Microwave assisted synthesis of 1,5-disubstituted hydantoins and thiohydantoins in solvent-free conditions

Article abstract of DOI:10.1055/s-2002-19308

1,5-Disubstituted hydantoins/thiohydantoins 3a-p have been synthesized in 81-95% yield by a microwave-promoted solvent-free condensation of arylglyoxals 1 and phenylurea/thiourea 2 using PPE as a reaction mediator. This method can be extended towards the parallel synthesis of 3. The workup is simple and involves treatment with ice-cold water.

Full text of DOI:10.1055/s-2002-19308

PAPER
75
Microwave Assisted Synthesis of 1,5-Disubstituted Hydantoins and
Thiohydantoins in Solvent-Free Conditions
Solvent-Free
M
a
icrowave
t
S
ynthe
y
sis of
H
ydan
a
T
hiohyd
P
antoins aul,*a Mukta Gupta,a Rajive Gupta,a André Loupyb
a
Department of Chemistry, University of Jammu, Jammu-180 006, India
Fax +91(191)505086; E-mail: paul7@rediffmail.com
b
Laboratoire des Réactions Sélectives sur Supports, CNRS UMR 8615, Université Paris-Sud, 91405, Orsay, France
Fax +33(169)154679; E-mail: aloupy@icmo.u-psud.fr
Received 28 June 2001; revised 18 October 2001
scales.17 Herein we wish to report a facile microwave syn-
thesis of 1,5-disubstituted hydantoins 3 from arylglyoxals
1 and phenylurea 2 using polyphosphoric ester (PPE) as a
reaction mediator. Additionally, this method has been ex-
Abstract: 1,5-Disubstituted hydantoins/thiohydantoins 3a–p have
been synthesized in 81–95% yield by a microwave-promoted sol-
vent-free condensation of arylglyoxals 1 and phenylurea/thiourea 2
using PPE as a reaction mediator. This method can be extended to-
wards the parallel synthesis of 3. The workup is simple and involves tended to the synthesis of thiohydantoins (by using phe-
treatment with ice-cold water.
nylthiourea instead of phenylurea) under identical
reaction conditions.
Key words: arylglyoxals, solvent-free conditions, polyphosphoric
ester (PPE), microwave activation, hydantoins
Hydantoins are compounds that have a reactive urea core.
They are well known for diverse biological activities and
play a key role as antiarrhythmics,1,2 anticonvulsants,3,4
antitumor compounds,5,6 aldose reductase inhibitors,7
anti-inflammatory compounds,8 and antiandrogens.9 They
also involved in lowering of blood sugar level in mam-
mals.10 Hydantoins have also been used for the prepara-
tion of moisturizing lotions,11 for increasing HDL
cholesterol concentration,12 and as antiserotoninergic
agents. 13 The most straightforward protocol for the syn-
thesis of 1,5-disubstituted hydantoins 3 involves the one-
pot condensation of arylglyoxals 1 with phenylurea 2 in
ethanol under strongly acidic conditions (concd HCl and
glacial HOAc).14 However, the combination of solvents,
strong acids and long reaction times makes this method
environmentally hazardous. Thus, a simple, general and
efficient procedure for the synthesis of this important het-
erocyclic system is required.
Scheme
Arylglyoxals were prepared from acetophenones either by
using SeO2/dioxane or SeO2/SiO2 under microwave irra-
diation. In order to carry out the synthesis of 1,5-disubsti-
tuted
hydantoins/thiohydantoins
under
efficient
environmentally benign conditions, the influence of mi-
crowave irradiation on a neat mixture of aryglyoxal 1,
phenylurea/thiourea 2 and PPE was investigated. The mo-
lar ratios of reagents, irradiation times, and microwave
power levels were optimized to achieve higher yields. Op-
timum conditions (Table) employed a 1.1:1.0 ratio of
aryglyoxal 1 and phenylurea/thiourea 2 with PPE as reac-
tion mediator (2.2 mmoles of 1 required 300mg of PPE).
The application of microwave irradiation to organic syn-
thesis has been the focus of considerable attention in re-
cent years and is becoming an increasingly popular
technology.15 The salient features of the microwave ap-
proach are rapid reaction rates, cleaner reaction conditions
and enhancements in chemical yields.15
To demonstrate the feasibility of using microwave irradi-
ation for the parallel synthesis of hydantoins/thiohydanto-
ins four reaction vessels containing the appropriate
mixtures of arylglyoxals 1, phenylurea/thiourea 2 and
PPE were simultaneously placed into the oven and irradi-
ated. After workup the individual hydantoins/thiohydan-
toins were obtained in good to excellent yields.
