Synthesis of thiohydantoins by phosphine-catalyzed reaction of thioureas with arylpropiolates

Article abstract of DOI:10.1055/s-2008-1032024

A simple and efficient method for constructing thiohydantoin heterocycles using a phosphine-catalyzed tandem umpolung addition and intramolecular cyclization of thioureas on arylpropiolates is described. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1032024

PAPER
417
Synthesis of Thiohydantoins by Phosphine-Catalyzed Reaction of Thioureas
with Arylpropiolates
Synthesis of
T
hiohyda
i
ntoins chael Carboni, Jean-Marie Gomis, Olivier Loreau,* Frédéric Taran*
Service de Chimie Bioorganique et de Marquage (SCBM), Institut de Biologie et de Technologies de Saclay (IBITECS),
Direction des Sciences du Vivant (DSV), Commissariat à l’Energie Atomique (CEA), Gif-sur-Yvette 91191, France
Fax +33(1)69087991; E-mail: frederic.taran@cea.fr
Received 15 October 2007; revised 25 October 2007
to sulfur heterocycles. Among the tested pronucleophiles,
Abstract: A simple and efficient method for constructing thiohy-
dantoin heterocycles using a phosphine-catalyzed tandem umpo-
lung addition and intramolecular cyclization of thioureas on
arylpropiolates is described.
aryl or cyclic thioureas were found to react with arylpro-
piolates through an a-S-addition reaction and subsequent
N-cyclization leading to (Z)-2-iminothiazolidin-4-ones
derivatives 1 (Scheme 1, path A in Scheme 2).
Key words: thioureas, alkynes, catalysis, phosphines
Ar
CO2Et
R
Small heterocyclic molecules are one of the predominant
types of building block in medicinal chemistry.1 New
methods allowing simple and straightforward preparation
of substituted heterocycles are powerful tools for explor-
ing chemical diversity around a pharmacophoric core and
therefore need to be developed. Among the ‘drug-like’
heterocycles, hydantoins and thiohydanthoins have been
widely used for constructing products with pharmaceuti-
cal applications. Their reported biological activities (anti-
cancer, anticonvulsant, antimuscarinic, antiulcer, anti-
arrythmic and schistosomicidal)2 are largely influenced
by the different constituents that are attached to the het-
erocyclic part. For this reason, there is a lot of interest in
developing new strategies for the straightforward synthe-
sis of substituted hydantoins and thiohydantoins.
S
HN
N
Bu3P
R
R
R
N
H
N
S
S
R
R
N
N
H
H
Bu
Bu
Bu
Bu
Bu
Bu
P
P
Ar
CO2Et
Path B
Ar
CO2Et
Path A
α-S-addition
H transfer
α-N-addition
H transfer
N
R
R
R
S
Ar
S
Ar
N
N
N
R
Bu
Bu
Bu
Bu
P
OEt
P
OEt
In continuation of our efforts directed toward the synthe-
sis of heterocyclic compounds using organocatalyzed re-
actions,3 we describe herein an efficient and practical one-
pot preparation of 5-arylidene-2-thiohydantoins 2. These
heterocyclic molecules are known to display interesting
biological activities in the areas of antimycobacterial,4
antiviral5 and anticonvulsant indications.6 The classical
method for their synthesis needs two steps and involves
the preparation of the thiohydantoin moiety followed by a
Knoevenagel condensation with aldehydes.7
O
O
Bu
Bu
cyclization
Bu3P
cyclization
Bu3P
R
N
S
R
Ar
S
N
R
N
N
Ar
(Z)-1
R
O
O
(E)-2
thiohydantoins
In a recent work,3b we have described a Bu3P-catalyzed
tandem umpolung addition and intramolecular cyclization
of bifunctional pronucleophiles on arylpropiolates leading
iminothiazolidinones
Scheme 2 Proposed routes to heterocycles 1 and 2
S
N
S
Ar
Bu3P (cat.)
Ar
Ar
+
COOEt
N
H
N
H
N
1
Ar
O
Scheme 1 Bu3P catalyzed reaction of aromatic thioureas with arylpropiolates
SYNTHESIS 2008, No. 3, pp 0417–0424
x
x
.
x
x
.2
0
0
7
Advanced online publication: 10.01.2008
DOI: 10.1055/s-2008-1032024; Art ID: Z24007SS
© Georg Thieme Verlag Stuttgart · New York

418
M. Carboni et al.
PAPER
We envisioned that, depending on the nature of the thio-
urea, another reactivity profile might be observed. Indeed,
thioureas displaying low level of SH tautomeric form
(e.g., alkylthioureas) should undergo a-N- rather than a-
S-addition on arylpropiolates under Bu3P catalysis
(Scheme 2, path B). The resulting umpolung a-N-adduct
might then undergo N-cyclization resulting in the forma-
tion of thiohydantoin 2.
