Synthesis of thiohydantoins under one-pot three-component solvent-free conditions

Article abstract of DOI:10.1007/s00706-007-0842-8

A direct and efficient one-pot three-component synthesis protocol was developed for the synthesis of thiohydantoins from readily and widely available substrates (isothiocyanates, ethyl chloroacetate, and amines) employing solvent-free conditions.

Full text of DOI:10.1007/s00706-007-0842-8

Monatsh Chem 139, 923–926 (2008)
DOI 10.1007/s00706-007-0842-8
Printed in The Netherlands
Synthesis of thiohydantoins under one-pot three-component
solvent-free conditions
Song Cao1;2, Longjie Zhu1, Chuanmeng Zhao1, Xiuhong Tang1, Huajun Sun1,
Xin Feng1, Xuhong Qian1
1
Shanghai Key Laboratory of Chemical Biology, School of Pharmacy,
East China University of Science and Technology, Shanghai, China
2
Key Laboratory of Organofluorine Chemistry, Chinese Academy of Sciences,
Shanghai Institute of Organic Chemistry, Shanghai, China
Received 24 October 2007; Accepted 30 October 2007; Published online 19 June 2008
# Springer-Verlag 2008
Abstract A direct and efficient one-pot three-com-
ponent synthesis protocol was developed for the
synthesis of thiohydantoins from readily and widely
available substrates (isothiocyanates, ethyl chloroace-
tate, and amines) employing solvent-free conditions.
A variety of synthesis methods for the formation of
thiohydantoins have been developed during past two
decades [8]. For example, Nielsen et al. developed
an efficient method for the synthesis of thiohy-
dantoins by treatment of isothiocyanates with N-
substituted ꢀ-amino acids under microwave-assisted
conditions [9]; The Ganesan group reported a solu-
tion-phase synthesis of a combinatorial thiohydantoin
ensemble by a one-pot three-component reaction
of ꢀ-amino acid ester, aromatic aldehyde, and iso-
thiocyanate in the presence of sodium triacetoxybo-
rohydride (as reducing agent) [10]. Kurth et al. have
established a viable route for the synthesis of no-
vel isoxazole- and thiohydantoin-containing hetero-
cycles via solid-phase method [11]; Kidwai et al.
also reported the potassium carbonate supported
solventless approach to this class of compounds
via the cyclization of diarylthoiurea with chloroace-
tylchloride under microwave irradiation [12]. How-
ever, the present methods have some drawbacks,
such as lack of versatility, use of expensive and cor-
rosive reagents and solvents, long reaction times,
and tedious work-up procedures. Therefore, the de-
velopment of an efficient and versatile method for
the preparation of thiohydantoins seems to be impor-
tant. Nowadays carrying out organic reactions in the
absence of solvents is one of the more important goals
in clean synthesis. Herein we wish to disclose a more
Keywords Heterocycles; Multicomponent reactions; Solvent-
free; Cyclizations; Isothiocyanates.
Introduction
Thiohydantoins are an important class of heterocy-
clic compounds in medicinal and agricultural chem-
istry because they display a fascinating array of
biological properties [1]. For example, some thiohy-
dantoins can be used as cardioprotective agents for
the prevention of atherosclerosis in man [2]. Lambert
et al. have proved the human CB1 and CB2 canna-
binoid receptor affinity of the thiohydantoins [3]. In
addition, several other compounds can act as gelati-
nase inhibitors, desmutagens and herbicides [4–6].
The classical method for the synthesis of thio-
hydantoins is the reaction of isothiocyanates with
N-substituted ꢀ-amino acids or their esters [2, 7].
Correspondence: Song Cao, Shanghai Key Laboratory of
Chemical Biology, School of Pharmacy, East China Univer-
sity of Science and Technology, Shanghai 200237, China.
E-mail: scao@ecust.edu.cn

