3l) are used to the next
steps directly. b reaction conditions: ureas (1 mmol), NaH (6 mmol), THF anhydrous, Nitrogen
atm. coverall isolated yields of three steps. d ee determined by chiral HPLC.
3. Conclusions
In conclusion, a practical method for enantioselective synthesis of thiohydantoins
and hydantoins via direct cyclization reactions of corresponding thioureas and ureas,
respectively, has been developed. The cyclization reactions were simply mediated by
NaH and completed within several hours at -78 to -60 °C. This method is efficient
for enantioselective synthesis of thiohydantoins and hydantoins from simple starting
materials. Most importantly, high enantiomeric purities were observed for a variety
of thiohydantoins, and the reaction conditions are very mild and can tolerate many
functional groups.
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4. Experimental section
4.1 General
NMR spectra were recorded on 300 MHz or 400 MHz instruments.
High-resolution mass spectra were obtained with a Q-TOF mass spectrometer. IR
spectra were recorded by a FT-IR instrument and were reported in wavenumbers
(cm–1). Melting points were uncorrected. Silica gel, 200−300 mesh, was used for the
chromatography. HPLC was performed by using an IA column, eluting with
hexane/ethanol (80: 20). Commercially available reagents and solvents were used
without further purification. Intermediates (1a-1l) and (3a-3l) were prepared from
corresponding amine according to the literatures methods respectively.
4.2. Procedures
4.2.1. General procedure for the preparation of α-amino acid thioureas (1a-1l).23, 24
To a mixture of amine (1 mmol) and K2CO3 (0.28 g, 2mmol) in 2 mL of water,
0.09 g of CS2 (1.2 mmol) in 1 ml of DMF was added dropwise in a period of
20-30 min at room temperature. After the addition was complete, the mixture was
stirred for several hours until complete conversion was determined by TLC. Then,
the reaction mixture was cooled to 0 °C and a solution of 0.09 g of Cyanuric
chloride (TCT) (0.5 mmol) in 2 mL of CH2Cl2 was added dropwise. After the
addition was complete, the mixture was stirred for another 0.5 h to finish the
reaction. The reaction mixture was then basified to pH > 11 with 6 N NaOH to
obtain a clear solution. The organic layer was separated and the aqueous phase
was extracted with CH2Cl2 (3 ×10 mL). The combined organic layers were dried
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over anhydrous MgSO4, filtered and the solvent was removed in vacuo. The
residual was purified by flash chromatography through a short silica column using
petroleum ether as eluent to give corresponding isothiocyanates (5a-5g). Then the
isothiocyanate was added to a solution of the α-amino acid methyl ester (1.2 mmol)
in CH2Cl2 dropwise at -20 °C. After the addition was completed, the reaction
solution was stirred for 30min. Then the reaction mixture was taken up with
CH2Cl2, after being dried with MgSO4 and condensed, α-amino acid thioureas
(1a-1l) were obtained without further purification.
4.2.2. General procedure for the preparation of α-amino acid ureas (3a-3l).25
A solution of triphosgene (0.15g, 0.5 mmol) in toluene was dropwise added the
amine (1 mmol) at room temperature. After the addition was completed, the reaction
suspension was refluxed for 6 hours, then toluene was evaporated, and the residue
was taken up by CH2Cl2, then added to a solution of the α-amino acid methyl ester
hydrochlorides (1.2 mmol) with triethylamine (0.17 ml, 1.2 mmol) in CH2Cl2
dropwise at 0 °C. After the addition was completed, the reaction solution was stirred
at room temperature for hours. Then CH2Cl2 evaporated, the residue was taken up
with ethyl acetate and washed with brine. After being dried with MgSO4 and
condensed, α-amino acid ureas (3a-3l) were obtained without further purification.
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4.2.3. General procedure for the preparation of thiohydantoins (2a-2l) from α-amino
acid thioureas (1a-1l).
To a suspension of NaH (0.14g, 6 mmol) in THF was slowly added (1a-1l) (1
mmol) in THF at -78 °C or -60 °C with nitrogen inlet. 10 min later, 2N NaHSO4
solution was added to quench the reaction. Then THF evaporated, the aqueous layer
was extracted with CH2Cl2 The organic layer was washed with brine and dried with
MgSO4, filtered and concentrated. The crude product was purified by silica gel
column chromatography using petrol ether/ethyl acetate (8:1 to 3:1) as eluant to give
the hydantoins (2a-2l).
