Traceless approach for the synthesis of 3,5-disubstituted thiohydantoins on functionalized ionic-liquid support

Article abstract of DOI:10.1080/00397910903013697

A traceless approach for the synthesis of 3,5-disubstituted thiohydantoins on a novel functionalized ionic-liquid support, 5, is described. Acylation of benzylamine functionalized ionic-liquid support with amino acids yielded ionic-liquid-supported amino acids, which reacted with isothiocyanates to afford ionic-liquid-supported thioureas. Following intramolecular cyclization cleavage from the ionic-liquid support by trifluoroacetic acid (TFA), the desired 3,5-disubstituted thiohydantoins were obtained in good yields and purities. The efficiency of this ionic-liquid-phase strategy facilitated isolation and analysis of intermediates and removal of excess reagents and by-products during the reaction process.

Full text of DOI:10.1080/00397910903013697

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Traceless Approach for the Synthesis
of 3,5-Disubstituted Thiohydantoins on
Functionalized Ionic-Liquid Support
Chao Yao a , Yandong Zhang a , Guolin Zhang a , Wenteng Chen a
Yongping Yu a & Richard A. Houghten a b
,
a College of Pharmaceutical Sciences, Zhejiang University, Zijin
Campus, Hangzhou, China
b Torry Pines Institute for Molecular Studies, San Diego, California,
USA
Version of record first published: 04 Feb 2010
To cite this article: Chao Yao, Yandong Zhang, Guolin Zhang, Wenteng Chen, Yongping Yu & Richard
A. Houghten (2010): Traceless Approach for the Synthesis of 3,5-Disubstituted Thiohydantoins on
Functionalized Ionic-Liquid Support, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 40:5, 717-724
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Synthetic Communications1, 40: 717–724, 2010
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910903013697
TRACELESS APPROACH FOR THE SYNTHESIS OF
3,5-DISUBSTITUTED THIOHYDANTOINS ON
FUNCTIONALIZED IONIC-LIQUID SUPPORT
Chao Yao,1 Yandong Zhang,1 Guolin Zhang,1 Wenteng Chen,1
Yongping Yu,1 and Richard A. Houghten1,2
1College of Pharmaceutical Sciences, Zhejiang University, Zijin Campus,
Hangzhou, China
2Torry Pines Institute for Molecular Studies, San Diego, California, USA
A traceless approach for the synthesis of 3,5-disubstituted thiohydantoins on a novel func-
tionalized ionic-liquid support, 5, is described. Acylation of benzylamine functionalized
ionic-liquid support with amino acids yielded ionic-liquid-supported amino acids, which
reacted with isothiocyanates to afford ionic-liquid-supported thioureas. Following intramol-
ecular cyclization cleavage from the ionic-liquid support by trifluoroacetic acid (TFA), the
desired 3,5-disubstituted thiohydantoins were obtained in good yields and purities. The
efficiency of this ionic-liquid-phase strategy facilitated isolation and analysis of intermedi-
ates and removal of excess reagents and by-products during the reaction process.
Keywords: Intramolecular cyclization; ionic-liquid support; thiohydantoins
Combinatorial organic synthesis has emerged as an important tool in lead com-
pound identification and optimization in drug discovery.[1,2] This approach permits
the rapid synthesis of large numbers of individual compounds, as well as mixture-
based combinatorial libraries, and facilitates their use in high-throughput screen-
ing.[3,4] However, the solid-phase-synthesis approach suffers from some disadvan-
tages such as nonlinear reaction kinetics and the heterogeneous nature of reaction
conditions. The resin-bound compounds cannot be characterized by analytical meth-
ods such as NMR and liquid chromatography–mass spectroscopy (LC-MS). Ionic
liquids, recognized as a novel class of solvents since the past decade, have attracted
more and more attention as green reaction media.[5–9] These potential solvents have
many special and fascinating properties such as low vapor, high thermal and chemi-
cal stability, easy separation from many organic solvents, and high loading capacity.
In addition, they also can be readily prepared from commercially available reagents
and recycled conveniently in most cases.[10–12] Many articles on preparation of small
molecules and peptides on ionic-liquid supports have been reported recently.[13–17]
Received May 24, 2008.
Address correspondence to Yongping Yu, College of Pharmaceutical Sciences, Zhejiang
University, Zijin Campus, Hangzhou, 310058, China. E-mail: yyu@zju.edu.cn
717