924
S. Cao et al.
Scheme 1
practical and efficient alternative for the synthesis of
thiohydantoins by a three-component condensation of
isothiocyanates, ethyl chloroacetate, and amines at
80ꢀC under solvent-free condition (Scheme 1).
Table 2 Yields for the synthesis of 3 under solvent-free
condition in different temperatures
Reaction
Temperature=ꢀC
Time=h
Yielda=%
50
60
70
80
90
100
6
6
5
3
3
3
80
80
87
90
88
80
Results and discussion
In the beginning, efforts were directed towards the
evaluation of the solvent in the synthesis of thiohy-
dantoins. According to literature, methylene chloride
can be used as solvent for the reaction of isothiocy-
anate and ꢀ-amino acids esters [10]. Therefore, our
initial experiments were carried out in methylene
chloride. To have a control experiment in hand, the
model reaction was accomplished using benzyl amine,
isothiocyanates, and ethyl chloroacetate in boiling
methylene chloride. Compound 3 was obtained in
80% yield after a 10 h reaction time. But this initial
attempt was not very encouraging. The reaction time
is too long and the yield is unsatisfactory. Therefore
it was necessary to optimize the reaction conditions.
To improve yields and purity, and to minimize chro-
matographic purifications, the effects of several
parameters (without solvent or solvent, as e.g., 1,2-
dichloroethane or THF; reaction temperature and
time, and the number of equivalents of triethyl-
amine) were studied. The influences of solvents on
the yield of the reaction are shown in Table 1. The
best results were obtained when the reaction was
conducted in the absence of solvent.
a
Yield of isolated product
The yield was also significantly affected by the re-
action temperature. The results are shown in Table 2.
As can be seen from Tables 1 and 2, to reach compa-
rable yields the solvent-free reactions needed much
shorter reaction time than the solvent reactions, but
required higher reaction temperature.
In addition, effects of molar ratio of triethylamine
to isothiocyanate on this one pot reaction without
solvent were investigated (Table 3). In the absence
of this catalyst, the reaction did not proceed well
even after prolonged reaction time under solventless
condition. Triethylamine catalyzed the reaction very
efficiently producing good yields of products in a
much shorter time. It was found that the molar ratio
between triethylamine and isothiocyanate could
play important role in determining the yield. When
the molar ratio is 1, the reaction can be carried out
successfully, but triethylamine=isothiocyanate of 1.05–
1.30 is a better ratio for preparing the thiohydan-
toins. Hence this ratio (1.05) was used in the next
Table 1 Effect of solvent on the synthesis of 3
Solvent
Reaction conditions
Yielda=%
Table 3 The influence of the amount of triethylamine on the
reaction of synthesis of thiohydantoins
Temperature=ꢀC Time=h
Methylene chloride 40
1,2-Dichloroethane 84
10
5
10
3
80
84
87
90
Triethylamine=
isothiocyanate
(mole ratio)
Yielda=%
0
1
1.05
1.3
1.4
1.5
2
THF
Without solvent
68
80
<60 82 90
90
87
82
74
a
a
Yield of isolated product
Yield of isolated product

