It is thiazolidine-2,4-dione and not thiohydantoins as the reaction product of monosubstituted thioureas and chloroacetylchloride

Article abstract of DOI:10.1080/17415993.2011.628995

The reaction products of monosubstituted phenylthioureas with chloroacetylchloride in a polyethylene glycol (PEG-400) medium and K2CO3 as base/catalyst at an elevated temperature are exclusively thiazolidine-2,4-diones and not thiohydantoins as has been reported. The core unit thiazolidine-2,4- dione is essentially derived from chloroacetylchloride and the thioamidic part of the phenylthiourea. The scope of this unprecedented transformation has been evaluated with electron-rich and electron-poor phenylthioureas.

Full text of DOI:10.1080/17415993.2011.628995

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It is ‘thiazolidine-2,4-dione’ and not
thiohydantoins as the reaction product
of monosubstituted thioureas and
chloroacetylchloride
a
a
a
Ramesh Yella , Raman Kumar Singh , Ganesh Majji & Bhisma
a
K. Patel
a
Department of Chemistry , Indian Institute of Technology
Guwahati , Guwahati , Assam , India
Published online: 02 Nov 2011.
To cite this article: Ramesh Yella , Raman Kumar Singh , Ganesh Majji & Bhisma K. Patel
(
2012) It is ‘thiazolidine-2,4-dione’ and not thiohydantoins as the reaction product of
monosubstituted thioureas and chloroacetylchloride, Journal of Sulfur Chemistry, 33:1, 43-47, DOI:
0.1080/17415993.2011.628995
1
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Journal of Sulfur Chemistry
Vol. 33, No. 1, February 2012, 43–47
It is ‘thiazolidine-2,4-dione’ and not thiohydantoins as the
reaction product of monosubstituted thioureas and
chloroacetylchloride
Ramesh Yella, Raman Kumar Singh, Ganesh Majji and Bhisma K. Patel*
Department of Chemistry, Indian Institute of Technology Guwahati, Guwahati, Assam, India
(Received 8 August 2011; final version received 27 September 2011)
The reaction products of monosubstituted phenylthioureas with chloroacetylchloride in a polyethy-
lene glycol (PEG-400) medium and K2CO3 as base/catalyst at an elevated temperature are exclusively
thiazolidine-2,4-diones and not thiohydantoins as has been reported. The core unit thiazolidine-2,4-dione
is essentially derived from chloroacetylchloride and the thioamidic part of the phenylthiourea. The scope of
thisunprecedentedtransformationhasbeenevaluatedwithelectron-richandelectron-poorphenylthioureas.
O
O
H
N
O
Cl
Cl
H
N
O
+
X
NH
2
Cl
S
Cl
S
X
X
O
N
K CO (5 mol %)
N
NH
2
K
2
CO
3
(5 mol %)
S
2
3
PEG-400, 80 o
C
H
PEG-400, 80 oC
2
H O
Keywords: monosubstituted thiourea; chloroacetylchloride; PEG-400; thiazolidine-2,4-dione
1
.
Introduction
Themechanismofthiazole-2-imineformationhasnotbeenwellunderstoodleadingtotheproposal
of incorrect structures for the products obtained by the reaction of thiourea analogs with α-
haloketones by two independent research groups (1). Based on the principle of hard–soft reactivity,
i.e. hard nucleophile attacks on hard electrophile and the soft nucleophile on soft electrophile,
we have suggested an alternative reaction mechanism for the formation of thiazole-2-imine. Our
mechanism is supported by isolating the reaction intermediate, confirming its structure and that of
the products by X-ray crystallography (2). Having understood the reactivity of thioureas toward
α-haloketones, recently, we have suggested an alternative structure for the product obtained by
the reaction of thiourea with chloroacetylchloride (3). The structure of the product is found to
*
Corresponding author. Email: patel@iitg.ernet.in
ISSN 1741-5993 print/ISSN 1741-6000 online
2012 Taylor & Francis
©
http://dx.doi.org/10.1080/17415993.2011.628995
http://www.tandfonline.com

