Synthesis of new thiohydantoin derivatives under phase transfer catalysis

Article abstract of DOI:10.1080/10426500601062007

A novel synthesis of thiohydantoin derivatives is achieved using phase transfer catalysis conditions via nucleophilic displacement of organohalogen compounds by 3-phenyl-2-thiohydantoin (1) and its arylidene derivative (5), yielding new thiohydantoin derivatives (2-9), which have pronounced biological activities and wide applications. Copyright Taylor & Francis Group, LLC.

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Phosphorus, Sulfur, and Silicon
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Synthesis of New
Thiohydantoin Derivatives
Under Phase Transfer Catalysis
M. K. Abou El-Regal a , A. A. Abdalha a , M. A. El-
Kassaby a & A. T. Ali a
a Chemistry Department , Ain Shams University ,
Abbassia, Cairo, Egypt
Published online: 24 Feb 2007.
To cite this article: M. K. Abou El-Regal , A. A. Abdalha , M. A. El-Kassaby & A. T. Ali
(2007) Synthesis of New Thiohydantoin Derivatives Under Phase Transfer Catalysis,
Phosphorus, Sulfur, and Silicon and the Related Elements, 182:4, 845-851, DOI:
10.1080/10426500601062007
To link to this article: http://dx.doi.org/10.1080/10426500601062007
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Phosphorus, Sulfur, and Silicon, 182:845–851, 2007
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500601062007
Synthesis of New Thiohydantoin Derivatives Under
Phase Transfer Catalysis
M. K. Abou El-Regal
A. A. Abdalha
M. A. El-Kassaby
A. T. Ali
Chemistry Department, Ain Shams University, Abbassia, Cairo, Egypt
A novel synthesis of thiohydantoin derivatives is achieved using phase transfer
catalysis conditions via nucleophilic displacement of organohalogen compounds by
3-phenyl-2-thiohydantoin (1) and its arylidene derivative (5), yielding new thiohy-
dantoin derivatives (2–9), which have pronounced biological activities and wide
applications.
Keywords Thiohydantoin; phase transfer catalysis; arylidene
INTRODUCTION
Phase Transfer Catalysis (PTC) is now a commercially mature disci-
pline with over 600 applications covering a wide spectrum of indus-
tries, such as pharmaceuticals, agrochemicals, perfumes, flavors, dyes,
specialty polymers, and pollution control.1−4
Moreover, the pronounced biological activities5,6 and wide
applications7−12 of thiohydantoin derivatives stimulated the authors
to synthesize new derivatives PTC alkylion13−16 of some heterocyclic
compounds were reported, which somewhat resembles our present
investigation.
RESULTS AND DISCUSSION
In our present PTC investigation, we used solid-liquid phases;17,18 the
solid phase was anhydrous potassium carbonate, and the liquid phase
was dioxane, while Tetrabutyl Ammonium Bromide (TBAB) was used as
Received June 6, 2006; accepted September 11, 2006.
Address correspondence to A. A. Abdalha, Chemistry Department, Faculty of Science,
Ain Shams University, Abbassia, Cairo, Egypt. E-mail: abdoelaal@yahoo.com
845