Under the framework of “Green Chemistry” we have de-
veloped an environmentally benign solvent-free approach
for the synthesis of hydantoins/thiohydantoins. This al-
lowed the elimination of solvents and strong mineral acids
in solution.16 Further attractions of this method are that it
allows reactions in open vessels (thus avoiding the risk of
high pressure development) and synthesis on preparative
Finally, the synthesis of 3a using PPE under neat condi-
tions was attempted using a thermostated oil-bath under
identical conditions as those employed as for the micro-
wave-assisted method (3 min and 120 °C). Lower yields
were obtained under thermal conditions (36%) as com-
pared to microwave irradiation (88%), demonstrating that
Synthesis 2002, No. 1, 28 12 2001. Article Identifier:
1437-210X,E;2002,0,01,0075,0078,ftx,en;Z07301SS.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881

76
S. Paul et al.
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in CDCl3–DMSO-d6/DMSO-d6 were recorded on Bruker DRX 300
(300 MHz) and Bruker AM-250 (250 MHz) instruments and 13C
NMR in CDCl3–DMSO-d6/DMSO-d6 on Jeol FX 90Q (90 MHz)
and Bruker DPX-200 (200 MHz) instruments using TMS as an in-
ternal standard. Mass spectral data were recorded on a Delsi-Ner-
mag spectral-30 spectrometer. Reactions were carried out in a BPL
BMO 800T microwave domestic oven with power output of 800
watts.
Table Microwave/PPE-Mediated Synthesis of 3a–p
Product
3a
R
X
O
O
Time
(min)
Yielda
(%)
mp ( °C) Found/
Reported
H
3
88
192–93/
19514
3b
Me
3
92
206–207/
209–21119
Synthesis of arylglyoxals 1 under microwave irradiation;
General Procedure.
3c
3d
3e
OMe
OEt
F
O
O
O
2.5
2.5
2.5
89
83
85
176–177
151–152
The appropriate acetophenone (2 mmol) and SeO2 (3 mmol) were
dissolved in CH2Cl2 (7 mL). Silica gel (2 g) was added and stirred
vigorously. After 5 min, the solvent was removed under vacuum
and the dry powder was irradiated in a domestic microwave oven
for 7–10 min at 450 W. After the completion of the reaction, the
product was extracted with CH2Cl2 (3 15 mL) and washed with
excess of water to remove unreacted SeO2. The CH2Cl2 extract after
drying over anhyd Na2SO4 and removal under reduced pressure
gave aryglyoxal 1 in 68–81% yield.
193–194/
185–18720
3f
Cl
Br
O
O
3
3
81
92
183–184/
196–19819
3g
205–206/
204–20619
Microwave/PPEMediated Synthesis of Hydantoins/
Thiohydantoins 3a–p; General Procedure
a) Single-Compound Method
3h
3i
NO2
H
O
S
S
S
S
S
S
S
S
3
80
88
93
83
85
87
95
91
95
143–144
232–233
242–243
220–221
223–224
223–224
229–230
206–207
244–245
3
The appropriate arylglyoxal 1 (2.2 mmol), phenylurea/thiourea 2 (2
mmol) and PPE (300 mg) were placed in a beaker (50 mL). After
the mixture was mixed thoroughly with the help of a glass rod a
paste formed (15–20 s). The beaker was introduced into the micro-
wave oven and irradiated for the appropriate time (Table) at 300 W.
Reaction progression was monitored by t.l.c. On cooling to room
temperature, crushed ice was added and the mixture was stirred
thoroughly (1–2 min), till the solid product was obtained, which
was filtered, dried and crystallized from a suitable solvent (ben-
zene–petroleum ether or benzene). The physical data are given in
the Table.
3j
Me
OMe
OEt
F
3.5
3
3k
3l
3
3m
3n
3o
3p
2.5
3
Cl
Br
3
NO2
3.5
b) Parallel synthesis of 3a–e/3i–m
The appropriate arylglyoxal 1 (2.2 mmol), phenylurea/thiourea 2 (2
mmol) and PPE (300 mg) were placed in 4 individual (25 mL) bea-
kers. The mixture in all the 4 beakers was mixed separately until a
paste fomed. They were irradiated on the turntable in the microwave
oven 5 times at 300 W for 30 s, with 1 min cooling time. After the
work up as above, the products were obtained in good to excellent
yields (Table). In the case of 3i–m, the irradiation is carried out 6
times at 300 W for 30 s with 1 minute cooling time.
a Yield of isolated products
the effect of microwave irradiation is not purely thermal.
Microwave irradiation facilitates the polarization of the
molecules under irradiation causing rapid reaction to oc-
cur. This is consistent with the reaction mechanism, which
involves a polar transition state.18 Nucleophilic attack of
an amine on a polarized carbonyl function (rate-determin-
ing step) is followed by an intramolecular cyclization.