4
4 R. Yella et al.
have the 2-imino-4-thiazolidinones moiety (3) and not the thiohydantoin as has been reported
previously by another group (4).
2
. Results and discussion
Based on our previous observations (2, 3) on the reactivity of thiourea analogs with
chloroacetylchloride and α-halo ketones, we had concluded that the reaction product of monosub-
stituted thioureas with chloroacetylchloride in the polyethylene glycol (PEG-400) medium using
K2CO3 as the base are not thiohydantoins (5) as had been previously and mistakenly assigned.
Instead, the reaction product is expected to have the isomeric iminothiazolidin-4-one skeleton
(
Scheme 1). Our assumption is based on the fact that the sulfur atom (soft nucleophile) of the
thiourea should preferentially attack the chloromethyl carbon of the α-haloketone (soft elec-
trophile) and the NH2 (hard nucleophile) should attack the carbonyl center (hard electrophile)
(
Scheme 1).
We envisaged the following two alternative mechanisms for the formation of iminothiazolidin-
4
-one (1a) (Scheme 2). The soft nucleophilic sulfur of thiourea attacks the soft electrophilic
chloromethyl carbon giving an intermediate (X) as proposed in Mechanism 1 (Scheme 2).
Intramolecular attack of the NH2 group of the intermediate (X) on the carbonyl group of acylchlo-
ride would give the expected product (1a). In an alternative path (Mechanism 2), the attacking
sequence is reversed; in the first step, the hard nucleophile NH2 first attacks the carbonyl group
(
hard electrophile) giving an intermediate (Y) followed by an intramolecular attack of the soft
sulfur nucleophile on the chloromethyl carbon (soft electrophile) leading to the formation of the
iminothiazolidin-4-one derivative (1a) (Scheme 2).
Withtheseassumptions, werepeatedthereactionofphenylthiourea(1)andchloroacetylchloride
under the identical conditions that had been reported by Kidwai et al. (5). A product was isolated
H
O
N
N
O
S
Cl
H
N
Cl
Ar
Cl
Cl
NH
NH2
Our expected product
N
O
Ar
O
Ar
H
O
N
S
S
PEG/ K CO3
PEG/ K CO
2 3
2
O
Kidwai et al.
5)
S
(
Actual product obtained
Scheme 1. Reported structure, our proposed structure and the actual structure.
H
N
H
O
O
N
NH2
N
NH2
N
O
S
Mechanism 1:
+
S
Cl
S
Cl
(
1)
Cl
(1a)
(X)
O
O
H
N
H
N
N
H
H
N
Cl
N
NH2
O
Cl
S
Mechanism 2:
+
S
S
Cl
(1a')
(
1)
(Y)
Scheme 2. Mechanism for the formation of iminothiazolidin-4-one (1a).

Journal of Sulfur Chemistry 45
Figure 1. Structure and Oak Ridge thermal ellipsoid plot view of thiazolidine-2,4-dione (1b).
purified and subjected to spectroscopic investigation. Surprisingly, the proton NMR analysis of the
compound showed the absence of any aromatic proton signals and the resultant product showed
the presence of a singlet at 3.95 ppm and another broad singlet at 11.9 ppm in the ratio of 2:1.
X-ray crystallography analysis of the product which crystallized from methanol further confirmed
the absence of any aromatic ring and the compound was found to be thiazolidine-2,4-dione (1b)
as shown in Figure 1.1
This result was bit surprising and unexpected to us but nevertheless the absence of a
thiohydantoin-type skeleton is confirmed from the crystal X-ray crystallography (Figure 1). The
presence of a iminothiazolidin-4-one (1a)-type skeleton can be clearly seen in the thiazolidine-2,4-
dione (1b) moiety (Figure 1) as was suggested by us at the beginning. As anticipated earlier, the
compoundiminothiazolidin-4-one(1a)(Scheme 2)wouldhaveformedbutinthebasicmediumthe
exocyclic imino group hydrolyzed as shown in Scheme 3 giving thiazolidine-2,4-dione (1b). Iso-
lation of the aniline as one of the product further confirmed the hydrolytic path (Scheme 3) and the
mechanism proposed earlier (Scheme 2). In an attempt to stop the reaction at the iminothiazolidin-
4
-one (1a) stage, the reaction was performed in the absence of K2CO3 (acidic medium) and three
equivalents of K2CO3 (basic medium) but in each case we failed to isolate the product (1a)
and thiazolidine-2,4-dione (1b) was obtained, suggesting the susceptibility of the substrate (1a)
toward acidic and basic hydrolytic conditions. Hydrolyses of similar substrates are well known
in the literature (6).
The product thiazolidine-2,4-dione (1b) was also obtained by reacting 1 with analogous bis-
electrophile bromoacetyl bromide instead of chloroacetylchloride.We were curious to see whether
other monosubstituted arylthioureas would behave similarly or differently. Substrates (Table 1,
Entries 2–4) containing weakly deactivating substituents (Cl and Br) in ortho- and para-positions
gave thiazolidine-2,4-dione (1b) in good yields with the expulsion of the corresponding amines
(
(
2c–4c). A monosubstituted thiourea containing a strong electron-withdrawing group (−NO2)
5) in its para-position also gave thiazolidine-2,4-dione (1b) but in a relatively lower yield. As
per the mechanism proposed, these results are not surprising because irrespective of the nature
of the aryl ring all are expected to give the same product but the rate of some of the steps
may vary with the nature of the substituents. To further support our claim, monosubstituted
thioureas possessing weakly electron-donating substituents (−CH3) (6–7) and strong electron-
donating substituents (OCH3 and −OH) (8 and 9) when reacted with chloroacetylchloride all
gave thiazolidine-2,4-dione (1b) and their corresponding amines (6c–9c).
H
N
H
N
O
O
H
H
N
O
N
N
NH2
S
O
H
S
O
+
S
(
1a)
OH2
(1b)
(1b)
Scheme 3. Mechanism for the formation of thiazolidine-2,4-dione (1b).

