Synthesis of hydantoins, thiohydantoins, and glycocyamidines under solvent-free conditions

Article abstract of DOI:10.1080/00397910903320662

Hydantoins, thiohydantoins, and glycocyamidines have been prepared in moderate to excellent yields at room temperature under solvent-free conditions. 3N-amino and carboamide derivatives of hydantoin (7-8) were prepared in single step by condensing benzil with semicarbazide and biuret respectively.

Full text of DOI:10.1080/00397910903320662

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Synthesis of Hydantoins, Thiohydantoins,
and Glycocyamidines Under Solvent-Free
Conditions
Imran Ali Hashmi a , Afshan Aslam a , Syed Kashif Ali b , Viqar-uddin
Ahmed b & Firdous Imran Ali a
a Department of Chemistry, University of Karachi, Karachi, Pakistan
b International Center for Chemical and Biological Sciences,
University of Karachi, Karachi, Pakistan
Version of record first published: 25 Aug 2010.
To cite this article: Imran Ali Hashmi, Afshan Aslam, Syed Kashif Ali, Viqar-uddin Ahmed & Firdous
Imran Ali (2010): Synthesis of Hydantoins, Thiohydantoins, and Glycocyamidines Under Solvent-Free
Conditions, Synthetic Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, 40:19, 2869-2874
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Synthetic Communications1, 40: 2869–2874, 2010
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910903320662
SYNTHESIS OF HYDANTOINS, THIOHYDANTOINS,
AND GLYCOCYAMIDINES UNDER SOLVENT-FREE
CONDITIONS
Imran Ali Hashmi,1 Afshan Aslam,1 Syed Kashif Ali,2
Viqar-uddin Ahmed,2 and Firdous Imran Ali1
1Department of Chemistry, University of Karachi, Karachi, Pakistan
2International Center for Chemical and Biological Sciences, University of
Karachi, Karachi, Pakistan
Hydantoins, thiohydantoins, and glycocyamidines have been prepared in moderate to
excellent yields at room temperature under solvent-free conditions. 3N-amino and carboa-
mide derivatives of hydantoin (7–8) were prepared in single step by condensing benzil with
semicarbazide and biuret respectively.
Keywords: Benzil; glycocyamidines; hydantoins; thiohydantoins; thiourea; urea
INTRODUCTION
Hydantoins, thiohydantoins, and glycocyamidines constitute an important
class of nitrogen-containing heterocyclic compounds, which exhibit a wide range
of biological activities, namely anticonvulsant and antimuscarinic,[1] antiviral,[2]
antimicrobial,[3] and antiulcer and arrythmic activities.[4] The present article deals
with a green, simple, and regioselective method for the preparation of 5,5-disubsti-
tuted analogs of hydantoins, thiohydantoins, and glycocyamidines under solvent-
free conditions at room temperature.
In the literature, a number of methods[5,6] have been reported for the synthesis
of 5,5-disubstituted analogs of hydantoins, thiohydantoins, and glycocyamidines,
but the majority of these suffer from disadvantages. The most common synthetic
route for the preparation of these analogs is condensation of 1,2-diketo compounds
with urea, thiourea, guanidine or their derivatives under basic conditions followed
by benzilic rearrangement under acidic conditions, which involves conventional
heating procedures for a long time at high temperatures.[5] Two groups of workers
reported microwave-assisted synthesis of phenytoins in 2003.[6] In both cases, toxic
solvents have been used (dimethylsulfoxide [DMSO] and dimethylformamide
[DMF]), dipolar solvents with high boiling points.
Received August 6, 2009.
Address correspondence to Imran Ali Hashmi, Department of Chemistry, University of Karachi,
Karachi 75270, Pakistan. E-mail: imran_ali_hashmi@yahoo.com
2869

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I. A. HASHMI ET AL.
RESULTS AND DISCUSSION
In view of the important therapeutic applications of hydantoin derivatives,
there is a need for rapid synthesis to minimize reaction steps and time and to improve
yield. Therefore, there is still demand for the introduction of a mild, convenient,
easy, and inexpensive as well as regioselective method for the preparation of these
molecules.
We herein report a green, efficient, simple, and regioselective method for the
preparation of 5,5-disubstituted analogs of hydantoins, thiohydantoins, and glyco-
cyamidines (Table 1) under solvent-free conditions in moderate to excellent yield.
Because of environmental and economical concerns, solvent-free reactions are
Table 1. Reaction of benzil with urea, thiourea, guanidine, or their derivatives
Compound
Reactant
Products
1
2
3
4
5
(Continued )