4.2.3.1 (S)-5-benzyl-3-(4-methoxyphenyl)-2-thioxoimidazolidin-4-one (2a).16
White solid, m.p. = 212-213 °C; Yield 52% (0.16 g); 1H NMR (400 MHz, DMSO)
δ 10.56 (s, 1H), 7.33 – 7.20 (m, 5H), 6.92 (d, J = 8.8 Hz, 2H), 6.68 (d, J = 8.8 Hz,
13
2H), 4.73 (t, J = 4.2 Hz, 1H), 3.74 (s, 3H), 3.11 (d, J = 4.4 Hz, 2H); C NMR (100
MHz, DMSO) δ 183.2 (s), 174.1 (s), 159.6 (s), 135.0 (s), 130.3 (s), 130.0 (s), 128.6
(s), 127.5 (s), 126.2 (s), 114.4 (s), 60.5 (s), 55.8 (s), 36.6 (s). HRMS (ESI-TOF) m/z:
[M+H]+ Calcd for C17H17N2O2S 313.1005; Found 313.1014. [α]25 -81.6 (c 0.2,
D
EtOAc).
4.2.3.2. (S)-5-benzyl-3-phenyl-2-thioxoimidazolidin-4-one (2b).26
White solid, m.p. = 186-187 °C; Yield 71% (0.20 g); 1H NMR (400 MHz, DMSO)
δ 10.62 (s, 1H), 7.40 – 6.78 (m, 10H), 4.77 (t, J = 4.0 Hz, 1H), 3.12 (d, J = 4.4 Hz,
2H); 13C NMR (100 MHz, DMSO) δ 182.7 (s), 173.9 (s), 134.9 (s), 133.7 (s), 130.3
13

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(s), 129.1 (s), 129.0 (s), 128.9 (s), 128.6 (s), 127.5 (s), 60.6 (s), 36.6 (s). HRMS
(ESI-TOF) m/z: [M+H]+ Calcd for C16H15N2OS 283.0900; Found 283.0908. [α]25
D
-74.4 (c 0.2, EtOAc).
4.2.3.3. (S)-5-benzyl-3-(4-phenylbutyl)-2-thioxoimidazolidin-4-one (2c).17
White solid, m.p. = 94-96 °C; Yield 58% (0.15 g); 1H NMR (400 MHz, DMSO) δ
10.34 (s, 1H), 7.26 – 7.13 (m, 5H), 4.57 (t, J = 4.2 Hz, 1H), 3.51 – 3.38 (m, 2H),
3.02 (d, J = 4.4 Hz, 2H), 1.20 – 1.13 (m, 2H), 1.00 – 0.86 (m, 2H), 0.74 (t, J = 7.2
13
Hz, 3H); C NMR (100 MHz, DMSO) δ 183.0 (s), 174.3 (s), 134.9 (s), 130.1 (s),
128.5 (s), 127.3 (s), 59.8 (s), 36.2 (s), 29.5 (s), 19.5 (s), 14.1 (s). HRMS (ESI-TOF)
m/z: [M+H]+ Calcd for C14H19N2OS 263.1213; Found 263.1218. [α]25D -11.0 (c 0.2,
EtOAc).
4.2.3.4. (S)-3,5-dibenzyl-2-thioxoimidazolidin-4-one (2d).15
White solid, m.p. = 210-212 °C; Yield 39% (0.12 g); 1H NMR (400 MHz, DMSO)
δ 10.68 (s, 1H), 7.47 (d, J = 8.8 Hz, 2H), 7.31 – 7.19 (m, 5H), 6.84 (d, J = 8.8 Hz,
2H), 4.77 (t, J = 4.4 Hz, 1H), 3.12 (d, J = 4.4 Hz, 2H); 13C NMR (100 MHz, DMSO)
δ 182.3 (s), 173.7 (s), 134.9 (s), 133.7 (s), 132.5 (s), 130.7 (s), 130.2 (s), 129.2 (s),
128.6 (s), 127.6 (s), 60.7 (s), 36.6 (s). HRMS (ESI-TOF) m/z: [M+H]+ Calcd for
C16H14ClN2OS 317.0510; Found 317.0514. [α]25D -54.2 (c 0.2, EtOAc).