To test the feasibility of this reaction, dialkylthioureas
were reacted with ethyl phenylpropiolate in the presence
of Bu3P. To our delight, the reaction was found to work in
the desired pathway and afforded the thiohydantoin het-
erocycle in moderate yield at room temperature (Table 1,
entries 1 and 2). Yields might be improved by elevating
the temperature (Table 1, entry 3) and by adding slowly
the activated alkyne in the solution, the optimum dosage
rate being 0.33 equivalent per hour (Table 1, entry 4). The
reaction seems however to be limited to nonhindered thio-
ureas: replacing dimethylthiourea by diethylthiourea
dropped the yield from 76% to 47%, only 15% of desired
product were observed with dibutylthiourea and no reac-
tion at all occurred with diisopropylthiourea (Table 1, en-
tries 4–7). No side product resulting from a-S-addition or
noncyclized a-N-adducts was observed; in the case of un-
successful reactions the starting alkyne was mostly recov-
ered unchanged. These observations demonstrated the
chemoselectivity of the reaction toward a-N- over a-S-ad-
dition when dialkylthioureas are used and let suppose that
this a-N-addition is the limiting step of the process and do
not tolerate bulky groups near the nitrogen atom.
Figure 1 ORTEP diagram showing the crystal structure of com-
pound 2a with atomic numbering scheme for non-H atoms only
uously assigned by comparison to published NMR data
and further proven by X-ray crystallography (Figure 1).8
We thus used this reaction to prepare a range of 5-
arylidene-2-thiohydantoins 3 and 4 by employing a panel
of dissymmetric thioureas as starting materials. Taking
into account the dramatic steric effect on the efficiency of
the a-N-addition step, we planned to carry out the synthe-
sis of thiohydantoins by employing dissymmetric thio-
ureas that bear only one bulky moiety. Such substrates
should undergo a-N-addition specifically with the less
hindered nitrogen atom and therefore should generate
only one regioisomer.
In contrast to the formation of iminothiazolidinones 1, the
phosphine elimination step generates pure E-isomers of
products 2 as the most thermodynamic stable isomers
(Scheme 2). The structure of compound 2a was unambig-
This assumption was confirmed by the results obtained
with 15 thiourea substrates that were reacted with ethyl
phenylpropiolate in the optimized conditions (Table 2).
As expected, only one regioisomer, 3, was obtained when
dialkylthioureas bearing one methyl group on one side
and a more bulky group on the other were used (Table 2,
entries 1–5), although some exceptions were observed
(Table 2, entries 6–8).
Table 1 Optimization of the Reaction
S
R
R
R
N
H
N
H
S
N
The reaction might also be successfully used with aryla-
lkylthioureas. For these substrates again, no trace of prod-
uct resulting from a-S-addition was observed. The
nitrogen atom bearing aryl group participates well to the
a-N-addition step and, depending on the size of the alkyl
group, this participation can be exclusive (Table 2, entries
13, 14).
(1.1 equiv)
N
CO2Et
R
Bu3P (20 mol%)
O
Entry R
Conditions
Alkyne
dosage rate
ProductYielda
(%)
1
2
3
4
5
6
7
Me
i-PrOH, 25 °C, 4 h
toluene, 25 °C, 4 h
toluene, 90 °C, 4 h
toluene, 90 °C, 4 h
toluene, 90 °C, 4 h
toluene, 90 °C, 4 h
toluene, 90 °C, 4 h
–
2a
2a
2a
2a
2b
2c
2d
48
46
56
76
47
15
n.d.
All the products were fully characterized and their struc-
ture established by NOESY experiments as well as by
comparison to published 1H and 13C NMR data.7
Me
Me
Me
Et
–
–
The presented methodology appeared to be applicable for
a variety of thiourea substrates affording a straightforward
route to 5-arylidene-2-thiohydantoins, although mixture
of regioisomers might be obtained for thioureas present-
ing no sufficient dissymmetry. There is indeed a competi-
tion in the a-N-addition step between the two nitrogen
atoms of the thiourea reagent. The reactivity of the NH
groups of the thiourea is influenced by steric hindrance,
0.33 equiv/h
0.33 equiv/h
0.33 equiv/h
0.33 equiv/h
Bu
i-Pr
a Isolated yield.
