Simple and Efficient Synthesis of 5-Substituted-3-phenyl-2-thioxoimidazolidin-4-one Derivatives from S -Amino Acids and Phenylisothiocyanate in et 3N/DMF-H 2O

Article abstract of DOI:10.1080/00397911.2015.1052506

A concise approach for the transformation of various S-amino acids into the 5-alkyl-3-phenyl-2-thioxoimidazolidin-4-one heterocycles using phenylisothiocyanate is described. Phenylthiohydantoins of amino acid were synthesized at room temperature in Et3N/DMF-H2O with easy workup and excellent yields.

Full text of DOI:10.1080/00397911.2015.1052506

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A Simple and Efficient Synthesis of 5-Substituted-3-
phenyl-2-thioxoimidazolidin-4-one Derivatives from S-
Amino Acids and Phenylisothiocyanate in Et3N/DMF-H2O
Asha D. Jangalea, Yogesh B. Wagha, Yogesh A. Tayadea & Dipak S. Dalala
a School of Chemical Sciences, North Maharashtra University, Jalgaon, M.S., India
Accepted author version posted online: 26 May 2015.
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To cite this article: Asha D. Jangale, Yogesh B. Wagh, Yogesh A. Tayade & Dipak S. Dalal (2015): A Simple and Efficient
Synthesis of 5-Substituted-3-phenyl-2-thioxoimidazolidin-4-one Derivatives from S-Amino Acids and Phenylisothiocyanate in
Et3N/DMF-H2O, Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,
DOI: 10.1080/00397911.2015.1052506
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A Simple and Efficient Synthesis of 5-Substituted-3-Phenyl-2-Thioxoimidazolidin-4-
One Derivatives from S-Amino Acids and Phenylisothiocyanate in Et3N/DMF-H2O
Asha D. Jangale1, Yogesh B. Wagh1, Yogesh A. Tayade1, Dipak S. Dalal1
Corresponding Author: Dipak S. Dalal, School of Chemical Sciences, North Maharashtra
University, Jalgaon, M.S. 425 001, India. Email: dsdalal2007@gmail.com
Abstract
A concise approach for the transformation of various S-amino acids into the 5-alkyl-3-
phenyl-2-thioxoimidazolidin-4-one heterocycles using phenylisothiocyanate is described.
Phenylthiohydantoins of amino acid (PTH- amino acid) was synthesized at room
temperature in Et3N/DMF-H2O with easy work-up and excellent yields.
Graphical Abstract:
KEYWORDS: Amino acids, phenylisothiocyanate, cyclization, 2-thiohydantoin.
1

INTRODUCTION
Thiohydantoins are hydantoins analogue, in which carbonyl group is replaced by
thiocarbonyl group are pharmaceutically active compounds and has been considerable
interest in 2-thiohydantoins which display promising biological activities. The derivatives
of 3-phenyl-2-thiohydantoins with nonpolar substituent at the 5-position inhibited the
peripheral effect of T4 (Fig. 1 Compound I, II, III).[1] These derivatives exhibit activities
like anticonvulsant[2], fungicide[3], antimutagenic, anticarcinogenic and antiviral agents[4]
and immune depressing activity.[5] The treatment of hormone independent prostate
cancers was done by thiohydantoins.[6-9] In literature, thiohydantoin derivatives were
reported for androgen receptor (AR) agonism and antagonism in human prostate cancer
cells. (Fig. 1 Compound IV and V)
Owing to N–H…S=C hydrogen bonds or a 1D H-bonded chain with N–H…O=C
interactions perform energetic balance between H-bonded structures with increased
potential for drug polymorph formation.[10] Thiohydantoins have also been used in crystal
engineering as spacers in metallo-organic frameworks[11], chemosensor[12a]
,
polymerization catalyst, corrosion inhibitors and as analytical reagents.[12b] The
thiohydantoins derived from amino acids were used for the step-wise sequence analysis
of the peptide or the protein from the carboxyl termini.[13]
In order to improve the efficiency of PTH-amino-acid synthesis, several attempts have
been carried out and encouraging results were obtained. The reaction has been conducted
with amino acid in the presence of KOH/EtOH[14], Na2CO3/Dioxane[15]
,
2