14

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4.2.3.5. (S)-5-benzyl-3-(4-chlorophenyl)-2-thioxoimidazolidin-4-one (2e).27
White solid, m.p. = 150-151 °C; Yield 64% (0.19 g); 1H NMR (400 MHz, DMSO)
δ 10.53 (s, 1H), 7.25 – 6.75 (m, 10H), 4.75 – 4.66 (m, 3H), 3.07 (d, J = 4.4 Hz, 2H);
13C NMR (100 MHz, DMSO) δ 182.8 (s), 174.2 (s), 136.4 (s), 134.9 (s), 130.2 (s),
128.7 (s), 128.6 (s), 127.4 (s), 127.3 (s), 127.0 (s), 60.2 (s), 43.6 (s), 35.9 (s). HRMS
(ESI-TOF) m/z: [M+H]+ Calcd for C17H17N2OS 297.1056; Found 297.1072. [α]25
D
-14.8 (c 0.2, EtOAc).
4.2.3.6. (S)-5-benzyl-3-butyl-2-thioxoimidazolidin-4-one (2f).
White solid, m.p. = 129-130 °C; Yield 65% (0.22 g); 1H NMR (400 MHz, DMSO)
δ 10.37 (s, 1H), 7.29 – 7.12 (m, 10H), 4.57 (t, J = 4.2 Hz, 1H), 3.54 – 3.42 (m, 2H),
13
3.01 (d, J = 4.8 Hz, 2H), 2.46 (t, J = 7.0 Hz, 2H), 1.30 – 1.23 (m, 4H); C NMR
(100 MHz, DMSO) δ 182.9 (s), 174.3 (s), 142.3 (s), 134.9 (s), 130.1 (s), 128.8 (s),
128.6 (s), 128.5 (s), 127.3 (s), 126.1 (s), 59.8 (s), 36.2 (s), 35.1 (s), 28.2 (s), 27.0 (s).
HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C20H23N2OS 339.1526; Found 339.1534.
IR (KBr): ν 3207, 2937, 2858, 1740, 1518, 1433, 1352, 1274, 1248, 1146, 1092, 897,
731, 699 cm–1. [α]25D -12.4 (c 0.2, EtOAc).
4.2.3.7. (S)-3-benzyl-5-methyl-2-thioxoimidazolidin-4-one (2g).28
White solid, m.p. = 152-153 °C; Yield 59% (0.13 g); 1H NMR (400 MHz, DMSO)
δ 10.45 (s, 1H), 7.34 – 7.26 (m, 5H), 4.92 – 4.83 (m, 2H), 4.41 – 4.35 (m, 1H), 1.30
13
(d, J = 6.8 Hz, 3H); C NMR (100 MHz, DMSO) δ 182.6 (s), 175.9 (s), 136.9 (s),
15

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128.8 (s), 127.8 (s), 127.7 (s), 55.0 (s), 43.7 (s), 16.7 (s). HRMS (ESI-TOF) m/z:
[M+H]+ Calcd for C11H13N2OS 221.0743; Found 221.0747. [α]25 -11.8 (c 0.2,
D
EtOAc).
4.2.3.8. (S)-3-(4-methoxyphenyl)-5-methyl-2-thioxoimidazolidin-4-one (2h).19
White solid, m.p. = 184-185 °C; Yield 24% (0.06 g); 1H NMR (400 MHz, DMSO)
δ 10.48 (s, 1H), 7.19 (d, J = 8.8 Hz, 2H), 7.01 (d, J = 8.8 Hz, 2H), 4.43 (q, J = 6.9
Hz, 1H), 3.80 (s, 3H), 1.38 (d, J = 7.2 Hz, 3H); 13C NMR (100 MHz, DMSO) δ
182.9 (s), 175.6 (s), 159.6 (s), 130.4 (s), 126.5 (s), 114.4 (s), 55.8 (s), 55.4 (s), 16.7
(s). HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C11H13N2O2S 237.0692; Found
237.0696. [α]25D -48.4 (c 0.2, EtOAc).
4.2.3.9. (S)-3-(4-fluorobenzyl)-5-methyl-2-thioxoimidazolidin-4-one (2i).