The structures of the products were confirmed by IR, 1H NMR, 13
C
NMR, mass spectral data and comparison with authentic samples
prepared according to the literature methods.14,19,20
Spectral data of compounds 3a–p
1,5-Diphenylhydantoin (3a)
We have developed a novel and efficient microwave-in-
duced method for the synthesis of hydantoins/thiohydan-
toins. The advantages of this environmentally safe and
benign protocol include a simple reaction set-up, high
product yields, short reaction times and elimination of sol-
vents and acid. The workup simply involves treatment
with ice-cold water. Additionally, we demonstrated that
the present procedure is readily amenable to parallel syn-
thesis of hydantoins/thiohydantoins. This rapid and easy
technique coupled with solvent-free conditions may con-
tribute to the dream of Green Technology.
IR (Nujol): 3190, 3005, 1750, 1690 cm–1.
1H NMR (250 MHz, CDCl3–DMSO-d6): = 5.51 (s, 1 H, CH),
7.02–7.52 (m, 10 H, Harom), 11.15 (br. s, 1 H, NH, exchangeable
with D2O).
13C NMR (200 MHz, DMSO-d6): = 171.4 (C2), 154.8 (C4), 136.5
(C11’’), 134.0 (C1’), 128.8 (C3’), 128.6 (C3’, C5’), 128.4 (C3”),
127.1 (C4’), 124.0 (C4”), 120.7 (C6’, C2”, C6”), 64.4 (C5).
MS (EI ): m/z (%) = 252 (31.72) [M+], 253 (100) [M + H+].
5-(4-Methylphenyl)-1-phenylhydantoin (3b)
IR (Nujol): 3200, 2975, 1755, 1690 cm–1.
Melting points (uncorrected) were determined by a Toshniwal melt-
1H NMR (250 MHz, CDCl3–DMSO-d6): = 2.31 (s, 3 H, CH3),
5.47 (s, 1 H, CH), 7.02-7.55 (m, 9 H, Harom), 11.11 (br. s, 1 H, NH,
exchangeable with D2O).
ing point apparatus. IR spectra
(
) were recorded on
max
Shimadzu435 spectrophotometer using KBr discs. 1H NMR spectra
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Solvent-Free Microwave Synthesis of Hydantoins and Thiohydantoins
77
MS (EI ): m/z (%) = 266 (26.57) [M+], 267 (100) [M + H+].
13C NMR (90 MHz, CDCl3–DMSO-d6): = 183.3 (C4), 172.9 (C2),
160.1 (C4’), 128.3 (C1’), 125.6 (C2’, C3”, C5”), 125.2 (C6’), 123.4
(C1”), 112.3 (C3’, C5’, C 2”, C4”, C6”), 61.9 (C5), 55.5 (OCH3).
MS (EI ): m/z (%) = 298 (31.12) [M+], 299 (100) [M + H+].
5-(4-Methoxyphenyl)-1-phenylhydantoin (3c)
IR (Nujol): 3195, 2973, 1750, 1690, 1265, 1055 cm–1.
1H NMR (300 MHz, DMSO-d6): = 3.89 (s, 3 H, OCH3), 5.88 (s, 1
H, CH), 6.86–6.89 (d, 2 H, Harom), 7.00–7.05 (t, 1 H, Harom), 7.23–
7.28 (m, 4 H, Harom), 7.46–7.48 (d, 2 H, Harom), 11.36 (br. s, 1 H, NH,
exchangeable with D2O).
5-(4-Ethoxyphenyl)-1-phenylthiohydantoin (3l)
IR (Nujol): 3163, 2979, 1754, 1246, 1186, 1044 cm–1.
1H NMR (250 MHz, CDCl3–DMSO-d6):
= 1.40 (t, 3 H,
OCH2CH3), 4.05 (q, 2 H, OCH2CH3), 5.25 (s, 1 H, CH), 6.87–7.49
(m, 9 H, Harom), 10.78 (br. s, 1 H, NH, exchangeable with D2O).
13C NMR (90 MHz, DMSO-d6): = 182.3 (C4), 172.2 (C2), 160.0
(C4’), 127.5 (C1’), 124.2 (C2’, C3”, C5”), 123.1 (C6’), 122.4 (C1”),
112.0 (C3’, C5’, C2”, C4”, C6”), 62.1 (C5), 61.1 (OCH2CH3), 13.81
(OCH2CH3).
5-(4-Ethoxyphenyl)-1-phenylhydantoin (3d)
IR (Nujol): 3190, 2975, 1750, 1700, 1250, 1048 cm–1.
1H NMR (250 MHz, CDCl3–DMSO-d6):
OCH2CH3), 3.8 (q, 2 H, OCH2CH3), 5.32 (s, 1 H, CH), 6.61–7.31
(m, 9 H, Harom), 10.75 (br. s, 1 H, NH, exchangeable with D2O).
= 1.22 (t, 3 H,
MS (EI ): m/z (%) = 296 (40.06) [M+].
MS (EI ): m/z (%) = 312 (100) [M+].