Synthesis of thiohydantoins
925
Table 4 Solvent-free three-component synthesis of thiohydantoins
Entry
R1
R2
Yielda=%
m.p.=ꢀC
Ref.
[13]
this work
[14]
this work
this work
this work
this work
this work
[7a]
this work
[15]
this work
1
2
3
4
5
6
7
8
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
CH3
C6H5
70
72
90
82
70
70
73
72
76
78
82
77
212
4-CH3–C6H4
C6H4CH2
C4H9
3-Cl–C6H4
4-F–C6H4
4-CH3O–C6H4
Cyclic-C6H11
C6H5
170–171
188.5–189.5
133–135
157–158
185–187
190–192
231–232
113–113.5
135–137
74
9
10
11
12
CH3
CH3
CH3
4-CH3–C6H4
C6H4CH2
C4H9
oil
a
Yield of isolated product
experiment. A further increase in the amount of
triethylamine showed no substantial improvement
in the yield, whereas the yield was reduced when
the ratio reached to 2. The results showed that the
optimum reaction conditions were triethylamine=
isothiocyanate: 1.05–1.30 (molar ratio), the range
of temperature from 70 to 90ꢀC, and the reaction
time from 2 to 3 h.
In conclusion, we developed a novel and efficient
one-pot three-component method for the synthesis of
thiohydantoins under solvent-free conditions provid-
ing good isolated yields. The reasonable reaction
times, solvent-free, high yields, simple work-up
procedure, and a one-pot reaction without the ne-
cessity to isolate the products are main merits of
this method.
Under these optimized reaction condition, a range
of structurally diverse amines and isothiocyanates
were subjected under this protocol to produce the
corresponding thiohydantoins (Table 4). Aliphatic
amines produced good yields of thiohydantoins. Ar-
omatic amines also worked well with this protocol,
but the yield was less than that of aliphatic amines.
The substituted aromatic amines having electron-
donating group gave thiohydantoins in good yields.
However, in the case of electron-withdrawing groups
relatively low yield were obtained. In addition, we
found that a strongly electron-withdrawing function-
ality such as CF3 on the aromatic amines dramatically
decreased the reactivity, cyclization (step 2) would
become difficult, and no reaction was observed even
after refluxing for a prolonged period (10h).
Finally, this method requires no product purifica-
tion and affords the desired product in good yields
without the formation of unwanted side products.
Therefore, only ionic impurities (i.e., NH4Cl) need
to be washed with the mixture of ethyl acetate=
petroleum ether (1=10) and water from the products.
The purity of the products was, in most cases,
in excess of 95% and no further purification was
necessary.
Experimental
Melting points were recorded in open capillary using Bu¨chi
melting point B540 apparatus. Analytical thin-layer chroma-
tography (TLC) was carried out on precoated plates (silica gel
60 F254), and spots were visualized with UV light. All chem-
icals used were reagent grade procured commercially and
used without further purification. H and 13C NMR spectra
1
were recorded on a Bruker AM-400 (400 MHz) spectrometer
with CDCl3 as the solvent using TMS as internal standard.
High-resolution mass spectra were recorded under electron
impact conditions using a MicroMass GCT CA 055 instru-
ment. Infrared spectra were recorded with a Nicolet Magna-
IR 550 spectrometer. All known compounds proved to be
1
identical (m.p., IR, H NMR, and MS) with those described
in the references.
General procedure for the one-pot synthesis of thiohydantoins
Ethyl chloroacetate (1.84 g, 15mmol) was added dropwise to a
mixture of 15mmol amine, 3.54g triethyl amine (15.8mmol).
After about 0.5 h of stirring at room temperature, the mixture
was gently heated to 80ꢀC for 0.5 h, and then 15mmol iso-
thiocyanate was added at 80ꢀC over a period of 2–3 h. After
the completion of reaction monitored by TLC, it was cooled
to room temperature and washed with the mixture of ethyl
acetate=petroleum ether (1=10) and water. The product was
collected by filtration. Some of the solid product can be further
purified by recrystallization from ethanol.