846
M. K. Abou El-Regal et al.
a catalyst20 in the nucleophilic displacement of some halo-compounds
by 3-phenyl-2-thiohydantoin (1) and its arylidene derivative (5). The
one-pot reaction of (1) with monohalocompounds as ethyl bromide or
benzyl chloride and carbondisulphide as a reactant and in presence
of dioxane as a solvent under PTC conditions afforded thiohydantoin
deravative (2a) and thiobenzylhydantoin derivative (2b), respectively.
On the other hand, the PTC reaction of (1) with dihalo-compounds,
namely ethylene dibromide or 1,3-dibromopropane in the presence of
CS2, yielded 1,3-dithiolidine derivative (3a) or 1,3-dithioxane deriva-
tive (3b), respectively. It was found that treatment of thiohydantoin
derivative (1) with carbon disulphide in the absence of mono or dihalo-
compounds gave bis-monopotassium salt thiohydantoindithione (4),
which implies the reactivity of the methylene group and ability for
dimerization.
In the previous examples, S- or N-alkylation was difficult to achieve
due to the presence of active methylene, which can attack carbon disul-
phide under PTC conditions. Therefore, the authors attended to block
the active methylene to enable N- or S-alkylation, and the formation
of new thiohydantoin derivatives by blocking active methylene was
achieved by condensation of 3-phenyl-2-thiohydantoin (1) with 3,4-
dimethoxybenzaldehyde in catalytic piperidine, which afforded aryli-
dene derivative (5). Alkylation of (5) with monohalocompounds, either
ethyl bromide or benzyl chloride under PTC conditions, proceeded via
S-alkylation to give thioethyl arylidene derivative (6a), or thiobenzyl
arylidene derivative (6b), respectively.
On the other hand, ally bromide alkylation proceeded via N-
alkylation, yielding arylidene derivative (7).
PTC alkylation of arylidene derivative (5) using dihalo-compounds;
namely ethylene dibromide or 1,3-dibromopropane, afforded thioalky-
lated dimers (8a) and (8b), respectively, which were produced according
to S-alkylation followed by dimerization.
Acylation of (5) using chloroacetylchloride under PTC conditions
yielded arylidene derivative salt (9), symbols, characterization, and
spectral data of prepared compounds are listed in Scheme 1, Table I,
and Table II, respectively.
CONCLUSION
From the previously discussed results, we concluded that position-5
of thiohydantoin (1) contains an active methylene group; which un-
derwent nucleophilic displacement in the presence of a base and PTC
catalyst with different electrophilic reagents as monoalkyl halides and
dialkyl halides.

Synthesis of New Thiohydantoin Derivatives
847
SCHEME 1
EXPERIMENTAL
Melting points were measured on an electrothermal melting point ap-
paratus and are uncorrected. Elemental, analyses were carried out at
the micro-analytical unit, Cairo University, Giza, Egypt. Infrared spec-
tra were measured one Unicam SP-1200 spectrometer using KBr wafer
1
technique. HNMR spectra were measured in DMSO-d6 or CDCl3 on
a Varian plus instrument (300 MHz). Mass spectra were determined
using HP model MS-5988 at electron energy 70 eV.

848
M. K. Abou El-Regal et al.
TABLE I Characterization Data of Prepared Compounds
Analysis
Calculated/Found
Compound
No.
M. P. ◦
(Color)
C
Yield %, Solvent
of Recryst.
Mol formula
(M. Wt.)
C%
H%
N%
(1)
259–60
yellow
>300
46
A
70
D
10–12
Ac
50
Pa
53
Pa
81
D
97
A
70
E
70
E
82
E
C9H8N2OS
(192.23)
56.23 4.19 14.57
56.26 4.16 14.55
(2a)
(2b)
(3a)
(3b)
(4)
C
12H10N2OS3
(294.40)
48.96 3.42
49.36 3.22
50.62 3.92
50.92 3.92
51.82 4.97
51.80 4.95
69.11 4.86
69.49 4.84
9.51
9.50
9.08
9.24
8.63
8.63
5.20
5.18
orange
239–41
brown
154–58
Yellow
96–100
Yellow
>300
Orange
190–91
Orange
121–123
Yellow
158–62
Yellow
135–37
Yellow
228–30
Yellow
296–98
Yellow
240–42
Yellow
C
13H12N2OS3
(308.44)
C14H16N2OS3
(324.48)
C31H26N2OS3
(538.75)
C19H15N2O2S4K
(498.72)
45.76 3.03 11.23
45.70 3.00 11.11
(5)
C
C
C
18H16N2O3S
(340.40)
20H20N2O3S
(368.44)
25H22N2O3S
(430.51)
63.51 4.74
63.53 4.71
65.19 5.47
65.59 5.44
69.75 5.15
70.13 5.13
66.29 5.29
66.66 5.27
64.98 5.03
64.94 5.00
64.57 4.85
64.50 4.84
52.99 4.00
52.77 4.21
8.23
8.22
7.60
7.62
6.51
6.48
7.36
7.34
7.77
7.73
7.93
7.91
6.18
6.00
(6a)
(6b)
(7)
C21H20N2O3S
(380.44)
39H36N4O6S2
(720.84)
38H34N4O6S2
(706.81)
20H18N2O4SCl2
(453.32)
(8a)
(8b)
(9)
40
D
42
D
12
A
C
C
C
A = acetic acid; D = dimethyl formamide; Ac = acetone; Pa = Pet-ether 60–80; E =
ethanol.
3-Phenyl-2-thiohydantoin (1)21–23
A mixture of phenylisothiocyanate (0.01 mole) (1.35 g) and ethyl glyci-
nate hydrochloride (0.01 mole) (1.40 g) in the presence of ammonium
acetate (0.15 mole) (1.16 g) in acetic acid (50 mL) was refluxed for 4 h.
The solid formed after cooling was collected and crystallized to give (1).
3-Phenyl-2-thiohydantoin-4-arylidene Derivative (5)
A mixture of 3-phenyl-2-thiohydantoin (1) (0.01 mol) (1.92 g), 50 mL
of ethanol, a catalytic amount of piperdine (2–3 drops), and (0.01 mol)
(1.66 g) of 3,4-dimethoxy benzaldehyde was refluxed for 2–3 h. The

