Novel and efficient protocol for the syntheses of N-1 substituted thiohydantoin and a bicyclothiohydantoin under solvent-free conditions

Article abstract of DOI:10.1016/j.tetlet.2012.02.087

A novel approach for the synthesis of N-1 substituted thiohydantoin has been developed to give quantitative yields of the desired products. The efficient synthesis of bis-thiohydantoin derivative and bicyclothiohydantoin has extended scope and applicabili

Full text of DOI:10.1016/j.tetlet.2012.02.087

Tetrahedron Letters 53 (2012) 2377–2379
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Novel and efficient protocol for the syntheses of N-1 substituted
thiohydantoin and a bicyclothiohydantoin under solvent-free conditions
Vinod Kumar a, , Hemlata Rana a, Ravish Sankolli b, M.P. Kaushik a
⇑
a Process Technology Development Division, Defence R&D Establishment, Jhansi Road, Gwalior 474002, MP, India
b Solid State and Structural Chemistry Unit, Indian Institute of Science, Bangalore 560012, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel approach for the synthesis of N-1 substituted thiohydantoin has been developed to give quanti-
tative yields of the desired products. The efficient synthesis of bis-thiohydantoin derivative and bicy-
clothiohydantoin has extended scope and applicability of present method. Solvent-free conditions and
very easy work-up procedure make the reaction convenient and eco-friendly. All the products were char-
acterized by spectroscopic techniques and elemental analysis, and finally the structure of representative
compound was also confirmed by X-ray crystallography.
Received 20 October 2011
Revised 16 February 2012
Accepted 19 February 2012
Available online 3 March 2012
Keywords:
Thiohydantoin
Ó 2012 Elsevier Ltd. All rights reserved.
Methyl N-cyano-N-alkyl/arylaminoacetate
Bicyclothiohydantoin and bis-
thiohydantoin
Diethylthiophosphate
Solvent-free conditions
Hydantoin1 exists in sulfur and nitrogen analogs and are called
thiohydantoin2 and iminohydantoin,3 respectively. Compounds
with hydantoin or its analogous structural motif have been identi-
fied to display a wide range of biological activities. Among these,
2-thiohydantoins are also notably known due to their wide applica-
tions as hypolipidemic,4 anticarcinogenic,5 antimutagenic,6 antithy-
roidal,7 antiviral (e.g., against herpes simplex virus, HSV),8 human
immunodeficiency virus (HIV)9 and tuberculosis10 antimicrobial
(antifungal and antibacterial),11 antiulcer and antiinflammatory
agents,12 as well as pesticides.13 Additionally, 2-thiohydantoins
have been used as reference standards for the development of C-ter-
minal protein sequencing,14 as reagents for the development of
dyes15 and in textile printing, metal cation complexation and poly-
merization catalysis.16 Thiohydantoins also furnish an interesting
feature in structural chemistry.17 Diversed applications of thiohyd-
antoin has encouraged researchers to develop a simple, rapid,
convenient and eco-friendly novel method for widely substituted
thiohydantoin.
practical and efficient methods. Further substitution in thiohydan-
toin ring at N-1 and C-5 position is very difficult and moreover sub-
stitution with aryl groups is not possible. Substitution in hydantoin
ring at N-1 position generally follow three steps (i) protection of N-
3 position, (ii) alkylation of N-1 position and, (iii) removal of pro-
tecting group.21 However, this strategy cannot be followed in case
of thiohydantoin because of invariable formation of S-alkylated
hydantoin.22 Keeping this in view, there is a need to develop a no-
vel, greener, practical and high yielding method which can result in
thiohydantoin substituted at desired positions.
Based on our previous experience on the studies on cyanamide
and hydantoin chemistry,23 we have adopted a novel strategy for
the synthesis of N-1 substituted thiohydantoin. The method is based
on the reaction of a cyanamide based precursor viz methyl N-cyano-
N-alkyl/arylaminoacetate 1 with diethyl thiophosphate 2. The pre-
cursors 1 were synthesised by the reaction of amines with cyanogen
bromide to give monoalkyl/aryl cyanamides.23a In the next step,
reaction of cyanamides takes place with methyl bromoacetate in
presence of sodium hydride to afford various derivatives of 1.23a
Transformation of methyl N-cyano-N-alkyl/arylaminoacetate 1 into
thiohydantoin 3 was carried out using diethyl thiophosphate 2.
Formation of 3 takes place at 60 °C in good to excellent yields under
solvent-free conditions. A library of thiohydantoins was generated
by this route which includes the formation of thiohydantions with
various substituents such as alkyl, cycloalkyl and aryl groups. In this
Although, a number of synthetic strategies for hydantoin ana-
logs have been reported,18 Most of these methodologies are suit-
able for the synthesis of (un)substituted thiohydantoin. There are
various synthetic methods for thiohydantoin,19 however, there is
only one method that can lead to the synthesis of N-1 substituted
thiohydantoin.20 Therefore, there is urgent need to develop more
reaction,
2 was converted into ethyl thiopyrophosphate 4
⇑
Corresponding author. Tel.: +91 751 2390204; fax: +91 751 2341148.
E-mail address: vkpal77@yahoo.co.in (V. Kumar).
(Scheme 1). By-product 4 can easily be removed from the reaction
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2012.02.087

