Mohammad Asif, Actapharmica. 2014,1(1).

,053-057

A Mini review
Synthesis of Hydantoin and Thiohydantoin and
related compounds using conventional, microwave
and green chemistry methods
Mohammad Asif
Department of Pharmacy, GRD (PG)IMT, Dehradun, (Uttarakhand), India
Abstract:
In alkaline medium the benzil reacts with urea or thiourea in presence of base like 30% w/v NaOH,
using ethanol as solvent to give the cyclic hydantoin compounds, or phenytoin (5,5’-
dipenylimidazolidine-2,4-dione) and thiohydantoin (5,5-diphenyl-2-thioimidazolidine-4-one)
respectively. The first step in the reaction involve the attack by urea or thiourea on the carbonyl group
of the benzil to give a diol, which then eliminate water and gave the final compounds. Phenytoin and
thiophenytoin is the anticonvulsant agents. The application of green chemistry principles,
thiophenytoins were prepared by condensation of benzil and substituted aryl thioureas in alkaline
condition and water as green solvent. These compounds were also prepared by microwave method, in
this method yield of phenytoin was obtained in 80% while in conventional Biltz’s method the yield
rarely exceeded 50%. The microwave method can be profitably performed using microwave activation.
All compounds were characterized by its spectral analysis.
Keywords: Phenytoin, thiophenytoin, green chemistry, synthesis, hydantoin, benzil.

Introduction: The hydantoin is also known as phenytoin (5,5-diphenylimidazolidine-2,4-dione or

diphenyl hydantoin) and used in the treatment of various types of seizures. Phenytoin acts on central
nervous system (CNS), its effects on the brain activity and decrease seizure frequency by reducing
electrical conductance among brain cells by stabilizing the inactive state of voltage gated sodium
channels. Phenytoin is also used to manage arhythmia and migraine headaches and facial nerve pain [1-
4]. Phenytoin was first synthesized by German physician H Biltz in 1908 [5] then it was used in 1938 as
antiseizures agent. Hydantoin and its analogues are also important intermediates in the preparation of
a number of amino acids. They are also used for prepation of the basic material of weather-proof high
temperature stable epoxy resins [6]. Other hydantoin analogues are used in many consumer products
like hair spray cosmetics, medications and photographic films [7]. The applications of optically active
polymers are the newly considerable matters which have paid more attention [8,9]. In microwave
synthetic method, the step involves the treatment of a benzyl derivative by thiourea in
dimethylsulfoxide (DMSO) in aqueous KOH under microwave activation. The resultant 2-
thiohydantoin was then oxidized to the analogous hydantoin using perhydrol in dimethylformamide
(DMF) in acetic acid. Both steps proceeded in high yield. The phenytoin was obtained in 80% yield
while by the conventional Biltz’s method, the yield seldom exceeded 50% [10].

Green chemistry is the design of chemical compounds and procedure that eliminates the use and
production of hazardous compounds [11]. Using green solvent, such as water, preparation of
pharmacologically active moiety with high percentage yield with high purity is the main objectives of
green chemistry. Purity of some drugs for CNS acting required high profile of purity and safety for
pertaining pharmacological activities [12]. Phenytoin is one of the most widely used drugs antiepileptic

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drug. However, its low solubility in water, both as free acid and sodium salt, makes its use to patients
complicate and rarely satisfactory. Phenytoin is given orally as sodium salt in a strong basic medium,
since it needs a pH between 10 and 12 to be keeps in solution [13]. Phenytoin is the first anticonvulsant
agent and act as a sodium channel blocker [14,15]. Generally, it is prepared by condensation of benzil
and urea in presence of base (30% w/v NaOH) using ethanol as solvent [16]. Removal of solvents after
synthesis is most difficult and non-assured process. In case of phenytoin conversion in polymorphism
plays an important role when solvent other than water is used. About 30% extra cost is intended if
solvent other than water is used. The substituted thiophenytoins were prepared by condensation of
benzil and substituted arylthioureas in presence of base and water, a green solvent [17].

General Method of Hydantoin synthesis: Due to the importance of these compounds, we have
decided to prepare the hydantoin and thiohydantoin and characterization of the compounds. The
hydantoin and thiohydantoin were prepared by reaction of benzil with urea and thiourea respectively
(Reaction 1and 2).