KOH/EtOH/AcOH[16], Ionic liquid[17], NaOH/water/acetone[18], NaOH/EtOH/HCl[19] and
NaOH/H2O/HCl[20], Pyridine/NaOH H2O/HCl[21], Et3N/dioxane/H2O/HCl[22], reflux at
higher temperature[23a], Ethyl thiophosphate [23b] and aldehyde with thiourea in phosphoric
acid[23c], Benzyl with thiourea in NaOH/EtOH[24a, 24b], DMF-K2CO3 and KOH/DMSO.[25]
Whereas with amino acid esters in the presence of CH2Cl2/Et3N[10, 26], Aqueous
pyridine/Et3N/Dioxane[27], KOH/H2O/HCl[28], NaHCO3/EtOH/HCl[29], AcOH/HCl[30]
,
alkaline Al2O3[31], DMF-H2O[32]. Also multiple-step procedures were reported including
benzaldehydes, glycine, and thiocyanate[33a], bromoacetyl bromide, sodium azide, amine
and CS2[33b] and vinyliminophosphoran with CS2[33c], amine α-amino esters, nitrostyrenes,
and aromatic isothiocyanates[33d], MeOH/H2SO4/PTSA[33e]. However, these
methodologies usually involve several steps that inevitably lead to decrease in the
quantitative yield of the reaction.
Water and aqueous-based solvent systems may represent an increasingly significant
choice for the replacement of traditional solvents in synthetic chemistry.[34] Preferably, it
is noteworthy that the aqueous solutions have potential advantages over the use of
volatile organic compounds and chemistry should occur at room temperature. Therefore,
there is a need for the development of more gentle methods. In persistence of our work in
organic synthetic methods [35], we herein described a simple and mild method for the
synthesis of thiohydantoins from S-amino acids and phenylisothiocyanate in
triethylamine by using mixture of DMF and water as solvent.
3

RESULT AND DISCUSSION
Literature survey revealed that the lower yields and higher reaction time were observed
with different bases and solvents for the synthesis of PTH-thiohydantoins (Table 1).
Subsequently, our initial approach for the preparation of 3,5-diphenyl-2-
thioxoimidazolidin-4-one (Table 3, entry 5), involved the condensation of S-amino acid
with phenylisothiocyanate in presence of an organic base and solvents such as water,
ethanol, DMF at room temperature. The screening of literature reports and our
optimizations, revealed that in Et3N/aq. DMF was the most efficient reaction condition
for the transformation (Table 1, entry 8). However, by our optimization base-catalyzed
reactions in aq. ethanol gave modest yield with elongated reaction time (Table 1, entry 6
and 7) while in aq. DMF about 98 % yield was obtained (Table 1, entry 8). Thereafter,
we studied effect of selected co-solvent on time and yields of the product. It appeared that
reaction time is elongated and also slight difference in yields in water and DMF when
used separately. But in co-solvent the reaction time decreased with increasing yields
(Table 2). The quantitative yield was obtained in DMF:H2O in ratio 8:2 with decrease in
reaction time (Table 2, entry 6). Remarkably, the influence of the solvent DMF:H2O has
been investigated resulting in a yield improvement. To examine the versatility of the
protocol, we used phenylisothiocyanate to react with the structurally diverse S-amino
acids under optimized reaction conditions and satisfied results were achieved ranging
from 88 % to 98 % (Table 3, entries 1–16).
To explore the scope of the reactions, we protracted the procedure to S-amino acids such
as, glycine, phenyl glycine, alanine, valine, leucine, serine, cysteine, asparagine, aspartic
4

acid, lysine, proline, methionine, phenylalanine, glutamic acid, glutamine, and threonine.
When the reaction was carried out in DMF and water in presence of triethyl amine, the
rate of reaction is noticeably increased and significant improvement in the yield was
observed at room temperature. It has been found that the reaction smoothly proceeds with
phenylisothiocyanate and various S-amino acids (Scheme 1), and forming the five
membered functionalized 5-aryl/alkyl-3-phenyl-2-thioxoimidazolidin-4-ones. It should be
noteworthy that no racemization at the 5-positions of 2-thiohydantoins is observed under
given reaction conditions. This was confirmed by the analysis of the 1H-NMR spectra of
the 2-thiohydantoins.[23a]
We obtained satisfied results under optimized conditions with structurally diverse S-
amino acids and phenylisothiocyanate (Table 3, entries 1–16). 2-Thiohydantoins resulting
from amino acids with non-polar side chain such as glycine, alanine, valine, leucine,
phenylglycine, phenylalanine, methionine, as well as polar side chains such as serine,
cysteine, aspartic acid, asparagine, glutamine, and lysine can be isolated simply by
precipitation after acidification by 1N HCl upto 98 % yields (Table 3). In divergence, the
corresponding 2-thiohydantoins arising from glutamic acid was not precipitated under our
reaction conditions hence derived by extraction with EtOAc after adding 1N HCl (Table
3, entry 11). While PTH-proline was isolated without acidifying the reaction mixture
after completion of reaction. Because on addition of HCl thiohydantoin ring was opened,
confirmed by 1H-NMR (Table 3, entry 13). It was isolated by addition of water and
extraction in EtOAc with good yield. All amino acid-thiohydantoin achieved 1-6 hrs for
completion with quantitative yields (Table 3, entries 1-16).
5