718
C. YAO ET AL.
Figure 1. Glucopyranosylidene-spiro-thiohydantoin.
The general procedure of ionic-liquid-supported organic synthesis starts from the
anchor reaction of the first reactant, and then the excess reagents and by-products
can be washed off smoothly. The second and the third reagents also can be linked
in the same way. Finally, the products can be cleaved from the ionic-liquid support.
Thiohydantoins possess a wide range of biological activities. For example,
glucopyranosylidene-spiro-thiohydantoin (Fig. 1) has been reported as an efficient
inhibitor of muscle and liver glycogen phosphorylases.[18,19] As a part of our ongoing
efforts directed toward combinatorial synthesis of heterocyclic compounds
using amino acids as starting materials, we report here an efficient traceless strategy
for the synthesis of 3,5-disubstituted thiohydantoins on a novel functionalized
ionic-liquid support.
Benzylamine functionalized ionic-liquid support was synthesized according
to the route shown in Scheme 1. Potassium phthalimide was reacted with 1,4-bis-
(chloromethyl)benzene to afford 2-(4-chloromethyl-benzyl) isoindole-1,3-dione 2
in dimethylformamide (DMF) at 80ꢀC for 8 h.[20] 2-(4-Chloromethyl-benzyl)
isoindole-1,3-dione 2 was then reacted with 1-methylimidazole to yield the ionic
Scheme 1. Synthesis of functionalized ionic-liquid support 5.

FUNCTIONALIZED IONIC-LIQUID SUPPORT
719
Scheme 2. Synthesis of 3,5-disubstituted thiohydantoins 9.
liquid 3. The anion-exchange reaction of 3 with NaBF4 afforded ionic liquid 4. The
functionalized ionic-liquid support 5 was obtained by the treatment of ionic liquid 4
with hydrazine in acetonitrile at 80ꢀC for 8 h in good yield and purity.
The general synthetic route of thiohydantoins on ionic-liquid support is
illustrated in Scheme 2. Ionic-liquid support 5 dissolved in CH3CN was coupled with
Boc-protected amino acids under DIC activation at room temperature for 8 h. The
mixture was filtered and the solution was concentrated. Ionic-liquid-supported Boc-
amino acid 6 was precipitated out by treatment of the residue with ether. Ionic-liquid-
supported Boc-amino acid 6 was treated with 55% trifluoroacetic acid (TFA) in
dichloromethane (DCM) to deprotect the ionic-liquid-supported amino acid 7, which
was reacted with a isothiocyanate to afford ionic-liquid-supported thiourea 8. The
desired 3,5-disubstituted thiohydantoin was obtained via intramolecular cyclization
and in situ cleavage reaction using 25% TFA in DCM in good yield and purity.
The products were characterized by NMR. The results are listed in Table 1.
In conclusion, a traceless approach for the synthesis of 3,5-disubstituted thio-
hydantoins on a novel functionalized ionic-liquid support 5 is described. This strat-
egy provides abundant advantages such as easy purification and characterization of
the intermediates. It is believed that this methodology constitutes an attractive
avenue for the rapid synthesis of heterocyclic products.
EXPERIMENTAL
The 1H NMR data were recorded on a Bruker AC-400 instrument with CDCl3
or dimethylsulfoxide (d6-DMSO) as solvent and tetramethylsilane (TMS) as the
internal standard, and the chemical shifts are expressed in parts per million (ppm).