5-(4-Fluorophenyl)-1-phenylhydantoin (3e)
5-(4-Fluorophenyl)-1-phenylthiohydantoin (3m)
IR (Nujol): 3200, 2980, 1755, 1695 cm–1.
IR (Nujol): 3188, 2995, 1770, 1185 cm1.
1H NMR (250 MHz, CDCl3–DMSO-d6): = 5.47 (s, 1 H, CH), 7.0–
7.42 (m, 9 H, Harom), 10.92 (br. s, 1 H, NH, exchangeable with D2O).
MS (EI ): m/z (%) = 270 (71.58) [M+], 271 (100) [M + H+].
1H NMR (300 MHz, CDCl3–DMSO-d6): = 5.25 (s, 1 H, CH),
7.08–7.51 (m, 9 H, Harom), 10.66 (br. s, 1 H, NH, exchangeable with
D2O).
5-(4-Chlorophenyl)-1-phenylhydantoin (3f)
5-(4-Chlorophenyl)-1-phenylthiohydantoin (3n)
IR (Nujol): 3150, 2975, 1760, 1690 cm–1.
IR (Nujol): 3150, 3005, 1800, 1182 cm–1.
1H NMR (300 MHz, CDCl3–DMSO-d6): = 5.25 (s, 1 H, CH),
7.23–7.44 (m, 9 H, Harom), 11.22 (br. s, 1 H, NH, exchangeable with
D2O).
1H NMR (250 MHz, DMSO-d6): = 5.30 (s, 1 H, CH), 7.25–7.55
(m, 9 H, Harom), 10.75 (br. s, 1 H, NH, exchangeable with D2O).
MS (EI ): m/z (%) = 302 (36.75) [M+], 303 (100) [M + H+].
5-(4-Bromophenyl)-1-phenylhydantoin (3g)
5-(4-Bromophenyl)-1-phenylthiohydantoin (3o)
IR (Nujol): 3155, 2975, 1755, 1690 cm–1.
IR (Nujol): 3158, 2971, 1758, 1195 cm–1.
1H NMR (300 MHz, CDCl3–DMSO-d6): = 5.31 (s, 1 H, CH),
7.25–7.60 (m, 9 H, Harom), 11.12 (br. s, 1 H, NH, exchangeable with
D2O).
13C NMR (200 MHz, DMSO-d6): = 171.4 (C2), 154.8 (C4), 136.3
(C1”), 133.2 (C5’), 131.7 (C3’), 129.1 (C2’, C6’), 128.6 (C3”, C5”),
124.1 (C4’, C4”), 121.9 (C1’), 120.6 (C2”, C6”), 63.7 (C5).
1H NMR (250 MHz, CDCl3–DMSO-d6): = 5.22 (s, 1 H, CH),
7.17–7.65 (m, 9 H, Harom), 11.11 (br. s, 1 H, NH, exchangeable with
D2O).
MS (EI ): m/z (%) = 347 (100) [M+].
5-(4-Nitrophenyl)-1-phenylthiohydantoin (3p)
IR (Nujol): 3152, 2975, 1735, 1177 cm–1.
5-(4-Nitrophenyl)-1-phenylhydantoin (3h)
1H NMR (250 MHz, DMSO-d6): = 5.52 (s, 1 H, CH), 7.20–8.35
(m, 9 H, Harom), 11.10 (br. s, 1 H, NH, exchangeable with D2O).
MS (EI ): m/z (%) = 313 (42.62) [M+], 314 (100) [M + H+].
IR (Nujol): 3160, 2975, 1755, 1695 cm–1.
1H NMR (300 MHz, DMSO-d6): = 6.20 (s, 1 H, CH), 7.02–7.07
(t, 1 H, Harom), 7.25–7.30 (t, 2 H, Harom), 7.47–7.49 (d, 2 H, Harom),
7.65–7.68 (d, 2 H, Harom), 8.16–8.20 (d, 2 H, Harom), 11.55 (br. s, 1
H, NH, exchangeable with D2O).
Acknowledgement
1,5-Diphenylhiohydantoin (3i)
Financial support from UGC, New Delhi and JRF to MG is grate-
fully acknowledged. We thank RSIC, CDRI Lucknow for recording
NMR and mass spectral data.
IR (Nujol): 3195, 2995, 1748, 1182 cm–1.
1H NMR (300 MHz, DMSO-d6): = 5.59 (s, 1 H, CH), 7.31-7.50
(m, 10 H, Harom), 11.00 (br. s, 1 H, NH, exchangeable with D2O).
References
5-(4-Methylphenyl)-1-phenylthiohydantoin (3j)
IR (Nujol): 3175, 2980, 1750, 1178 cm–1.
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Synthesis 2002, No. 1, 75–78 ISSN 0039-7881 © Thieme Stuttgart · New York