Cyclododecanone as a recyclable protecting group for the synthesis of highly functionalized 3-amino-2-thiohydantoins from conventional starting materials

Article abstract of DOI:10.1039/c3ra47680d

A simple and efficient approach has been developed for the synthesis of highly substituted 3-amino-2-thiohydantoins using cyclododecanone as a protecting group and thiosemicarbazide, chloroacetic acid and substituted benzaldehyde as reactants. This high yielding (79-96%) protocol is a milder alternative to the traditional method that uses unprotected thiosemicarbazide. It was identified that the preferred pathway is the deprotection of 3-amino-2-thiohydantoins followed by the attack of chloroacetic acid on a secondary nitrogen with subsequent formation of the Knoevenagel product and its reaction with imine leading to the final product. The Royal Society of Chemistry.

Full text of DOI:10.1039/c3ra47680d

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Cyclododecanone as a recyclable protecting group
for the synthesis of highly functionalized 3-amino-
2-thiohydantoins from conventional starting
materials†
Cite this: RSC Adv., 2014, 4, 8498
Munusamy Sathishkumar, Gunasekar Ramachandran
*
and Kulathu Iyer Sathiyanarayanan
A simple and efficient approach has been developed for the synthesis of highly substituted 3-amino-2-
thiohydantoins using cyclododecanone as a protecting group and thiosemicarbazide, chloroacetic acid
and substituted benzaldehyde as reactants. This high yielding (79–96%) protocol is a milder alternative to
the traditional method that uses unprotected thiosemicarbazide. It was identified that the preferred
pathway is the deprotection of 3-amino-2-thiohydantoins followed by the attack of chloroacetic acid on
a secondary nitrogen with subsequent formation of the Knoevenagel product and its reaction with imine
leading to the final product.
Received 16th December 2013
Accepted 15th January 2014
DOI: 10.1039/c3ra47680d
www.rsc.org/advances
3-amino-2-thiohydantoins and its derivatives. Some of the most
commonly used methods are the Bucherer–Bergs reaction, but
1. Introduction
the use of KCN and the special condition required for this
reaction restricts this method.15 The coupling reaction between
a-amino acids with ammonium thiocyanate or isothiocyanate
leads to the product 2-thiohydantoin.16,17 Another convergent
method is the three components reaction, combining 1,2-diaza-
1,3-dienes, primary amines, and isothiocyanates.18
Functional group protection/deprotection plays an impor-
tant role in organic synthesis. The protection of amines is one of
the most fundamental and useful transformations to decrease
the nucleophilicity of the amino group in order to perform other
transformations in the molecule. One of the major applications
of protecting group strategy is the synthesis of peptides from
amino acids.19
Now we report a recyclable protecting group approach for the
synthesis of some highly functionalized 3-amino-2-thio-
hydantoins derivatives using simple and easily available start-
ing materials. These compounds are thiosemicarbazide,
benzaldehyde, chloroacetic acid and cyclododecanone (CDD)
functioning as protecting group. In this method, we used CDD
to protect free amino group present in the thiosemicarbazide to
avoid unwanted side product20 so that the yield could be
improved. Cyclododecanone is a typical cyclic ketone and exists
in solid form. It easily reacts with free amino group and forms
stable ketimine in the presence of an acid catalyst. Based on the
above considerations we chose CDD as the protecting group to
protect free amino group in thiosemicarbazide for the synthesis
of highly substituted 3-amino-2-thiohydantoins. To the best of
our knowledge, this is the rst time a protecting group
approach is used for the synthesis of 3-amino-2-thiohydantoins,
Synthesizing molecules that have maximum structural diversity
and complexity using a minimum number of synthetic steps for
the rapid generation of highly functionalised molecules with
interesting properties represents a major challenge to modern
synthesis. In this context, multicomponent reactions (MCRs)
have played an important role in these processes.1 Because of
their convergent nature, superior atom economy and straight-
forward experimental procedures, MCRs have been investigated
extensively in organic and diversity oriented synthesis. In a
similar way, many MCRs such as Passerini reaction,2 Mannich
reaction,3 Petasis reaction,4 and Ugi reaction,5 have been
developed.