720
C. YAO ET AL.
Table 1. Individual 3,5-disubstituted thiohydantoins 9
Entry
Product
R1
R2
Yield (%)a
1
2
9a
9b
9c
9d
9e
9f
H
C6H5
77
80
79
81
87
83
73
85
83
69
79
H
CH3
3-CH3C6H4
C6H5
C6H5
3
4
(CH3)2CH
(CH3)2CH
5
3-CH3C6H4
3-CH3C6H4
CH3(CH2)2CH2
C6H5
6
CH3CH2(CH3)CH
C6H5CH2
C6H5CH2
7
9g
9h
9i
8
9
C6H5CH2
C6H5CH2OOCCH2CH2
C6H5CH2OOCCH2CH2
3-CH3C6H4
CH3(CH2)2CH2
3-CH3C6H4
10
11
9j
9k
aIsolated yield.
The melting points of the synthetic products were determined on an X-4 melting-
point measurement device. The infrared (IR) spectra were recorded on a Bruck Vec-
tor 200 spectrophotometer (KBr film). Electroscopy ionization–mass spectrometry
(ESI-MS) data were recorded on a Bruker Esquire 3000 þ spectrometer. Acetonitrile
was treated with P2O5 before use.
Preparation of Ionic-Liquid–Supported Benzylamine 5
Potassium
phthalimide
(12.25 g,
70 mmol)
was
reacted
with
1,4-bis-(chloromethyl)benzene 1 (12.95 g, 70 mmol) to afford 2-(4-chloromethyl-
benzyl) isoindole-1,3-dione 2 (8.18 g, 41%) in DMF at 80ꢀC for 8 h.[20] Mp
143–146ꢀC. 1H NMR (400 MHz, CDCl3 [ppm]) d 7.82–7.84 (2H, m), 7.68–7.70
(2H, m), 7.42–7.43 (2H, m), 7.32–7.34 (2H, m), 4.84 (2H, s), 4.54 (2H, s). A mixture
of 2 (4.35 g, 15 mmol) and 1-methylimidazole (1.23 g, 15 mmol) in acetonitrile (60 ml)
was heated at 80ꢀC for 8 h, and the solution was concentrated. The residue was
washed with ether (30 ml) and filtered through a plug of celite to afford the crude
product ionic liquid 3 (5.18 g, 96%), which was used directly with further purifi-
cation. A crude product of 3 (0.94 g, 2.56 mmol) and NaBF4 (0.31 g, 2.82 mmol) in
acetonitrile (30 ml) was heated at 80ꢀC for 72 h. The mixture was filtered, and the
organic phase was concentrated in vacuum. The crude residue was washed with ether
1
(30 ml) and filtered to afford ionic liquid 4 (1.05 g, 99%). Mp 185ꢀC. H NMR
(400 MHz, d6-DMSO [ppm]) d 9.26 (1H, s), 7.85–7.91 (4H, m), 7.79–7.80 (1H, d,
J ¼ 1.6 Hz), 7.70–7.71 (1H, d, J ¼ 1.6 Hz), 7.39–7.41 (2H, m), 7.34–7.36 (2H, m),
5.39 (2H, s), 4.77 (2H, s), 3.83 (3H, s). IR (film) n ¼ 2944, 1712, 1572, 1395, and
1340 cmꢁ1
.
Ionic liquid 4 (0.43 g, 1.1 mmol) reacted with 85% hydrazine hydrate (0.26 g,
4.4 mmol) in acetonitrile (30 ml) at 80ꢀC for 8 h, and then the solvent was evaporated
under reduced pressure. The residue was washed twice with ether, dried over
Na2SO4, and concentrated to afford ionic-liquid support 5 (0.31 g, 98%) as a pale
1
yellow oil. H NMR (400 MHz, d6-DMSO [ppm]) d 9.17 (1H, s), 7.74–7.75 (1H, d,
J ¼ 1.8 Hz), 7.67–7.68 (1H, d, J ¼ 1.8 Hz), 7.41–7.42 (2H, m), 7.39–7.40 (2H, m),
5.38 (2H, s), 3.85 (3H, s), 3.77 (2H, s), 3.72–3.73 (2H, brs).