Synthesis 2008, No. 3, 417–424 © Thieme Stuttgart · New York

PAPER
Synthesis of Thiohydantoins
419
nucleophilicity, and pKa. Attempts to improve the that the reaction is trivial to run and uses readily available
chemoselectivity of the reaction by changing the experi- substrates,9 product recovery is particularly easy. After
mental conditions such as replacing toluene by i-PrOH or evaporation of the crude reaction mixture, the thiohydan-
decreasing the temperature were unsuccessful.
toins were precipitated in i-PrOH and were obtained as
pure E-isomer after simple filtration and washing. This re-
action is therefore well adapted to the preparation of li-
braries of these biologically active compounds.
Although the procedure showed some limitations (poor
yields with hindered thioureas, mixture of regioisomers
for certain substrates), it presents many practical advan-
tages over previous reported methods. Besides the fact
Table 2 Phosphate-Catalyzed Reaction of Thioureas with Arylpropiolates Leading to Thiohydantoin Derivativesa
S
R
R'
R'
N
R
N
H
N
H
S
S
N
(1.1 equiv)
+
N
CO2Et
N
Bu3P (20 mol%)
toluene, 90 °C, 4 h
R
R'
O
O
4
3
Entry
1
R
R¢
Product(s)
Ratiob 3/4 Yield (%)c
S
N
Me
Bu
100:0
53
N
O
3a
S
N
2
3
Me
Me
Bn
100:0
100:0
73
45
N
N
N
O
3b
S
N
i-Pr
O
3c
S
N
4
5
Me
Me
100:0
100:0
68
53
O
3d
S
N
N
O
3e
N
S
S
N
N
6
Me
80:20
65
N
N
N
+
N
O
O
3f
4f
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420
M. Carboni et al.
PAPER
Table 2 Phosphate-Catalyzed Reaction of Thioureas with Arylpropiolates Leading to Thiohydantoin Derivativesa (continued)
S
R
R'
R'
N
R
N
H
N
H
S
S
N
(1.1 equiv)
+
N
CO2Et
N
Bu3P (20 mol%)
toluene, 90 °C, 4 h
R
R'
O
O
4
3
Entry
7
R
R¢
Product(s)
Ratiob 3/4 Yield (%)c
O
S
S
N
N
Me
80:20
85:15
73
73
O
N
N
+
O
O
O
3g
4g
MeO
S
S
N
N
OMe
8
Me
N
+
N
O
O
MeO
3h
4h
S
N
S
N
9
Me
Ph
70:30
67
N
+
N
O
O
3i
4i
MeO
S
S
S
N
10
Me
S
S
S
60:40
69
N
N
N
MeO
N
N
N
+
N
N
N
O
O
OMe
3j
4j
N
11
Bu
Ph
25:75
40
+
O
O
3k
4k
N
12
Bn
Ph
30:70
44
+
O
O
3l
4l
Synthesis 2008, No. 3, 417–424 © Thieme Stuttgart · New York

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Synthesis of Thiohydantoins
421
Table 2 Phosphate-Catalyzed Reaction of Thioureas with Arylpropiolates Leading to Thiohydantoin Derivativesa (continued)
S
R
R'
R'
N
R
N
H
N
H
S
S
N
(1.1 equiv)
+
N
CO2Et
N
Bu3P (20 mol%)
toluene, 90 °C, 4 h
R
R'
O
O
4
3
Entry
13
R
R¢
Product(s)
Ratiob 3/4 Yield (%)c
S
N
i-Pr
Ph
0:100
39
N
O
4m
MeO
S
14
0:100
51
N
MeO
N
O
4n
a Alkyne (1 equiv) was added dropwise over 3 h (dosage rate = 0.33 equiv/h).
b Ratios were determined after precipitation.
c Total isolated yield.
1,3-Dimethyl-5-[(E)-1-phenylmethylidene]-2-thioxoimidazoli-
din-4-one (2a)
Yellow solid; mp 140–142 °C.
In conclusion, we have developed a simple and practical
method for the preparation of arylidenethiohydantoin het-
erocycles via Bu3P-catalyzed tandem a-N-addition and
intramolecular N-cyclization of thioureas on arylpropi-
olates. This strategy offers a new and straightforward way
for constructing this type of heterocycles and, by its prac-
tical aspects, has potential application in combinatorial
chemistry.
IR (KBr): 3089, 2922, 1960, 1892, 1716, 1619, 1568, 1482, 1389,
1141, 1092, 1046, 752, 683, 566 cm–1.
1HNMR (400 MHz, CDCl3): d = 7.98 (m, 2 H), 7.45–7.35 (m, 3 H),
6.44 (s, 1 H), 3.57 (s, 3 H), 3.34 (s, 3 H).
13CNMR (100 MHz, CDCl3): d = 177.1, 161.5, 131.9, 130.7, 129.9,
129, 128.3, 120.6, 30.5, 28.1.
MS (ESI): m/z = 233 [M + H]+.