CONCLUSION
In conclusion, we developed a effective method for the synthesis of thiohydantoins from
the reaction of S-amino acid with phenylisothiocyanate by using triethylamine in DMF-
H2O at room temperature affords pure products in excellent yields. The advantages of this
procedure include mild reaction conditions, broad application scope, high yields and
simple workup process.
EXPERIMENTAL SECTION
Typical Experimental Procedure For The Preparation Of Amino Acid
Thiohydantoin
To a solution of of amino acid (02 mmol) with TEA in (8:2) DMF and water (10 mL),
phenylisothiocyanate (02 mmol) was added. The reaction mixture was stirred at room
temperature. The progress of reaction was monitored by TLC (30% EtOAc: Hexane or 5-
10% MeOH: CHCl3). The solid product was obtained after acidification with 1N HCl.
Filter the solid and recrystallize with aq. EtOH to afford pure products.
ACKNOWLEDGEMENT
The authors are thankful to SAIF, Punjab University, Chandigarh for providing the
spectral analysis. One of the authors ADJ is thankful to University Grant Commission,
New Delhi for SAP fellowship under the scheme ‘Research Fellowship in Sciences for
Meritorious Students’.
6

SUPPLEMENTAL MATERIAL
Supplementary material includes experimental details, characterization data of all
compounds and FT-IR, 1H-NMR, 13C-NMR and mass spectra for this work, which can be
accessed on the publisher’s website.
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13

Table 1. Comparison for preparation methods of 5-alkyl/aryl-3-phenyl-2-
thioxoimidazolidin-4-one
Entry Base
Reaction condition
EtOH, reflux, HCl
Time (h) Yield (%)
1
2
3
4
5
6
7
8
KOH
2
50 [14]
Na2CO3
Ionic Liquid
NaOH
Et3N
Dioxane, reflux, HCl
TFA/Dry ACN, Na2CO3, rt
H2O/Acetone, reflux
CH2Cl2, reflux, HCl
1:1 EtOH + H2O, rt, HCl
1:1 EtOH + H2O, rt, HCl
DMF/H2O, rt, HCl
4
80 [16]
8
77 [17]
2
60 [18]
2
52 [26]
Et3N
9
87
NaHCO3
Et3N
9.5
1.5
85
98 (Present work)
14

Table 2. Optimization of ratio of DMF: Water mixture for reaction solventa
Entry Reaction Conditions
Time (h)
Yield (%)
1
2
3
4
5
6
7
8
H2O
9
90
91
92
92
93
98
89
84
8:2 H2O:DMF
6:4 H2O:DMF
5:5 H2O:DMF
4:6 H2O:DMF
2:8 H2O:DMF
1:9 H2O:DMF
DMF
5
3.5
3
2
1.5
7
7.5
aReaction conditions: 02 mmol phenylisothiocyanate, 02 mmol S-phenylglycine, Et3N
and 10 mL solvent, stir, rt.
15

Table 3. Synthesis of PTH-amino acidb
Entry Substrate
Product
Reaction
Yield (%)
Time (hr.)
1
2
95
2
3
4
1.5
2.5
3
92
97
97
16

5
1.5
98
6
7
6
3
96
96
8
9
5
6
88 c,d
95
10
5
91
17

11
5.5
96c
12
13
3
95
1.5
90c
14
1.5
97
15
16
6
6
95
93d
b Reaction conditions: S-amino acid (02 mmol), phenylisothiocyanate (02 mmol), Et3N
(02 mmol) and 8:2 DMF: H2O (10 mL), stir, rt., c EtOAc for extraction of product, d Et3N
(04 mmol)
18

Figure 1. Bioactive heterocycles containing thiohydantoin moiety possesses antithyroid
and anticancer activities.
19

Scheme 1. Synthesis of PTH-amino acid from S-amino acids and phenylisothiocyanate.
20