SYNTHESIS OF HYDANTOIN AND ITS ANALOGS
2871
Table 1. Continued
Compound
Reactant
Products
6
7
8
increasingly a topic of interest for scientists in the past few decades[7] because
solvent-free reactions present a number of advantages over conventional heating
methods, including ease of purification, minimization of the amount of solvent used,
reduced reaction times, and comparatively good yields.[7]
In a typical procedure, benzil, NaOH, and urea (thiourea, guanidine, or their
derivatives) were ground in a pestle and mortar at room temperature (Scheme 1).
After some time, we observed that the reaction mixture started to become sticky,
Scheme 1. Solvent-free synthesis of hydantoins, thiohydantoins, and glycocyamidines.

2872
I. A. HASHMI ET AL.
Table 2. Comparison of solvent-free synthesis with conventional methods
Yield (%)
Time
Conventional
method
Solvent-free
synthesis
Conventional
method (h)
Solvent-free
synthesis (min)
Compound
1
2
3
4
5
6
7
8
–
44[5e], 60[6a]
80[5a]
93[5f]
62[5b]
–
86.2
70
2.5
2.5
3.5
3
30
30
5
70
70
50
10
5
67.4
70
12
–
38[5d]
–
45
80
6
10
30
–
and stickiness reached its maximum in the times shown in Table 2, resulting in
difficulty in grinding. The reaction mixture was then dissolved in water and filtered,
and the resulting filtrate was acidified with concentrated HCl to obtain rearranged
products in excellent yields. From this observation, it is evident that via green
chemistry we can save energy, solvents, and time with improved yield (Table 2).
Furthermore, in contrast to regioselectivity, we observed that monosubstituted
urea and thiourea derivatives always furnished 3-N substituted products (4–8). In
addition, phenyl derivatives of urea or thiourea containing an electron-withdrawing
group at the para position of the phenyl group did not furnish the expected products.
This can be attributed to electronic factors that affect the availability of the nitrogen
lone pair during condensation. In addition, N,N0-disubstituted urea or thiourea
analogs did not proceed for hydantoin or thiohydantoin formation, which can be
ascribed to the increasing steric effects.
Interestingly, condensation of semicarbazide with benzil under the same
conditions furnished 3N-amino derivative 7, which has been reported in literature
in two steps.[8] 3N-carboamide derivative 8 has been also synthesized in a single step
by condensing biuret with benzil, although it was previously prepared in three steps.[9]
All compounds were characterized through comparison with the published
spectral data and melting points.[1b,5,6,10]
EXPERIMENTAL
General Procedure for Synthesis of 5,5-Disubstituted Hydantoins
and Thiohydantoins
NaOH (50 mmol, 2 g) was added to a mixture of benzil (11.94 mmol, 2.5 g) and
urea (25 mmol, 1.5 g) in a mortar and was ground with a pestle for the specified time
(Table 2) at room temperature. The progress of the reaction was monitored through
thin-layer chromatography (TLC). After disappearance of the starting material,
water (150 ml) was added to the reaction, which was stirred vigorously and filtered
to remove impurities. The resulting filtrate was acidified with concentrated HCl to
obtain 5,5-diphenyl hydantoins as white precipitate, which was filtered on a Buchner
funnel, dried, and recrystallized from methanol to obtain the pure products.

SYNTHESIS OF HYDANTOIN AND ITS ANALOGS
2873
CONCLUSION
Regioselective synthesis of hydantoins, thiohydantoins, and glycocyamidines
was achieved in moderate to excellent yield by employing a greener methodology.
Reactions were carried out under solvent-free conditions at room temperature.
3 N-Amino derivative (7) and 3N-carboamide derivative (8) of hydantoin were
prepared in a single step by condensing semicarbazide and biuret with benzil.
Previously, multistep synthesis of these compounds was reported.
ACKNOWLEDGMENT
One of the authors is thankful to the Higher Education Commission of
Pakistan for providing a fellowship.
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