All reagents were used directly as obtained commercially unless
otherwise noted. Melting points were determined on a Büchi 535
capillary melting point apparatus and are uncorrected. Flash chro-
matography was carried out on Merck silica gel (40–63 mm). IR
spectra were obtained on a PerkinElmer system 2000 FT-IR spec-
HRMS: m/z calcd for C12H12N2OS + Na: 255.0568; found:
255.0564.
1,3-Diethyl-5-[(E)-1-phenylmethylidene]-2-thioxoimidazolidin-
4-one (2b)
1
trophotometer. H NMR (400 MHz), 13C NMR (100 MHz) were
measured on a Bruker Avance 400 MHz spectrometer. Electrospray
mass spectra were obtained using an ESI/TOF Mariner mass spec-
trometer.
Yellow solid; mp 105 °C.
IR (KBr): 3092, 2981, 2934, 1958, 1902, 1766, 1717, 1617, 1572,
1470, 1388, 1313, 1268, 1184, 1136, 1111, 1068, 1020, 928, 883,
837, 753, 687 cm–1.
1HNMR (400 MHz, CDCl3): d = 8.00 (m, 2 H), 7.45–7.35 (m, 3 H),
6.49 (s, 1 H), 4.21 (q, J = 6.8 Hz, 2 H), 3.99 (q, J = 6.8 Hz, 2 H),
1.40–1.20 (m, 6 H).
13C NMR (100 MHz, CDCl3): d = 175.7, 161.5, 132, 130.7, 129.8,
128.3, 127.7, 119.9, 38.3, 36.8, 13, 12.0.
MS: m/z = 261 [M + H]+.
Bu3P-Catalyzed Construction of Thiohydantoins; Typical Pro-
cedure
A mixture of 1,3-disubstituted thiourea (5 mmol, 1.1 equiv) and
Bu3P (250 mL, 0.2 equiv) in anhyd toluene (5 mL) was heated at
90 °C under argon. Ethyl phenylpropiolate (5 mmol, 1 equiv) in an-
hyd toluene (5 mL) was added dropwise over 3 h (syringe pump,
0.33 equiv/h). After the addition, the mixture was heated for 1 h and
then concentrated under reduced pressure. The residue was precip-
itated by the addition of EtOH, recovered by filtration, and washed
with i-PrOH to afford the desired product as the pure E-isomer.
HRMS: m/z calcd for C14H16N2OS + Na: 283.0881; found:
283.0870.
Synthesis 2008, No. 3, 417–424 © Thieme Stuttgart · New York

422
M. Carboni et al.
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1,3-Dibutyl-5-[(E)-1-phenylmethylidene]-2-thioxoimidazolidin-
4-one (2c)
The title compound was purified by flash chromatography (hexane–
CH2Cl2, 7:3); yellow oil.
1HNMR (400 MHz, CDCl3): d = 7.96 (m, 2 H), 7.45–7.35 (m, 3 H),
6.46 (s, 1 H), 4.69 (m, 1 H), 3.61 (s, 3 H), 2.40–2.25 (m, 2 H), 1.90–
1.60 (m, 5 H), 1.45–1.15 (m, 3 H).
13CNMR (100 MHz, CDCl3): d = 177.3, 161.5, 131.9, 130.7, 129.7,
IR (film): 2959, 2933, 2872, 1727, 1656, 1622, 1573, 1402, 1293,
1220, 1084, 970, 753, 690, 569 cm–1.
1HNMR (400 MHz, CDCl3): d = 7.98 (m, 2 H), 7.45–7.35 (m, 3 H),
6.48 (s, 1 H), 4.14 (t, J = 7.6 Hz, 2 H), 3.92 (t, J = 7.6 Hz, 2 H),
1.85–1.65 (m, 4 H), 1.46 (m, 2 H), 1.37 (m, 2 H), 1.01 (t, J = 7.6 Hz,
3 H), 0.95 (t, J = 7.6 Hz, 3 H).
129.4, 128.3, 119.8, 55.9, 31.0, 28.6, 28.5, 25.9, 25.0.
MS (ESI): m/z = 301 [M + H]+.
HRMS: m/z calcd for C17H20N2OS + Na: 323.1194; found:
323.1201.
3-Allyl-1-methyl-5-[(E)-1-phenylmethylidene]-2-thioxoimida-
zolidin-4-one (3e)
13C NMR (100 MHz, CDCl3): d = 176.4, 161.7, 132, 130.7, 129.7,
128.3, 128, 119.9, 43.2, 41.7, 29.8, 29, 20.06, 20.03, 13.8, 13.7.
Yellow solid; mp 147–149 °C.
MS (ESI): m/z = 339 [M + Na]+.
IR (KBr): 3092, 3067, 1723, 1621, 1474, 1412, 1378, 1227, 1178,
1093, 929, 887, 751, 688 cm–1.