General procedure for the synthesis of Benzil from Benzoin: Benzoin (1.0 g) was placed in a flask
and concentrated nitric acid (50 mL) was added into it in a fumecupboard. The mixture was heated on a
hot plate with occasional shaking until all the red coloured nitrogen oxide gas was evolved (about 2
hours). The mixture was transferred to another 500 ml flask which contained 200 ml distilled water and
stirred vigorously until the oil solidified as a yellow crystalline material. It was filtered over a Buchner
funnel and washed with a liberal quantity of cold water until all the excess HNO3 was removed. The
solid material was recrystallized from 95% ethanol which resulted yellow needle crystalline material. Its
m.p. was found to be 92 (Reaction1).
OH O O O
Coc.HNO3

Benzoin Benzil
Reaction 1 Synthesis of Benzil from benzoin.

Preparation of hydantoin and thiohydantoin (Ia and Ib): In a round-bottomed flask equipped with
a reflux condenser, a mixture of benzil (0.025 mol), urea or thiourea (0.05 mol), 15 mL of 30% aqueous
sodium hydroxide solution and 75 mL of ethanol were placed. The mixture was heated under reflux for
4 hrs, after cooling to room temperature; the reaction mixture was poured into 125 mL of cold water and
mixed thoroughly. The reaction mixture was allowed to stand for 15 min and it was filtered under
suction. Then the filtrate was acidified with concentrated hydrochloric acid and the resulting
precipitate was filtered and washed with water (Reaction2). The crude products were recrystallized
from 95% ethanol [3,6,9].

X
O O H2N HN
NaOH
X
C2H5OH NH
H2 N
O
5,5-Diphenylhydantoin (Ia, X=O) 5,5-Diphenylthiohydantoin (Ib, X=S)

Reaction 2 Synthesis of 5,5-Diphenylhydantoin and 5,5-Diphenylthiohydantoin.

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5,5-Diphenyl-2-thiohydantoin (X=S) (thermal activation): To a solution of 2.1 g of benzil (10 mmol)

and 1.14 g of thiourea (15 mmol) in 10 ml of DMSO was added in one portion and under stirring 1.71 g of
potassium hydroxide (30 mmol), dissolved in 5 ml of distilled water. The reaction was stirred and
heated in an oil bath thermostatized at 125°C for 1 h. The dark red reaction mixture was poured onto ice
(~500 g) and acidified with concentrated HCl. The resulting precipitate was collected on a filter, dried
and recrystallized from ethanol. Mp 238-240°C.
General method for the synthesis of substituted aryl thiourea: To substituted aniline (5 mL),
concentrated hydrochloric acid (5 mL) was added and the solution was warmed. A saturated solution of
ammonium thiocyanate in water (6 g in 12 mL) was added slowly in above solution. The mixture was
boiled until the solution got turbid. The turbid solution was poured in cold water. The separated
precipitate as phenylthiourea was filtered and crystallized from aqueous ethanol (80%) so as to obtain
pure compound (Reaction 3).
X
NH 2
Con. HCl S
NH4SCN
N NH2
X H
Substituted aniline Substituted Aryl thiourea
X= 4a H; 4b 2-NO2; 4c 3-NO2; 4d 4-NO2; 4e 2-Cl; 4f 3-Cl; 4g 4-Cl; 4h 4-OH; 4i 4-Br

Reaction 2 Synthesis of substituted aryl thiourea from substituted aniline.

Green chemistry method for the synthesis of Thiophenytoin: Benzil (0.025 mol) and Aryl thiourea
(0.05 mol), 15 ml of 30% w/v sodium hydroxide solution and 40 ml of water was placed in a 250 ml
round bottom flask and heated for 2 hours. After cooling to room temperature, the reaction mixture
was poured into 100 ml of water with stirring. It was allowed to stand for 15 minutes and filtered under
suction to remove the insoluble by-product. The filtrate thus obtained was cooled and acidified by using
concentrate hydrochloric acid. The precipitates obtained were separated by filtration. The crude
product obtained was washed with cold water.