2378
V. Kumar et al. / Tetrahedron Letters 53 (2012) 2377–2379
R
O
P
S
R'
O
O
EtO
EtO
R
N
C
N
O
P
OEt
N
O
O
O
EtO
OEt
NH
R1
N
HC
C N
P
SH
HS
OEt
HS
P
OEt
O
2
EtO
P
S
P
OEt
CH
1
S
N
H
OEt
COOMe
R2
R'
OEt
OEt
COOMe
60° C
No solvent
R1
N
C
3
4
R1 = alkyl/aryl/cyclic
CH
R2
R
2 = H and Me
S
COOMe
NH
5
Scheme 1. Synthesis of thiohydantoin derivatives.
HS
O
P
OEt
R1
N
CH
C NH2
S
P
OEt
EtO
R1
R2
N
C
mixture with mixture of petroleum ether and/ or diethyl ether. Even
the by-product ethyl thiopyrophosphate 4 was obtained in quanti-
tative yields with high purity. The class of thiopyrophosphates
chemistry have also a great importance in organophosphorous
chemistry. The results and reaction conditions are summarized in
Table 1. All the products were characterized by IR, NMR, MS, and
elemental analysis. In order to substantiate our spectroscopic data,
recrystallization of the representative product 3g (Table 1, entries 7)
in CHCl3 was carried out to obtain single crystals. The X-ray struc-
ture is given in Figure 1.
6
OEt
CH
R2
COOMe
COOMe
H+/
-CH3OH
R2
R1
N
S
O
N
H
3
Scheme 2. Mechanism for the formation of 3.
Table 1
Various 2-thiohydantoins from 124
S
S
NC
Entry
Products
R
R0
H
Time (h)
0.5
Yielda (%)
90
2
NH
N
H2C
C N
H2N
N
°
100 C, 2 h
O
1
3a
COOMe
8 = C(S)NH2 at 3position (Yields: 72%)
9 = C(S)NH2 at 4 position (Yields: 75%)
7 = CN at 3 or 4 position
2
3b
H
0.5
88
Scheme 3. Reactivity of nitrile and cyanamide groups in 1.
noctyl
3
4
3c
H
H
1
1
82
90
Ethyl thiophosphate 2 being more acidic and better nucleophile
than butyl phosphate reacts faster with 1. From Table 1, it is evi-
dent that the rate of reaction for the formation of products with al-
kyl substituents was found to be faster in comparison with aryl
substituents. This may be attributed to the fact that the donation
of aromatic electron density to cyanamide moiety reduces its reac-
tivity for nucleophilic attack.
3d
5
6
3e
3f
Me
H
H
1.5
1.5
89
90
MeO
Probable mechanism for the formation of 3 is shown in Scheme
2.23b The electrophilic center in cyanamide group of 1 reacts with
diethyl thiophosphate 2 to give an unstable intermediate 5 which
futher reacts with 2 to give thioureido derivative that isomerizes
into stable thiourea derivatives. The intermediate, under the influ-
ence of heat, cyclizes into 3 with the loss of MeOH.
7
8
9
3g
3h
3i
Me
H
2
2
2
84
85
83
H
In order to investigate the effect of 2 on to the reactivity of ni-
trile (C–CN) and cyanamide group (N–CN), we have chosen a sub-
strates 7 (where nitrile group lies at 3 and 4 position of aromatic
ring) that possess nitrile and cyanamide functionality in the same
molecule. This was reacted with 2 under given sets of reaction con-
ditions and we found that 2 also converts nitrile group of 1 into thi-
oamide functionality. This has resulted into the formation of 1-(3-
thiobenzamide) thiohydantoin 8 as well as 1-(4-thiobenzamide)
thiohydantoin 9, respectively (Scheme 3). It is presumably due to
stronger acidity and nucleophilicity of 2 than dibutyl phosphate
as reported earlier.23b
10
11
12
13
3j
F
H
1.5
1.5
2
88
90
75
90
3k
3l
Cl
F
Me
H
3m
Br
H
2
a
Isolated yields.
Bicyclohydantoin and bicyclothiohydantoin25 represent two of
the most important classes of 5-HT1A receptor ligands which have
been attractive targets for medicinal chemists.26 In view of this, we
also extended this method for the synthesis of bicyclothiohydan-
toin 11. From retro-synthetic analysis, it is evident that product
11 can be obtained from N-cyano proline methyl ester 10 which
2
N
COOMe
N
CN
°
60 C, 1 h
S
O
N
H
10
11
Figure 1. ORTEP diagram of 5-methyl 1-phenylthiohydantoin 3g.
Scheme 4. Synthesis of bicyclothiohydantoin 11.

V. Kumar et al. / Tetrahedron Letters 53 (2012) 2377–2379
2379
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Scheme 5.
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Supplementary data
Supplementary data (copies of 1H NMR and 13C NMR spectra of
all synthesized compounds are reported along with the crystallo-
graphic data of compound 3g) associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.2012.02.087.
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arylaminoacetate
1 (0.0025 mol) and diethyl thiophosphate 2 (0.005 mol)
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to precipitate the products. The products were washed with same solvent
(10 mL ꢀ 2) to remove any trace of ethyl thiopyrophosphate 4 to give pure
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