White solid, m.p. = 163-164 °C; Yield 76% (0.18 g); 1H NMR (400 MHz, DMSO)
δ 10.48 (s, 1H), 7.37 (dd, J = 8.8, 5.6 Hz, 2H), 7.15 (t, J = 8.8 Hz, 2H), 4.91 – 4.82
(m, 2H), 4.40 – 4.35 (m, 1H), 1.30 (d, J = 7.2 Hz, 3H); 13C NMR (100 MHz, DMSO)
δ 182.4 (s), 175.9 (s), 161.9 (d, J = 241.7 Hz), 133.1 (d, J = 3.0 Hz), 130.1 (d, J = 8.2
Hz), 115.6 (d, J = 21.3 Hz), 55.0 (s), 43.1 (s), 16.6 (s). HRMS (ESI-TOF) m/z:
[M+H]+ Calcd for C11H12FN2OS 239.0649; Found 239.0652. IR (KBr): ν 3176, 3081,
3006, 1752, 1606, 1530, 1514, 1433, 1219, 1174, 1097, 986, 917, 738 cm–1. [α]25
D
-15.4 (c 0.2, EtOAc).
16

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4.2.3.10. (S)-5-methyl-3-(4-phenylbutyl)-2-thioxoimidazolidin-4-one (2j).
White solid, m.p. = 101-102 °C; Yield 45% (0.12 g); 1H NMR (400 MHz, DMSO)
δ 10.32 (s, 1H), 7.28 – 7.14 (m, 5H), 4.29 – 4.24 (m, 1H), 3.73 – 3.63 (m, 2H), 2.59
13
(t, J = 7.2 Hz, 2H), 1.60 – 1.50 (m, 4H), 1.26 (d, J = 7.2 Hz, 3H); C NMR (100
MHz, DMSO) δ 182.7 (s), 176.0 (s), 142.4 (s), 128.8 (s), 128.7 (s), 126.1 (s), 54.8
(s), 35.2 (s), 28.6 (s), 27.4 (s), 16.7 (s). HRMS (ESI-TOF) m/z: [M+H]+ Calcd for
C14H19N2OS 263.1213; Found 263.1215. IR (KBr): ν 3295, 3257, 2934, 2857, 1720,
1510, 1447, 1382, 1352, 1248, 1146, 1027, 911, 703 cm–1. [α]25D -9.6 (c 0.2, EtOAc).
4.2.3.11. (S)-5-isobutyl-3-(4-phenylbutyl)-2-thioxoimidazolidin-4-one (2k).
White solid, m.p. = 129-130 °C; Yield 49% (0.15 g); 1H NMR (400 MHz, DMSO)
δ 10.41 (s, 1H), 7.28 – 7.14 (m, 5H), 4.28 – 4.25 (m, 1H), 3.68 (t, J = 6.6 Hz, 2H),
2.58 (t, J = 7.0 Hz, 2H), 1.86 – 1.76 (m, 1H), 1.58 – 1.41 (m, 6H), 0.87 (t, J = 5.8 Hz,
6H); 13C NMR (100 MHz, DMSO) δ 182.9 (s), 175.7 (s), 142.4 (s), 128.8 (s), 128.7
(s), 126.2 (s), 57.7 (s), 35.2 (s), 28.7 (s), 27.3 (s), 24.4 (s), 23.4 (s), 22.1 (s). HRMS
(ESI-TOF) m/z: [M+H]+ Calcd for C17H25N2OS 305.1682; Found 305.1693. IR
(KBr): ν 3178, 2956, 2936, 2856, 1748, 1532, 1348, 1277, 1250, 1146, 994, 893, 699,
649 cm–1. [α]25D -10.2 (c 0.2, EtOAc).