3-Amino-2-thiohydantoins are ve membered heterocyclic
compounds containing two nitrogen atoms in the ring with
privileged structures as they belong to a class of compounds
with diverse biological activity.6 Many biological applications
such as antiarrhythmics,7 anticonvulsants,8 antitumor,9 anti-
inammatory,10 antiandrogens11 and aldose reductase
inhibitors12 have been unearthed from thiohydantoins. These
can also act as herbicidal and fungicidal reagents.13 Recently, a
new class of substituted thiohydantoins were synthesized and
tested as DNA uorescence probes, which showed excellent
results.14 Considering their potential applications, various
different synthetic methods have been developed to prepare
Chemistry Division, School of Advanced Sciences, VIT University, Vellore-632014,
Tamilnadu, India. E-mail: sathiya_kuna@hotmail.com; Fax: +914162243092
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c3ra47680d
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to avoid cross reactions, leading to substantial yield and less methanol, ethanol, isopropanol and aprotic solvents such as
reaction time. Though many protecting groups are available for THF, DCM, DMF and DMSO were screened. Among these, acetic
the protection of the amino group, this method is very easy to acid was found to be the best solvent to get a good yield (Table
execute, and the reusability of protecting group is also possible. 1). It was observed that in aprotic solvents such as THF, DCM,
As part of our continued interest in establishing multicompo- DMF and DMSO there was no product formation at all.
nent reactions,21 we undertook a detailed investigation on the
The exibility of this reaction has been tested with various
stepwise formation of 3-amino-2-thiohydantoins. The key substituted benzaldehydes and cinnamaldehyde; the resultant
objectives of this work are the use of a protecting group products are listed in Table 2. Having optimized the solvent for
approach for the synthesis of 3-amino-2-thiohydantoins and the the reaction condition, we then examined the reaction of a
identication of preferred mechanistic pathway for the forma- number of substituted benzaldehydes with chloroacetic acid
tion of 3-amino-2-thiohydantoins.
and protected thiosemicarbazide. Generally the reaction pro-
ceeded well with these substrates and delivered highly
substituted 3-amino-2-thiohydantoins (7a–7n) in good to
excellent yields. (Table 2, entries) The results demonstrated
that both the electronic feature (EWG & EDG) and the orien-
tation of benzaldehydes have limited inuence on this
reaction.
Another notable characteristic of this reaction is that a
wide range of functional groups such as uoro, chloro, nitro
and hydroxy remain intact in the reaction condition. Since the
formed product and CDD have immense polarity difference, it
was decided to wash the product with n-hexane to recover
CDD. This can be used a number of times for further
reactions. Initially we have carried out the reaction between
thiosemicarbazide and chloroacetic acid to synthesize
2. Results and discussion
2.1. Solvent screening for assembling 3-amino-2-
thiohydantoins
3-Amino-2-thiohydantoin derivatives (7) were prepared by two
step sequence that is outlined in Table 1. In the rst step, we
carried out a reaction between CDD and thiosemicarbazide in
order to protect the free amino group in thiosemicarbazide to
avoid the formation of nucleophilic substituted product with
chloroacetic acid in the presence of an acid catalyst, and we got
thiosemicarbazone quantitatively. The cyclisation of the
3-amino-2-thiohydantoins ring system was brought out via
reactions between protected thiosemicarbazide (2), chloroacetic
acid (3) and substituted benzaldehyde (4) over reux in acetic
acid medium. This protecting group protocol was found to be of
wide scope in terms of high yields with no side reactions. A
number of highly substituted 3-amino-2-thiohydantoins deriv-
atives were obtained by varying the substitutions on aromatic
aldehyde.
Table
2 Protecting group approach for the synthesis of highly
substituted 3-amino-2-thiohydantoin derivatives in acetic acid
mediuma
To optimize the reaction condition, we screened different
solvents for this reaction. Protic solvents like acetic acid,
Table 1 Solvent optimization for step-2a
Entry
R
Product
Time (h)
Yieldb (%)
m.p (ꢀC)
1
2
3
4
5
6
7
8
2-F
2-Cl
3-OH
3-NO2
3,4-diOH
4-OCH3
4-CH3CH2
4-F
4-OCH3CH2
4-CH3
7a
7b
7c
7d
7e
7f
7g
7h
7i
2.0
2.5
2.5
2.0
3.0
3.0
3.5
2.5
3.5
3.0
2.5
2.0
2.5
94
92
91
95
94
83
86
92
80
85
89
91
88
220–223
213–215
283–285
254–257
275–278
210–212
231–232
246–249
240–243
221–223
217–220
292–295
263–266
Entry
Solvent
%Yieldb
1
2
3
4
5
6
7
8
9
None
—
92
44
32
22
—
—
—
—
9
Acetic acid
Methanol
Ethanol
Isopropanol
DMF
DMSO
THF
DCM
10
11
12
13
7j
7k
7l
4-Br
4-OH
4-Benzyloxy
7m
14
7n
2.5
79
227–230
a
a
Unless otherwise stated, all the reactions have been carried out by
Unless otherwise stated, all the reactions have been carried out by
reuxing 2 mmol of (5) and 4 mmol of chloroacetic acid and 4 mmol reuxing 2 mmol of (5) and 4 mmol of chloroacetic acid and 4 mmol
of 2-chlorobenzaldehyde in 5 ml of solvent. b Isolated yield.