Synthesis of New Thiohydantoin Derivatives
849
TABLE II IR, 1HNMR, and MS Data of Prepared Compounds
IR cm−1
Compound
No.
1HNMR (δ in ppm)
MS (m/z), %
OH
—
NH
C=O
(1)
9.1 (b, 1H), 7.41 (m,
5H), 4.34 (s, 2H)
193 (M+1, 20.3%), 192
(M+, 38.7%), 135
(2.2%), 77(100%)
325 (M + 1, 24.7%),
324 (M+, 82.3%),
192 (3.8%), 77
3145
1755
(2a)
9.16 (b, 1H), 7.54–7.3
(m, 5H), 3.1–2.95 (m,
4H), 1.4–1.3 (m, 6H)
—
3184.1 1724
(100%)
(2b)
(3a)
(3b)
7.49–7.29 (m, 20H),
4.52, 4.49 (2s, 4H),
4.29 (s, 2H)
12.52 (s, 1H), 7.5–7.3
(m, 5H), 3.6 (s, 4H)
538 (M+, 3.5%), 448
(7.3%), 447 (20.0%),
77(100%)
295 (M + 1, 23%), 294
(M+, 100%), 135
(21.4%), 77 (56.4%)
311 (M+3, 2.6%), 308
(M+, 100%), 135
(3.8%), 77 (18.5%)
—
—
—
—
1696
3103.1 1704
3108.4 1710
12.24 (s, 1H), 7.5–7.3
(m, 5H), 3.2 (t, 2H),
3.04 (t, 2H), 2.2, 2.02
(m, 2H)
(4)
(5)
13.13 (b, 2H), 10.5 (s,
1H), 7.77–6.96 (m,
10H), 3.9 (s, 2H)
12.56 (s, 1H),
500 (M + 1, 30.8%),
192 (11.8%), 135
(55%), 77 (97%)
341 (M + 1, 28.2%),
340 (M+, 100%), 162
(30.6%), 77 (18.4%)
—
3099.9 1719
3576
3408
1705
7.025–7.55 (m, 8H),
6.6 (s, 2H), 3.86–3.83
(2s, 6H)
(6a)
(6b)
(7)
7.5–6.8 (m, 8H), 4.18 (s, 368 (M+, 100%), 340
—
—
—
—
—
—
1713
1717
1714
1H), 3.3 (Q, 2H),
1.65–1.47 (t, 3H)
8.33 (s, 1H), 7.59–6.9
(m, 13H), 4.6 (s, 2H),
3.98–3.9 (2s, 6H)
8.32 (s, 1H), 7.54–6.9
(m, 8H), 6.15 (m, 1H),
5.4–5.2 (two d, 2H),
4.02 (d, 2H), 3.98 (two
s, 6H)
8.09 (s, 1H), 7.5–6.85
(m, 16H), 3.9–3.85
(two s, 6H), 3.7 (s, 4H)
(25.4%), 324
(42.3%), 77 (27.8%)
430 (M+, 68.2%), 340
(10.7%), 91 (100%),
77(22.3%)
381 (M + 1, 25.8%),
380 (M+, 100%), 340
(9%), 77 (33.1%)
(8a)
(8b)
7.07 (M+, 5.4%), 3.69
(M – 340, 7.3%), 367
(77.2%), 366 (100%)
3585.3
—
—
—
1631
1711
8.1 (s, 2H), 7.6–6.89 (m, 381 (M – 239, 98%),
16H), 3.9, 3.7 (two s,
6H), 4.47 (t, 4H),
2.5–2.4 (m, 2H)
8.19 (s, 1H), 7.6–6.96
(m, 8H), 4.17 (s, 2H),
3.86–3.85 (two s, 6H)
380 (M- 340, 100%),
340 (76.4%), 77
(34.4%)
(9)
454 (M+, 7.3%), 340
(99.6%), 324 (100%),
77 (71.3%)
—
—
1733