4.2.3.12. (S)-5-((1H-indol-3-yl)methyl)-3-butyl-2-thioxoimidazolidin-4-one (2l).19
White solid, m.p. = 186-188 °C; Yield 36% (0.11 g); 1H NMR (400 MHz, DMSO)
δ 10.90 (s, 1H), 10.33 (s, 1H), 7.54 (d, J = 8.0 Hz, 1H), 7.30 (d, J = 8.0 Hz, 1H),
17

ACCEPTED MANUSCRIPT
7.08 (d, 1H, J = 1.6 Hz), 7.04 (t, 1H, J = 7.4 Hz), 6.96 (t, 1H, J = 7.4 Hz), 4.52 (t, J =
4.0 Hz, 1H), 3.47 – 3.33 (m, 2H), 3.25 – 3.10 (m, 2H), 1.05 – 0.92 (m, 2H), 0.85 –
13
0.73 (m, 2H), 0.63 (t, J = 7.2 Hz, 3H); C NMR (100 MHz, DMSO) δ 183.2 (s),
174.9 (s), 136.3 (s), 127.7 (s), 124.7 (s), 121.3 (s), 119.0 (s), 118.8 (s), 111.6 (s),
107.3 (s), 59.8 (s), 29.3 (s), 26.4 (s), 19.4 (s), 14.0 (s). HRMS (ESI-TOF) m/z:
[M+H]+ Calcd for C16H20N3OS 302.1322; Found 302.1323. [α]25 -15.2 (c 0.2,
D
EtOAc).
4.2.4. General procedure for the preparation of hydantoins (4a-4l) from α-amino acid
ureas (3a-3l).
To a suspension of NaH (6 mmol) in THF was slowly added (3a-3l) (1 mmol) in
THF at -60 °C with nitrogen inlet. 10 min later, 2N NaHSO4 solution was added to
quench the reaction. Then THF evaporated, the aqueous layer was extracted with
ethyl acetate. The ester layer was washed with brine and dried with MgSO4, filtered
and concentrated. The crude product was purified by recrystallization (ethyl
acetate-hexance) or silica gel column chromatography using petrol ether/ethyl
acetate (6:1 to 2:1) as eluant to give the hydantoins (4a-4l).
4.2.4.1. (S)-3-(4-Methoxy-phenyl)-5-benzyl-imidazolidine-2,4-dione (4a).29
1
White solid, m.p. = 144-146 °C; Yield 68% (0.20 g); H NMR (400 MHz,
DMSO-d6): δ 8.46 (s, 1H), 7.31-7.21 (m, 5H), 6.94-6.83 (m, 4H), 4.52 (t, J = 4.4 Hz,
1H), 3.74 (s, 3H), 3.10-3.01 (m, 2H); 13C NMR (75 MHz, DMSO-d6): δ 172.7, 158.5,
155.6, 135.0, 129.8, 128.0, 127.8, 126.8, 124.5, 113.9, 57.0, 55.3, 36.6; HRMS
18

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(ESI-TOF) m/z: [M+H]+ Calcd for C17H17N2O3 297.1234; Found 297.1237. [α]25
-192.8 (c 0.2, MeOH).
D
4.2.4.2. (S)-3-(4-Fluoro-benzyl)-5-benzyl-imidazolidine-2,4-dione (4b).30
1
White solid, m.p. = 142-144 °C; Yield 77% (0.22 g); H NMR (400 MHz,
DMSO-d6): δ 8.38 (s, 1H), 7.25-7.13 (m, 5H), 7.02-6.97 (m, 2H), 6.83-6.79 (m, 2H),
4.49 (t, J = 4.2 Hz, 1H), 4.41-4.27 (m, 2H), 3.00-2.98 (m, 2H); 13C NMR (100 MHz,
CDCl3): δ 172.8, 162.3(d, J =244.7 Hz), 157.1, 134.8, 131.6(d, J =3.2Hz), 130.1(d, J
=8.2Hz), 129.4, 128.8, 127.4, 115.5(d, J =21.4 Hz), 58.3, 41.4, 37.6; HRMS
(ESI-TOF) m/z: [M+H]+ Calcd for C17H16FN2O2 299.1190; Found 299.1195. [α]25
D
-44.0 (c 0.2, MeOH).
4.2.4.3. (S)-3-Butyl-5-benzyl-imidazolidine-2,4-dione (4c).29
1
White solid, m.p. = 130-131 °C; Yield 54% (0.13 g); H NMR (400 MHz,
DMSO-d6): δ 8.21 (s, 1H), 7.28-7.14 (m, 5H), 4.38-4.35 (m, 1H), 3.21-3.06 (m, 2H),
2.95 (d, J = 4.4 Hz, 2H), 1.19-1.09 (m, 2H), 0.93-0.80 (m, 2H), 0.73 (t, J = 7.2 Hz,
3H); 13C NMR (100 MHz, CDCl3): δ 173.3, 156.5, 135.0, 129.8, 127.9, 126.6, 56.8,
37.0, 36.2, 29.3, 19.0, 13.5; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C14H19N2O2
247.1441; Found 247.1446. [α]25D -79.6 (c 0.2, MeOH).