of benzaldehyde in 5 ml of acetic acid. b Isolated yield.
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3-amino-2-thiohydantoins without any protecting group. But
the product obtained in this reaction was a mixture of various
imidazolidines as shown in Fig. 1. Thus we have protected the
free amino group of thiosemicarbazide using CDD as pro-
tecting group thereby it forms stable ketimine. From these
stable ketimine (protected thiosemicarbazide – (5)) we have
successfully recovered CDD by deprotecting it from free
amino group of thiosemicarbazide and this protecting group
could be used for several times as it regenerates quantita-
tively, whereas with other cyclic ketone it is very difficult to
recover it and separate the product from the deprotected
cyclic ketone. Under the same conditions chloroacetic acid
was added to the protected thiosemicarbazide to yield the
desired product (6). The product thus obtained from the (5)
was very selective and gave higher yield as shown in Fig. 2.
Thus it clearly shows that the synthesis of 3-amino-2-thio-
hydantoins proceeds smoothly without any side product when
the reaction was carried out in the presence of CDD as pro-
tecting group as shown in Fig. 3.
3. Conclusion
A simple and high yielding synthetic protocol has been devel-
oped for the synthesis of highly functionalized 3-amino-2-thio-
hydantoins using cyclododecanone as a protecting group for
thiosemicarbazide. The value of this method lies in the easily
available starting material, short reaction time with excellent
yield and avoidance of column chromatography. Protecting
group cyclododecanone can be isolated and reused for the
further reactions number of times.
4. Experimental section
General methods: All reactions were performed under reux
conditions and open to air. Melting points were determined in
1
open capillary tubes and are uncorrected. H NMR (400 MHz)
and 13C NMR (100 MHz) spectra were recorded in DMSO-d6.
Chemical shis are given in d values referenced to TMS. All the
yields mentioned in the experimental data are of isolated
products unless otherwise mentioned.
4.1. Synthesis of 2-cyclododecylidenehydrazine
carbothiamide from CDD (5)
In an oven dried three necked RB ask mixture of CDD (2 mmol)
and thiosemicarbazide (2 mmol) was taken and dissolved in
ethanol (5 ml). To this 0.2 ml of acetic acid was added and
reuxed for about 30 min in a water bath. The completion of the
reaction was monitored from TLC and the formed precipitate
was ltered, washed with water and dried.
Fig. 1 Synthesis of 3-amino-2-thiohydantoins without protecting
group.
4.2. Synthesis of 2-((E) - 5-(2-uorobenzylidine)-3-((E)-2-
uorobenzylidineamino)-4-oxo-2-thioxoimidazolidine-1-yl)
acetic acid from 5a: pale yellow color solid
With 5 ml of acetic acid 2 mmol of (5) and 2 mmol of chloro-
acetic acid were taken in an oven dried three necked RB ask
and reuxed for about 1 h. The disappearance of (5) was
monitored from TLC. Aer the disappearance of (5) 3 mmol of
2-uorobenzaldehyde was added and reuxed further for about
2 h. Aer the completion of the reaction, the reaction mass was
poured into ice cooled water and the formed yellow precipitate
was ltered, dried and washed with n-hexane. The obtained
ltrate was dried in vacuum and the recovered CDD can be used
for further reactions for a number of times.
Fig. 2 Synthesis of 3-amino-2-thiohydantoins with CDD as protecting
group.
Acknowledgements
Munusamy Sathishkumar thanks Vellore Institute of Tech-
nology, Tamilnadu, India, for providing Research Associate-
ship. The DST-FIST NMR facility at VIT University is greatly
acknowledged.
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