4
6
R. Yella et al.
Table 1. Reaction product of monosubstituted thiourea with chloroacetylchloride in
a
PEG and K2CO .
3
Thiourea
Productb
Yield (%)c
NH2
Amined
H
N
NH2
S
(1)
88
(1c)
Cl
Cl
H
N
NH2
NH2
(
2)
S
S
79
80
(2c)
H
N
NH2
NH2
(3)
(3c)
Cl
Br
Cl
Br
H
N
NH2
(4)
NH2
S
S
S
S
82
65
(4c)
H
N
O
H
N
O
NH2
NH2
(1b)
S
(5)
(5c)
O N
O N
2
2
H
N
NH2
NH2
(6)
84
82
(6c)
H
N
NH2
NH2
(7)
(7c)
H
N
NH2
NH2
S
S
(8)
80
78
(8c)
H CO
H CO
3
3
H
N
NH2
NH2
(9)
(9c)
HO
HO
a
Notes: Reactions were completed in 2 h and monitored by TLC.
b
c
d
Confirmed by 1H NMR, C NMR and X-ray diffractometer (XRD).
Isolated yield.
13
Compared by TLC and gas chromatography mass spectra.
3
.
Conclusion
In conclusion, we have unambiguously proved that the reaction product of monosubsti-
tuted thiourea with chloroacetylchloride in the presence of K2CO3 using PEG-400 sol-
vent is thiazolidine-2,4-dione and not the reported thiohydantoins or the expected isomeric
iminothiazolidine-4-one. Furthermore, the scope of this transformation was evaluated with
different monothioureas under identical conditions.
4
. Experimental
All the reagents were of commercial grade and purified according to established procedures.
Organic extracts were dried over anhydrous sodium sulfate. Solvents were removed in a rotary

Journal of Sulfur Chemistry 47
evaporator under reduced pressure. Reactions were monitored by thin-layer chromatography
(
TLC) on silica gel 60 F254 (0.25 mm). Column chromatography was performed using silica
gel (60–120 meshes). NMR spectra were recorded in CDCl3 with tetramethylsilane as the inter-
1
13
nal standard for H NMR (400 MHz) and C NMR (100 MHz); the chemical shifts are expressed
as δ values (ppm). Melting points were recorded in a Buchi B-545 melting point apparatus and are
uncorrected. IR spectra were recorded in KBr or neat on a Nicolet Impact 410 spectrophotometer.
4
.1. General procedure for the preparation of thiazolidine-2,4-dione (1b) from
monosubstituted thiourea (1)
A mixture of monosubstituted thiourea (2 mmol), chloroacetylchloride (2 mmol), K2CO3
◦
(
10 mol%) and PEG 400 (3 ml) was added to a 25 ml round-bottom flask and stirred at 80 C
for 2 h. During this time, complete consumption of the starting material was observed as judged
by TLC. After completion of the reaction, the reaction mixture was cooled to room temperature
and admixed with diethyl ether (3 × 5 ml). Diethyl ether layer was decanted from PEG-400 and
evaporated in a rotary evaporator. The product was purified over a column of silica gel and eluted
◦
◦
1
with (9:1 hexane/ethylacetate) to give 1b (90% yield). m.p. 120 C [Lit. (7) m.p. 122 C]. H
1
3
NMR (CDCl3 + DMSO-d6): δ 3.95 (s, 2H), 11.88 (br s, 1H). C NMR (CDCl3 + DMSO-d6) δ
5.7, 172.8, 173.5. IR (KBr): 3461 (m), 3133 (s), 3044 (s), 2948 (m), 2823 (m), 1738 (s), 1681
s), 1667 (s), 1391 (m), 1342 (s), 1315 (s), 1227 (s), 1163 (s), 890 (m), 805 (s), 789 (s), 717 (s)
3
(
cm
−
1
.
Acknowledgements
B.K.P. acknowledges the support of this research from DST New Delhi (SR/S1/OC-15/2006 and SR/S5/NM-01/2005)
and CSIR 01(1688)/00/EMR-II, R.Y. to CSIR and G.M. to UGC for fellowships. Thanks are due to Central Instruments
Facility (CIF) IIT Guwahati for NMR and mass spectra and DST-FIST for XRD facility.
Notes
1
.
Crystallographic description of thiazolidine-2,4-dione (1b) Crystal dimmension (mm), 0.28 × 0.24 × 0.20,
C3H3NO2S, Mr = 117.13; Triclinic, space group Pbca; a = 7.3839(8) Å, b = 9.4279(10) Å, c = 13.2912(15) Å,
◦
3
3
α = β = γ = 90 , V = 925.26(17) Å , Z = 8, ρcal = 1.682 Mg/m ; reflection collected/unique = 1160/1000;
2
refinement method = full matrix least squares on f ; final R indices [I > 2σ1], R1 = 0.0599, wR2 = 0.1844, R
indices (all data), R1 = 0.0640, wR2 = 0.1882; goodness of fit = 1.168. #CCDC 842108.
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