4.2.4.4. (S)-3-Benzyl-5-isobutyl-imidazolidine-2,4-dione (4d).31
1
White solid, m.p. = 121-122 °C; Yield 86% (0.21 g); H NMR (300 MHz,
19

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DMSO-d6): δ8.40 (s, 1H), 7.35-7.23 (m, 5H), 4.57-4.46 (m, 2H), 4.17-4.13 (m, 1H),
1.84-1.69 (m, 1H), 1.59-1.35 (m, 2H), 0.89-0.86 (m, 6H); 13C NMR (100 MHz,
CDCl3): δ 174.6, 156.6, 136.8, 128.4, 127.3, 54.9, 40.9, 40.7, 24.1, 23.0, 21.4;
HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C14H19N2O2 247.1441, found 247.1440.
[α]25D -49.6 (c 0.2, MeOH).
4.2.4.5. (S)-3-Benzyl-5-benzyl-imidazolidine-2,4-dione (4e).32
1
White solid, m.p. = 139-141 °C; Yield 68% (0.19 g); H NMR (300 MHz,
DMSO-d6): δ 8.35 (s, 1H), 7.26-7.14 (m, 8H), 6.80-6.76 (m, 2H), 4.51-4.28 (m, 3H),
3.01-2.99 (m, 2H); 13C NMR (100 MHz, CDCl3): δ 173.2, 156.2, 136.3, 135.0, 129.8,
128.2, 128.1, 126.9, 126.8, 126.5, 57.2, 40.6, 36.0; HRMS (ESI-TOF) m/z: [M+H]+
Calcd for C17H17N2O2 281.1285; Found 281.1290. [α]25D -58.2 (c 0.2, MeOH).
4.2.4.6. (S)-3-Hexyl-5-benzyl-imidazolidine-2,4-dione (4f).33
1
White solid, m.p. = 123-124 °C; Yield 74% (0.20 g); H NMR (400 MHz,
DMSO-d6): δ 8.21 (s, 1H), 7.23-7.14 (m, 5H), 4.37-4.35 (m, 1H), 3.20-3.05 (m, 2H),
2.95 (d, J = 4.8 Hz, 2H), 1.24-1.06 (m, 6H), 0.94-0.89 (m, 2H), 0.82 (t, J = 7.0 Hz,
3H); 13C NMR (100 MHz, CDCl3): δ; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for
C16H23N2O2 275.1754; Found 275.1761. [α]25D -51.4 (c 0.2, MeOH).
4.2.4.7. (S)-3-Phenyl-5-benzyl-imidazolidine-2,4-dione (4g).13
1
White solid, m.p. = 159-161 °C; Yield 79% (0.21 g); H NMR (300 MHz,
20

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DMSO-d6): δ 8.51 (s, 1H), 7.42-7.21 (m, 8H), 6.97-6.95 (m, 2H), 4.57-4.54 (m, 1H),
3.12-3.01 (m, 2H); 13C NMR (75 MHz, DMSO-d6): δ 172.5, 155.3, 135.0, 131.9,
129.8, 128.6, 128.1, 127.7, 126.8, 126.4, 57.0, 36.6; HRMS (ESI-TOF) m/z: [M+H]+
Calcd for C16H15N2O2 267.1128; Found 267.1131. [α]25D -163.0 (c 0.2, MeOH).
4.2.4.8. (S)-3-Furan-2-ylmethyl-5-benzyl-imidazolidine-2,4-dione (4h).34
1
White solid, m.p. = 124-125 °C; Yield 56% (0.15 g); H NMR (400 MHz,
DMSO-d6): δ 8.33 (s, 1H), 7.50-7.49 (m, 1H), 7.22-7.12 (m, 5H), 6.30-6.29 (m, 1H),
5.85-5.84 (m, 1H), 4.46-4.31 (m, 3H), 3.01-2.93 (m, 2H); 13C NMR (75 MHz,
DMSO-d6): δ 172.9, 155.7, 149.2, 142.3, 135.1, 129.6, 128.1, 126.6, 110.3, 107.3,
57.1, 36.3, 34.2; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C15H15N2O3 271.1077;
Found 271.1086. [α]25D -92.4 (c 0.2, MeOH).