3-Butyl-1-methyl-5-[(E)-1-phenylmethylidene]-2-thioxoimida-
zolidin-4-one (3a)
Yellow solid; mp 117–119 °C.
1HNMR (400 MHz, CDCl3): d = 8.00 (m, 2 H), 7.45–7.35 (m, 3 H),
6.49 (s, 1 H), 5.88 (m, 1 H), 5.35–5.2 (m, 2 H), 4.56 (d, J = 5.6 Hz,
2 H), 3.62 (s, 3 H).
IR (KBr): 3071, 2959, 2869, 1722, 1623, 1570, 1475, 1388, 1316,
1220, 1141, 1095, 926, 881, 832, 748, 685, 521 cm–1.
1HNMR (400 MHz, CDCl3): d = 7.99 (m, 2 H), 7.45–7.35 (m, 3 H),
6.47 (s, 1 H), 3.93 (t, J = 7.6 Hz, 2 H), 3.61 (s, 3 H) 1.69 (m, 2 H),
1.37 (m, 2 H), 0.95 (t, J = 7.6 Hz, 3 H).
13CNMR (100 MHz, CDCl3): d = 176.4, 161.1, 131.9, 130.8, 130.7,
129.9, 129, 128.4, 120.7, 118.5, 43.9, 30.5.
MS (ESI): m/z = 259 [M + H]+.
HRMS: m/z calcd for C14H14N2OS + Na: 281.0725; found:
281.0725.
13CNMR (100 MHz, CDCl3): d = 176.9, 161.5, 131.9, 130.7, 129.8,
129.1, 128.3, 120.3, 41.8, 30.4, 29.8, 20.0, 13.7.
MS (ESI): m/z = 275 [M + H]+.
1-Methyl-5-[(E)-1-phenylmethylidene]-3-pyridin-2-ylmethyl-2-
thioxoimidazolidin-4-one (3f) and 3-Methyl-5-[(E)-1-phenyl-
methylidene]-1-pyridin-2-ylmethyl-2-thioxoimidazolidin-4-one
(4f)
The title compounds were obtained by precipitation as a mixture
(3f/4f = 80:20); yellow solid.
1H NMR (400 MHz, CDCl3): d = 8.59 (d, J = 4.8 Hz, 0.25 H, 4f),
8.54 (d, J = 4.8 Hz, 1 H, 3f), 8.02 (m, 2 H, 3f), 7.91 (m, 0.5 H, 3f),
7.70–7.60 (m, 1.25 H, 3f and 4f), 7.45–7.1 (m, 6.25 H, 3f and 4f),
6.76 (s, 0.25 H, 4f), 6.52 (s, 1 H, 3f), 5.54 (s, 0.5 H, 4f), 5.29 (s, 2
H, 3f), 3.63 (s, 3 H, 3f), 3.43 (s, 0.75 H, 4f).
HRMS: m/z calcd for C15H18N2OS + Na: 297.1038; found:
297.1029.
3-Benzyl-1-methyl-5-[(E)-1-phenylmethylidene]-2-thioxoimi-
dazolidin-4-one (3b)
Yellow solid; mp 184–186 °C.
IR (KBr): 3065, 2942, 1710, 1616, 1570, 1473, 1431, 1413, 1377,
1327, 1221, 1087, 753, 706, 684, 516 cm–1.
1HNMR (400 MHz, CDCl3): d = 8.00 (m, 2 H), 7.51 (d, J = 6.8 Hz,
MS (ESI): m/z = 310 [M + H]+ (3f and 4f).
2 H), 7.45–7.25 (m, 6 H), 6.49 (s, 1 H), 5.14 (s, 2 H), 3.63 (s, 3 H).
13CNMR (100 MHz, CDCl3): d = 176.7, 161.4, 135.8, 131.9, 130.7,
129.9, 129, 128.8, 128.4, 128.3, 127.8, 120.7, 45.1, 30.6.
MS (ESI): m/z = 309 [M + H]+.
3-Furan-2-ylmethyl-1-methyl-5-[(E)-1-phenylmethylidene]-2-
thioxoimidazolidin-4-one (3g) and 1-Furan-2-ylmethyl-3-meth-
yl-5-[(E)-1-phenylmethylidene]-2-thioxoimidazolidin-4-one
(4g)
The title compounds were obtained by precipitation as a mixture
(3g/4g = 80:20); yellow solid.
HRMS: m/z calcd for C18H16N2OS + Na: 331.0881; found:
331.0883.