850
M. K. Abou El-Regal et al.
arylidene derivative formed during reflux, which was collected after
cooling and recrystallized from the proper solvent.
3-Phenyl-2-thiohydantoin-4-diethylthiomethylidene (2a),
3-phenyl-2-thio-benzyl Hydantoin-4-dibenzylthiomethylidene
(2b), 2-(3-phenyl-2-thiohydan-toin-4-ylidene)-1,3-dithiolidine
(3a), and 2-(3-phenyl-2-thiohydantoin-4-ylidene)-1,3-
dithioxane (3b)
To a solution of (1) (0.01 mol) (1.92 g) in dry dioxane (50 mL), potassium
carbonate anhydrous (0.02 mol) (2.76 g), TBAB (0.003 mol) (0.97 g), and
halogen compounds as ethyl bromide (0.02 mol) (1.1 g), benzyl chlo-
ride (0.02 mol) (2.5 g), ethylene dibromide (0.01 mol) (1.9 g), or 1,3-
dibromopropane (0.01 mol) (2.02 g) were added in the presence of CS2
(0.1 mol) (7.6 g). The reaction mixture was stirred at 25◦C for 2–6 h.
the organic layer was separated and the solvent was removed under
reduced pressure; then the residue obtained was crystallized from the
proper solvent to give (2a, b) and 3b. On the other hand, (3a) was pre-
cipitated during the reaction and was isolated from the solid carbonate
phase, which was filtered and recrystallized from the proper solvent.
Bis-mono Potassium Salt Thiohydantoin Dithione (4)
To a solution of (1) (0.01 mol) (1.92 g) in dry dioxane (50 mL), potassium
carbonate anhydrous (0.02 mol) (2.76 g), TBAB (0.003 mol) (0.97 g), and
CS2 (0.1 mol) (7.6 g) were added. The reaction mixture was stirred at
25◦C for 2–3 h. The product was isolated from the carbonate phase and
recrystallized from the proper solvent.
1-Phenyl-2-thioethyl-4-arylidene imidazole-5-one (6a),
1-phenyl-2-thiobenzyl-4-arylidene imidazole-5-one (6b),
1-allyl-3-phenyl-2-thiohydan-toin-4-arylidene (7), Thioalkated
Dimers (8a), and (8b), and 1-phenyl-2-thiochloroacetate-
4-arylidene Imidazole-5-one (9)
To a solution of (5) (0.01 mol) (3.40 g) in dry dioxane (50 mL), potas-
sium carbonate anhydrous (0.02 mol) (2.76 g), TBAB (0.003 mol)
(0.97 g), halogen compounds as ethyl bromide (0.02 mol) (1.1 g),
benzyl chloride (0.02 mol) (2.5 g), allyl bromide (0.02 mol) (1.21 g),
1,2-dibromoethane (0.01 mol) (1.9 g), 1,3-dibromopropane (0.01 mol)
(2.02 g), and chloroacetyl chloride (0.01 mol) (1.13 g) were added. The
reaction mixture was stirred at 25◦C for 2–6 h, the organic layer was
separated, and the solvent was removed under reduced pressure; then

Synthesis of New Thiohydantoin Derivatives
851
the residue obtained was crystallized from the proper solvent to give
(6a, b), and (7). On the other hand, (8a, b) and (9) were isolated from
the solid carbonate phase, filtered, and crystallized also from the proper
solvent.
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