FUNCTIONALIZED IONIC-LIQUID SUPPORT
721
Preparation of Thiohydantoin 9d
DIC (0.38 g, 3 mmol, 1.5 eq) was added to a mixture of ionic liquid 5 (0.58 g,
2 mmol) and Boc-Val (0.65 g, 3 mmol, 1.5 eq) in dry acetonitrile (35 ml). The mixture
was stirred vigorously for 8 h at room temperature under nitrogen and filtered
through a plug of celite. The celite plug was rinsed with acetonitrile, and the com-
bined organic phase was concentrated. Ionic-liquid-supported Boc-Val 6 was preci-
pitated out by adding ether (20 ml) to the residue. The precipitation was then
collected to afford ionic-liquid-supported Boc-Val 6. TFA (55% in CH2Cl2, 10 ml)
was added to ionic-liquid-supported Boc-Val 6 (2 mmol) under nitrogen for 0.5 h
at room temperature. Upon concentration under reduced pressure, the residue was
washed twice with ether (20 ml ꢂ 2) and dried on a vacuum line to yield the depro-
tected ionic-liquid-supported Val 7 as a TFA salt. The ionic liquid 7 was then dis-
solved together with isothiocyanato-benzene (0.45 g, 3 mmol, 1.5 eq) and
diisopropylethyl amine (DIPEA, 0.39 g, 3 mmol, 1.5 eq) in dry acetonitrile, and
the resulting reaction mixture was stirred at 80ꢀC under nitrogen atmosphere for
8 h. The solvent was removed under vacuum, and the residue was washed with ether
(20 ml ꢂ 3) to afford the ionic-liquid-supported thiourea 8 as yellow oil. Cyclization
reaction of the ionic-liquid-supported thiourea 8 was carried out using TFA (25% in
CH2Cl2, 10 ml) at room temperature instantaneously. After the solvent was removed
under the reduced pressure, the desired compound was extracted by ether
(20 ml ꢂ 3), and then the combined organic phase was washed with saturated
Na2CO3 (30 ml ꢂ 2). The organic phase was dried over Na2SO4 and concentrated
to afford 5-isopropyl-3-phenyl-2-thioxo-imidazolidin-4-one (9d) (0.38 g, 81%) after
1
recrystallization from methanol. Mp 208ꢀC. H NMR (400 MHz, CDCl3 [ppm]) d
7.70 (1H, brs), 7.46–7.53 (3H, m), 7.28–7.30 (2H, m), 4.17–4.18 (1H, d, J ¼ 3.6 Hz),
2.36–2.41 (1H, m), 1.14–1.15 (3H, d, J ¼ 6.8 Hz), 1.04–1.06 (3H, d, J ¼ 6.8 Hz). 13C
NMR (100 MHz, CDCl3) d 184.3, 172.9, 132.3, 129.3, 129.2, 128.3, 65.0, 31.2,
18.8. IR (film) n ¼ 3191, 2962, 1758, 1517, 1268 and 1192 cmꢁ1; ESIMS m=z 235
([M þ H]þ).
Data
3-Phenyl-2-thioxo-imidazolidin-4-one (9a). Mp > 300ꢀC. 1H NMR
(400 MHz, d6-DMSO) 0.37 (1H, brs), 7.42–7.50 (3H, m), 7.26–7.29 (2H, m), 4.29
(2H, s). IR (film) v ¼ 3158, 3002, 2918, 1762, 1522, 1410, 1325, 1276, 1196 cmꢁ1
;
ESIMS m=z 193 ([M þ H]þ).
2-Thioxo-3-m-tolyl-imidazolidin-4-one (9b). Mp 171–172ꢀC. 1H NMR
(400 MHz, CDCl3) d 7.47 (1H, brs), 7.38–7.42 (1H, m), 7.28 (1H, s), 7.11 (2H, m),
4.25 (2H, s), 2.41 (3H, s). IR (film) v ¼ 3166, 3001, 1760, 1600, 1520, 1409, 1324,
1281, 1222 cmꢁ1; ESIMS m=z 207 ([M þ H]þ).
1
5-Methyl-3-phenyl-2-thioxo-imidazolidin-4-one (9c). Mp 184–185ꢀC. H
HMR (400 MHz, CDCl3) d 7.80 (1H, brs), 7.44–7.53 (3H, m), 7.31–7.33 (2H, m),
4.30–4.36 (1H, q, J ¼ 7.2 Hz), 1.57–1.59 (3H, d, J ¼ 7.2 Hz). IR (film) v ¼ 3189,
3000, 1759, 1525, 1446, 1408, 1275, 1197 cmꢁ1; ESIMS m=z 207 ([M þ H]þ).