1H NMR (400 MHz, CDCl3): d = 8.05–7.95 (m, 2.5 H, 3g and 4g),
7.45–7.3 (m, 5 H, 3g and 4g), 6.83 (s, 0.25 H, 4g), 6.50 (s, 1 H, 3g),
6.45–6.4 (m, 1.25 H, 3g and 4g), 6.35 (dd, J = 3.2, 1.6 Hz, 0.25 H,
4g), 6.31 (dd, J = 3.2, 1.6 Hz, 1 H, 3g), 5.40 (s, 0.5 H, 4g), 5.15 (s,
2 H, 3g), 3.62 (s, 3 H, 3g), 3.39 (s, 0.75 H, 4g).
3-Isopropyl-1-methyl-5-[(E)-1-phenylmethylidene]-2-thioxo-
imidazolidin-4-one (3c)
Yellow solid; mp 152–153 °C.
IR (KBr): 2987, 2974, 2933, 1724, 1621, 1474, 1415, 1396, 1351,
1247, 1122, 1082, 1059, 929, 833, 753, 689 cm–1.
1HNMR (400 MHz, CDCl3): d = 7.96 (m, 2 H), 7.45–7.35 (m, 3 H),
6.47 (s, 1 H), 5.09 (sept, J = 7 Hz, 1 H), 3.61 (s, 3 H), 1.50 (d,
J = 7.2 Hz, 6 H).
13CNMR (100 MHz, CDCl3): d = 177.1, 161.5, 131.9, 130.7, 129.7,
129.4, 128.3, 119.9, 48.1, 30.9, 19.1.
MS (ESI): m/z = 299 [M + H]+ (3g and 4g).
3-(4-Methoxybenzyl)-1-methyl-5-[(E)-1-phenylmethylidene]-2-
thioxoimidazolidin-4-one (3h) and 1-(4-Methoxybenzyl)-3-
methyl-5-[(E)-1-phenylmethylidene]-2-thioxoimidazolidin-4-
one (4h)
The title compounds were obtained by precipitation as a mixture
(3h/4h = 85:15); yellow solid.
MS (ESI): m/z = 261 [M + H]+.
HRMS: m/z calcd for C14H16N2OS + Na : 283.0881; found:
283.0889.
1H NMR (400 MHz, CDCl3): d = 8.00 (m, 2 H, 3h), 7.88 (m, 0.4 H,
4h), 7.49 (d, J = 8.8 Hz, 2 H, 3h), 7.45–7.32 (m, 3.6 H, 3h and 4h),
7.26 (d, J = 8.8 Hz, 0.4 H, 4h), 6.89 (d, J = 8.8 Hz, 0.4 H, 4h), 6.83
(d, J = 8.8 Hz, 2 H, 3h), 6.48 (s, 0.2 H, 4h), 6.45 (s, 1 H, 3h), 5.36
(s, 0.4 H, 4h), 5.08 (s, 2 H, 3h), 3.79 (s, 0.6 H, 4h), 3.77 (s, 3 H, 3h),
3.59 (s, 3 H, 3h), 3.43 (s, 0.6 H, 4h).
3-Cyclohexyl-1-methyl-5-[(E)-1-phenylmethylidene]-2-thioxo-
imidazolidin-4-one (3d)
Yellow solid; mp 174–176 °C.
IR (KBr): 2923, 2857, 1721, 1621, 1571, 1473, 1414, 1394, 1361,
1228, 1181, 1146, 1097, 1080, 752, 688, 534 cm–1.
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Synthesis of Thiohydantoins
423
13C NMR (100 MHz, CD2Cl2): d = 177.8 (4h), 176.7 (3h), 161.6
(4h), 161.4 (3h), 159.2, 132.2 (3h), 132.1 (4h), 130.7, 130.1, 129.7,
129.1, 128.9, 128.3, 128.26, 128.23, 128.16, 128.1, 127.8, 126.9,
125.2, 121.1 (4h), 120.4 (3h), 114.2 (4h), 113.6 (3h), 55.2 (4h),
55.1 (3h), 46.5 (4h), 44.5 (3h), 30.5 (3h), 28.2 (4h).
IR (KBr): 3064, 3030, 1727, 1627, 1594, 1501, 1453, 1442, 1404,
1364, 1303, 1259, 1123, 1047, 1023, 931, 878, 840, 757, 737, 693
cm–1.
1H NMR (400 MHz, CDCl3): d = 7.89 (m, 2 H), 7.60–7.30 (m, 13
H), 6.56 (s, 1 H), 5.54 (s, 2 H).
MS (ESI): m/z = 339 [M + H]+ (3h and 4h).
13CNMR (100 MHz, CDCl3): d = 177.2, 161.3, 134.7, 133.3, 131.7,
130.9, 130, 129.2, 129.1, 129, 128.4, 128.3, 128, 127.5, 127, 122.1,
47.6.