926
S. Cao et al.
(400MHz, CDCl3): ꢂ ¼ 182.66, 169.91, 138.04, 135.49,
129.99, 125.16, 54.88, 28.43, 21.14 ppm; HRMS: m=z [M]þ:
Calcd for C11H12N2OS: 220.0670, found: 220.0671.
1-(4-Methylphenyl)-3-phenyl-2-thiohydantoin
(2, C16H14N2OS)
Pale yellow solid; IR (KBr): ꢁꢀmax ¼ 3055, 1753, 1507, 1456,
1306, 1273, 1172, 754, 699 cmꢁ1 1H NMR (400 MHz,
;
CDCl3): ꢂ ¼ 7.57–7.30 (m, 9H), 4.60 (s, 2H), 2.42 (s, 3H)
ppm; 13C NMR (400MHz, CDCl3): ꢂ ¼ 182.31, 169.31,
138.27, 135.50, 133.29, 130.08, 129.37, 129.24, 128.55,
125.44, 55.36, 21.21 ppm; HRMS: m=z [M]þ: Calcd for
C16H14N2OS: 282.0827; found: 282.0830.
Acknowledgements
This work was financially supported by National Key Project
for Basic Research (2003CB114405), the National High Tech-
nology Research and Development Program of China (863
Program, 2006AA10A201), the Shanghai Foundation of
Science of Technology (073919107), and Shanghai Leading
Academic Discipline Project (B507) for financial support.
1-(3-Chlorophenyl)-3-phenyl-2-thiohydantoin
(5, C15H11ClN2OS)
White solid; IR (KBr): ꢁꢀmax ¼ 3069, 2953, 1716, 1646, 1585,
1486, 1375, 1275, 1154, 728 cmꢁ1 1H NMR (400MHz,
;
References
CDCl3): ꢂ ¼ 7.49–6.92 (m, 9H), 4.01 (s, 2H) ppm; 13C NMR
(400 MHz, CDCl3): ꢂ ¼ 171.02, 154.32, 147.73, 135.68,
134.81,130.21, 129.26, 129.23, 128.47, 126.38, 124.82, 120.81,
32.86 ppm; HRMS: m=z [M]þ: Calcd for C15H11ClN2OS:
302.0281; found : 302.0281.
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1-(4-Fluorophenyl)-3-phenyl-2-thiohydantoin
(6, C15H11FN2OS)
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Pale yellow solid; IR (KBr): ꢁꢀmax ¼ 3054, 2941, 1758, 1514,
1455, 1400, 1309, 1264, 1170, 1092, 836, 760 cmꢁ1; 1H NMR
(400 MHz, CDCl3): ꢂ ¼ 7.57–7.18 (m, 9H), 4.61 (s, 2H) ppm;
13C NMR (400 MHz, CDCl3): ꢂ ¼ 182.85, 168.93, 133.17,
129.43, 129.26, 128.47, 127.66, 127.57, 116.57, 116.34,
55.27 ppm; HRMS: m=z [M]þ: Calcd for C15H11FN2OS:
286.0576; found: 286.0576.
1-(4-Methoxyphenyl)-3-phenyl-2-thiohydantoin
(7, C16H14N2O2S)
Pale yellow solid; IR (KBr): ꢁꢀmax ¼ 3054, 2933, 2836, 1758,
1516, 1456, 1247, 1168, 1028, 833, 757 cmꢁ1 1H NMR
;
(400 MHz, CDCl3): ꢂ ¼ 7.56–7.00 (m, 9H), 4.59 (s, 2H),
3.86 (s, 3H) ppm; 13C NMR (400 MHz, CDCl3): ꢂ ¼ 182.61,
169.28, 159.15, 133.31, 130.78, 129.33, 129.21, 128.51,
127.13, 114.69, 55.60, 55.54 ppm; HRMS: m=z [M]þ: Calcd
for C16H14N2O2S: 298.0775 found: 298.0776.
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1-Cyclohexyl-3-phenyl-2-thiohydantoin (8, C15H18N2OS)
Pale yellow solid; IR (KBr): ꢁꢀmax ¼ 3052, 2942, 2855, 1762,
8. a) Nizamuddin MG, Khan MH, Srivastava MK, Tiwari S
(2000) Indian J Chem Sect B Org Chem Incl Med Chem
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Chem 3:278
1588, 1474, 1297, 1248, 1233, 1170, 700 cmꢁ1 1H NMR
;
(400 MHz, CDCl3): ꢂ ¼ 7.52–7.34 (m, 5H), 4.78–4.72 (m,
1H), 4.13 (s, 2H), 2.06–1.24 (m, 10H) ppm. 13C NMR
(400 MHz, CDCl3): ꢂ ¼ 181.69, 170.19, 133.16, 129.14,
129.07, 128.46, 55.48, 48.44, 30.05, 25.23 ppm. HRMS: m=z
[M]þ: Calcd for C15H18N2OS: 274.1140, found: 274.1140.
1-(4-Methylphenyl)-3-methyl-2-thiohydantoin
(10, C11H12N2OS)
Pale yellow solid; IR (KBr): ꢁꢀmax ¼ 3065, 2958, 1740, 1513,
1
1453, 1336, 1278, 1116, 818, 667 cmꢁ1; H NMR (400MHz,
13. Wheeler HL, Brautlecht CA (1911) Am Chem J 45:446
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CDCl3): ꢂ ¼ 7.40 (d, J ¼ 8.10 Hz, 2H), 7.27 (d, J ¼ 8.10 Hz,
2H), 4.40 (s, 2H), 3.35 (s, 3H), 2.39 (s, 3H) ppm; 13C NMR