4.2.4.9. (S)-3-(4-Phenyl-butyl)-5-benzyl-imidazolidine-2,4-dione (4i).34
1
White solid, m.p. = 127-128 °C; Yield 81% (0.26 g); H NMR (400 MHz,
DMSO-d6): δ 8.22 (s, 1H), 7.19-7.12 (m, 10H), 4.38-4.36 (m, 1H), 3.24-3.10 (m,
2H), 2.95 (d, J = 4.8 Hz, 2H), 2.45 (t, J = 7.0 Hz, 2H), 1.25-1.16 (m, 4H); 13C NMR
(75 MHz, DMSO-d6): δ 173.4, 156.5, 141.8, 135.0, 129.7, 128.3, 128.1, 127.9, 126.7,
125.6, 56.8, 37.0, 36.2, 34.5, 27.7, 26.9; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for
C20H23N2O2 323.1754, found 323.1762. [α]25D -40.6 (c 0.2, MeOH).
21

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4.2.4.10. (S)-3-(4-Fluoro-phenyl)-5-benzyl-imidazolidine-2,4-dione (4j).34
White solid, m.p. = 147-148 °C; Yield 66% (0.19 g); 1H NMR (400 MHz, CDCl3):
δ7.30-7.10 (m, 9H), 6.86 (s, 1H),4.39-4.37 (m, 1H), 3.24-3.04 (m, 2H); 13C NMR
(100 MHz, CDCl3): δ 172.1, 162.1(d, J =246.8 Hz), 156.5, 134.5, 129.6, 128.8,
128.1(d, J =8.6 Hz), 127.6, 127.2(d, J =3.1 Hz), 116.1(d, J =22.8Hz), 58.1, 37.8;
HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C16H14FN2O2 285.1034; Found 285.1038.
[α]25D -86.8 (c 0.2, MeOH).
4.2.4.11. (S)-3-Thiophen-2-ylmethyl-5-benzyl-imidazolidine-2,4-dione (4k).34
1
White solid, m.p. = 140-142 °C; Yield 74% (0.21 g); H NMR (400 MHz,
DMSO-d6): δ 8.35 (s, 1H), 7.37-7.36 (m, 1H), 7.20-7.11 (m, 5H), 6.88-6.86 (m, 1H),
6.66-6.65 (m, 1H), 4.58-4,43 (m, 3H), 3.01-2.92 (m, 2H); 13C NMR (75 MHz,
DMSO-d6): δ 172.9, 155.8, 138.3, 135.1, 129.6, 128.0, 126.7, 126.6, 126.4, 125.7,
57.1, 36.3, 35.7; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C15H15N2O2S 287.0849;
Found 287.0857. [α]25D -75.2 (c 0.2, MeOH).
4.2.4.12. (S)-3-(4-Methoxy-benzyl)-5-benzyl-imidazolidine-2,4-dione (4l).34
1
White solid, m.p. = 129-131 °C; Yield 81% (0.25 g); H NMR (400 MHz,
DMSO-d6): δ 8.32 (s, 1H), 7.24-7.13 (m, 5H), 6.80-6.73 (m, 4H), 4.47-4.45 (m, 1H),
4.36-4.22 (m, 2H), 3.71 (s, 3H), 2.98 (d, J = 4.8 Hz, 2H); 13C NMR (100 MHz,
CDCl3): δ 173.2, 158.2, 156.2, 135.0, 129.8, 128.4, 128.2, 128.1, 126.7, 57.1, 55.0,
36.1; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C18H19N2O3 311.1390; Found
22

ACCEPTED MANUSCRIPT
311.1391. [α]25D -58.8 (c 0.2, MeOH).
Acknowledgements
We thank Prof. Weiping Tang from University of Wisconsin for valuable
discussions. This work was supported by National Natural Science Foundation
China (No. 21172133, 81373281), Shandong Natural Science Fund for
Distinguished Young Scholars (No. JQ201319), the Program for New Century
Excellent Talents in University (No. NCET120337), the China-Australia Centre for
Health Sciences Research (CACHSR no. 2014GJ02).
Supplementary data
1
Supplementary data (Copies of H and 13C NMR spectra, experimental
chromatograms and HRMS Spectra for all products are available.) associated with
this article can be found in the online version, at
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