1-Methyl-3-phenyl-5-[(E)-1-phenylmethylidene]-2-thioxoimi-
dazolidin-4-one (3i) and 3-Methyl-1-phenyl-5-[(E)-1-phenyl-
methylidene]-2-thioxoimidazolidin-4-one (4i)
MS (ESI): m/z = 371 [M + H]+.
The title compounds were obtained by precipitation as a mixture
(3i/4i = 70:30); yellow solid.
1HNMR (400 MHz, CDCl3): d = 8.00 (m, 2 H, 3i), 7.91 (m, 0.85 H,
4i), 7.65–7.30 (m, 11.4 H, 3i and 4i), 6.59 (s, 1 H, 3i), 6.20 (s, 0.4
H, 4i), 3.72 (s, 3 H, 3i), 3.48 (s, 1.25 H, 4i).
13C NMR (100 MHz, CDCl3): d = 177.2 (4i), 176.6 (3i), 161.4 (4i),
161.2 (3i), 134.9, 133.2, 131.8, 130.9, 130.8, 130, 129.7, 129.25,
129.13, 129.06, 128.8, 128.41, 128.37, 128.32, 122.1 (4i), 121.1
(3i), 30.8 (3i), 28.2 (4i).
3-Benzyl-1-phenyl-5-[(E)-1-phenylmethylidene]-2-thioxoimi-
dazolidin-4-one (4l)
Precipitation gave a mixture of 3l/4l (30:70). A pure analytical sam-
ple of the title compound 4l was obtained by flash chromatography
(hexane–CH2Cl2, 50:50); yellow solid; mp 141–142 °C.
IR (KBr): 3059, 2360, 1726, 1622, 1593, 1497, 1452, 1423, 1397,
1378, 1303, 1282, 1147, 1061, 1027, 990, 929, 882, 759, 733, 691
cm–1.
1HNMR (400 MHz, CDCl3): d = 7.90 (m, 2 H), 7.65–7.50 (m, 5 H),
MS (ESI): m/z = 295 [M + H]+ (3i and 4i).
7.45–7.30 (m, 8 H), 6.20 (s, 1 H), 5.25 (s, 2 H).
13CNMR (100 MHz, CDCl3): d = 176.7, 161.2, 135.8, 134.9, 131.8,
130.85, 130.79, 130, 129.7, 129.3, 129.2, 128.5, 128.3, 127.9,
122.2, 45.2.
3-(4-Methoxyphenyl)-1-methyl-5-[(E)-1-phenylmethylidene]-2-
thioxoimidazolidin-4-one (3j) and 3-(4-Methoxyphenyl)-1-
methyl-5-[(E)-1-phenylmethylidene]-2-thioxoimidazolidin-4-
one (4j)
The title compounds were obtained by precipitation as a mixture
(3j/4j = 60:40); yellow solid.
1H NMR (400 MHz, CDCl3): d = 8.02 (m, 2 H, 3j), 7.93 (m, 1.4 H,
4j), 7.45–7.35 (m, 5.1 H, 3j and 4j), 7.27 (d, J = 8.8 Hz, 3.4 H, 3j
and 4j), 7.09 (d, J = 8.8 Hz, 1.4 H, 4j), 7.01 (d, J = 8.8 Hz, 2 H, 3j),
6.57 (s, 1 H, 3j), 6.21 (s, 0.7 H, 4j), 3.89 (s, 2.1 H, 4j), 3.84 (s, 3 H,
3j), 3.70 (s, 3 H, 3j), 3.46 (s, 2.1 H, 4j).
13CNMR (100 MHz, CDCl3): d = 177.5 (4j), 177 (3j), 161.4 (2-2j),
161.39 (3j), 160.2 (4j), 159.8 (3j), 131.89, 131.86, 131, 130.9,
130.8, 130.3, 129.99, 129.98, 129.5, 128.9, 128.4, 128.3, 127.2,
125.7, 122.2 (4j), 121 (3j), 115.2 (4j), 114.4 (3j), 55.5 (4j), 55.4
(3j), 30.8 (3j), 28.2 (4j).
MS (ESI): m/z = 371 [M + H]+.
3-Isopropyl-1-phenyl-5-[(E)-1-phenylmethylidene]-2-thioxo-
imidazolidin-4-one (4m)
Yellow solid; mp 168–170 °C.
IR (KBr): 3049, 2976, 2937, 1723, 1625, 1593, 1571, 1497, 1452,
1396, 1337, 1151, 1088, 1069, 921, 851, 752, 686 cm–1.
1HNMR (400 MHz, CDCl3): d = 7.91 (m, 2 H), 7.65–7.50 (m, 3 H),
7.45–7.30 (m, 5 H), 6.19 (s, 1 H), 5.21 (sept, J = 6.8 Hz, 1 H), 1.63
(d, J = 6.8 Hz, 6 H).