722
C. YAO ET AL.
5-Isopropyl-2-thioxo-3-m-tolyl-imidazolidin-4-one (9e). Mp 182–183ꢀC.
1H NMR (400 MHz, CDCl3) d 7.80 (1H, brs), 7.37–7.41 (1H, m), 7.27 (1H, s),
7.07–7.08 (2H, m), 4.17 (1H, d, J ¼ 3.2 Hz), 2.41 (3H, s), 2.36–2.39 (1H, m),
1.13–1.15 (3H, d, J ¼ 6.8 Hz), 1.03–1.05 (3H, d, J ¼ 6.8 Hz). IR (film) v ¼ 3178,
2963, 1758, 1603, 1515, 1403, 1348, 1267, 1219, 1177 cmꢁ1; ESIMS m=z 249
([M þ H]þ).
5-sec-Butyl-2-thioxo-3-m-tolyl-imidazolidin-4-one (9f). Mp 158–159ꢀC.
1H NMR (400 MHz, CDCl3) d 7.75–7.77 (1H, brs), 7.37–7.40 (1H, m), 7.26–7.27
(1H, s), 7.06–7.08 (2H, m), 4.21–4.30 (1H, m), 2.36 (3H, s), 2.11–2.16 (1H, m),
1.40–1.60 (2H, m), 0.97–1.20 (6H, m). IR (film) v ¼ 3164, 2983, 1752, 1514, 1404,
1333, 1265, 1179 cmꢁ1; ESIMS m=z 263 ([M þ H]þ).
5-Benzyl-3-butyl-2-thioxo-imidazolidin-4-one
(9g). Mp
109–110ꢀC.
1H NMR (400 MHz, d6-DMSO) d 10.34 (1H, brs), 7.18–7.24 (3H, m), 7.10–7.12
(2H, m), 4.55–4.57 (1H, t, J ¼ 5.2 Hz), 3.38–3.45 (2H, t, J ¼ 7.6 Hz), 2.99–3.00
(2H, d, J ¼ 4.8 Hz), 1.10–1.15 (2H, m), 0.88–0.94 (2H, m), 0.70–0.73 (3H, t,
J ¼ 7.6 Hz). IR (film) v ¼ 3279, 2927, 2862, 1719, 1509, 1434, 1344, 1291, 1256,
1189, 1120 cmꢁ1; ESIMS m=z 263 ([M þ H]þ).
5-Benzyl-3-phenyl-2-thioxo-imidazolidin-4-one (9h). Mp 189–190ꢀC.
1H NMR (400 MHz, CDCl3) d 7.42–7.48 (4H, m), 7.34–7.40 (3H, m), 7.26–7.28
(1H, m), 7.06–7.09 (2H, m), 4.51–4.54 (1H, m), 3.32–3.37 (1H, m), 3.07–3.13 (1H,
m). IR (film) v ¼ 3165, 1753, 1516, 1407, 1335, 1265, 1192, 1101 cmꢁ1; ESIMS m=z
283 ([M þ H]þ).
5-Benzyl-2-thioxo-3-m-tolyl-imidazolidin-4-one
(9i). Mp
87–88ꢀC.
1H NMR (400 MHz, CDCl3) d 7.36–7.41 (5H, m), 7.30 (1H, s), 7.24 (1H, m),
6.86–6.89 (2H, m), 4.52–4.55 (1H, m), 3.35–3.39 (1H, m), 3.07–3.13 (1H, m), 2.39
(3H, s). IR (film) v ¼ 3253, 2931, 1744, 1697, 1502, 1404, 1348, 1239, 1125 cmꢁ1
ESIMS m=z 297 ([M þ H]þ).
;
3-(1-Butyl-5-oxo-2-thioxo-imidazolidin-4-yl)-propionic acid benzyl ester
(9j). Mp 150–151ꢀC. 1H NMR (400 MHz, CDCl3) d 7.36–7.37 (3H, m), 7.35 (2H, m),
5.14 (2H, s), 4.10–4.13 (1H, t, J ¼ 5.4 Hz), 3.76–3.80 (2H, t, J ¼ 7.2 Hz),
2.50–2.54 (2H, t, J ¼ 7.2 Hz), 2.24–2.29 (1H, m), 2.03–2.09 (1H, m), 1.61–1.67 (2H,
m), 1.30–1.36 (2H, m), 0.91–0.95 (3H, t, J ¼ 7.6 Hz). IR (film) v ¼ 3172, 2965,
2923, 1575, 1602, 1515, 1455, 1405, 1344, 1257, 1177 cmꢁ1; ESIMS m=z 334
([M þ H]þ).
3-(5-Oxo-2-thioxo-1-m-tolyl-imidazolidin-4-yl)-propionic acid benzyl
ester (9k). Mp 131–132ꢀC. 1H NMR (400 MHz, d6-DMSO) d 10.56 (1H, brs),
7.33–7.39 (6H, m), 7.23–7.27 (1H, s), 7.06–7.10 (2H, m), 5.12 (2H, s), 4.45–4.47
(1H, t, J ¼ 5.6 Hz), 2.57–2.62 (2H, t, J ¼ 7.0 Hz), 2.33 (3H, s), 2.11–2.14 (1H, m),
1.99–2.03 (1H, m). IR (film) v ¼ 3239, 1752, 1695, 1506, 1405, 1334, 1256,
1178 cmꢁ1; ESIMS m=z 369 ([M þ H]þ).

FUNCTIONALIZED IONIC-LIQUID SUPPORT
723
ACKNOWLEDGMENTS
Yongping Yu thanks the Foundation of NCET-05–0523, NSFC
(No. 20572098), Zhejiang Science and Technology Program (No. 2005c34001),
and 985 Platform of Zhejiang University. Richard A. Houghten thanks the National
Science Foundation (No. CHE0455072).
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