X S
O O S Green solvent HN
X
N
N NH 2
H
O

Benzil Substituted Aryl thiourea Thiophenytoin derivatives

Microwave activation method for synthesis of phenytoin:

In 250 mL, Erlenmeyer flak was placed under stirring 100 mL of distilled water and 10.14 g (178 mmol) of
potassium hydroxide; an exothermal reaction resulted. When a clear solution was obtained, a solution
of 19.97 g of benzil (95 mmol) and 9.97 g of urea (166 mmol) in 40 mL of DMSO was added portion wise
over 2 min. Efficient stirring was ensured throughout the operation to obtain a homogeneous paste. The
reaction flask was then placed in a microwave oven and heated initially for 1.5 min at 1100 watt power.
At times 6, 9, 12, 15, 18, 21, 24, and 30 min, a 30 sec pulse of 1100 watt were applied. The reaction mixture
was then set aside for 10 min and then quenched with 250 mL of ice water. After 15 min stirring, the
suspension was filtered to remove any flocculent precipitate and the filtrate was acidified with glacial

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acetic acid till pH 4. An abundant white precipitate was formed. It was collected, washed twice with 100
mL of cold distilled water, dried and recrystallized from 380 mL of redistilled 95% ethanol to yield 18.3 g
of 3. MP. 297-298°C.

X
O O H2N HN
Method A
X
Method B NH
H2 N
O
Method A. Biltz’s approach to the synthesis of phenytoin (Method A: X=O, KOH, C2H5OH, reflux 3-4 h;
yield: ~50 % or microwave) and alternative improved method [Method B: (a) 2 (X=S)], aqueous KOH,
DMSO, microwave, yield 92%; (b) H2O2, DMF, CH3COOH, rt, 24 h, yield: 87%).
R1 R2
O R2 HN O
(a), (b)
N
R1 O O
R3
Method B. (a) H2NC (=S)NH2, aqueous KOH, DMSO, microwave irradiation; (b) H2O2, DMF,
CH3COOH, rt, 24 h; (c) overall yield (%) from the corresponding benzil for the two-step procedure
involving procedures (a) and (b) of M.

Microwave activation: A reaction mixture composed of a solution of 2.1 g of benzil (10 mmol) and 1.14
g of thiourea (15 mmol) in 10 ml of DMSO and 1.71 g of potassium hydroxide (30 mmol) in 5 ml of
distilled water was irradiated by 10 pulses for 30 s (power set at 750 W), each pulse being spaced out by
150 s to allow thermal equilibration. The reaction mixture initially blue turned to dark red. After
precipitation by addition of 250 ml of ice water and acidification with concentrated HCl, isolation
proceeded as described earlier.

Discussion:
An interesting and useful synthesis of hydantoin and thiohydantoin, is the condensation of α-diketone
with urea and thiourea respectively. The formation of these compounds (Ia and Ib) involves a
molecular rearrangement in which a phenyl group undergoes a 1,2-shift and has been cited as an
example of the pinacol rearrangement. The reaction proceeds stepwise with the formation of the
intermediate 4,5-diphenyl-4,5-dihydroxy-2-imidazolone followed by a pinacol rearrangement leads to
the formation of hydantoin or thiohydantoin. The reaction is carried out in aqueous ethanol and in
basic media, the products were crystallizes out from the reaction mixture on cooling [19]. Subtistuted
thiophenytoins were synthesized by condensation of benzil and Substituted aryl thioureas in presence
of 30% w/v NaOH solution and water as a green solvent. The reaction between different substituted
aniline and ammonium thiocyninde result in the formation of substituted aryl thioureas and Benzil was
synthesized from Benzoin. The structures of the compounds were established on the basis of spectral
data [20].

Conclusion: While the Biltz synthesis is an “old” reaction that has been many times revisited, the
present work shows that it is often worthwhile reinvestigating so-called “old reactions” that can be
revitalized to provide interesting pharmacological probes for the medicinal chemists. In a further effort

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to find an alternative to reaction procedure presented earlier, extend these calculations to a series of
phenytoin analogs in which the carbonyl in position 2 was substituted by a function easily hydrolyzable
to the original carbonyl group. Thiophenytoin is the prime examples of anticonvulsant agent but their
syntheses involve non-green approach along with some hyzardous output. Therefore in present work,
thiophenytoins were synthesized by condensation of benzil and substituted aryl thioureas in presence
of base and water, a green solvent.

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