13C NMR (100 MHz, CDCl3): d = 177, 161.3, 135.2, 131.8, 131,
130.8, 129.9, 129.8, 129.6, 129.2, 128.2, 121.4, 58.2, 48.2, 19, 18.3.
MS (ESI): m/z = 323 [M + H]+.
MS (ESI): m/z = 325 [M + H]+ (3j and 4j).
HRMS: m/z calcd for C19H18N2OS + Na : 345.1038; found:
345.1049.
1-Butyl-3-phenyl-5-[(E)-1-phenylmethylidene]-2-thioxoimida-
zolidin-4-one (3k) and 3-Butyl-1-phenyl-5-[(E)-1-phenylmeth-
ylidene]-2-thioxoimidazolidin-4-one (4k)
3-Cyclohexyl-1-(4-methoxyphenyl)-5-[(E)-1-phenylmeth-
ylidene]-2-thioxoimidazolidin-4-one (4n)
Yellow solid; mp 202–204 °C.
The title compounds were obtained by precipitation as a mixture
(3k/4k = 25:75); yellow solid.
1H NMR (400 MHz, CDCl3): d = 8.00 (m, 0.7 H, 3k), 7.90 (m, 2 H,
4k), 7.65–7.30 (m, 10.8 H, 3k and 4k), 6.59 (s, 0.35 H, 3k), 6.17 (s,
1 H, 4k), 4.22 (t, J = 7.6 Hz, 0.7 H, 3k), 4.01 (t, J = 7.6 Hz, 2 H, 4k),
1.85–1.70 (m, 2.7 H, 3k and 4k), 1.55–1.35 (m, 2.7 H, 3k and 4k),
1.03 (t, J = 7.6 Hz, 1.05 H, 3k), 0.97 (t, J = 7.6 Hz, 3H, 4k).
13CNMR (100 MHz, CDCl3): d = 176.9 (4k), 176.1 (3k), 161.3 (3k
and 4k), 134.9, 133.2, 131.8, 130.9, 130.8, 130, 129.9, 129.6, 129.3,
129.07, 129.01, 128.4, 128.31, 128.28, 127.8, 121.9 (4k), 120.7
(3k),43.6 (3k), 41.8 (4k), 29.7 (4k), 28.9 (3k), 20.13 (4k), 20.09
(3k), 13.8 (3k), 13.7 (4k).
IR (KBr): 3072, 3014, 2918, 2850, 1719, 1625, 1585, 1511, 1462,
1446, 1396, 1320, 1247, 1147, 1047, 1023, 926, 885, 835, 756, 688
cm–1.
1HNMR (400 MHz, CDCl3): d = 7.90 (m, 2 H), 7.40–7.30 (m, 3 H),
7.27 (d, J = 8.8 Hz, 2 H), 7.09 (d, J = 8.8 Hz, 2 H), 6.17 (s, 1 H),
4.79 (m, 1 H), 3.89 (s, 3 H), 2.50–2.35 (m, 2 H), 1.95–1.80 (m, 4 H),
1.70 (m, 1 H), 1.45–1.20 (m, 3 H).
13CNMR (100 MHz, CDCl3): d = 177.6, 161.4, 160.1, 131.9, 131.2,
130.8, 130.3, 129.7, 128.2, 127.7, 121.4, 115.2, 56, 55.5, 28.5, 26,
25.1.
MS (ESI): m/z = 337 [M + H]+.
MS (ESI): m/z = 393 [M + H]+.
HRMS: m/z calcd for C23H24N2O2S + Na: 415.1456; found:
415.1467.
1-Benzyl-3-phenyl-5-[(E)-1-phenylmethylidene]-2-thioxoimi-
dazolidin-4-one (3l)
Precipitation gave a mixture of 3l/4l (30:70). An analytically pure
sample of 3l was obtained by flash chromatography (hexane–
CH2Cl2, 50:50); yellow solid; mp 186–187 °C.
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424
M. Carboni et al.
PAPER
(4) Kiec-Kononowicz, K.; Szymanska, E. Farmaco 2002, 57,
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Acknowledgment
We warmly thank Dr. A. Chiaroni from the CNRS (ICSN, Gif-sur-
Yvette, France) for the resolution of X-ray crystal structure of 2a.
We are grateful to E. Zekri and D. Buisson for experimental assi-
stance with NMR, MS, and LC/MS measurements.
(6) Mehta, N.; Risiger, C. A.; Soroko, F. E. J. Med. Chem. 1981,
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Synthesis 2008, No. 3, 417–424 © Thieme Stuttgart · New York