[HSO4]-catalyzed eco-friendly and expeditious synthesis of thiazolidine and oxazolidine derivatives

Article abstract of DOI:10.1039/c4ra15590d

The present study reports a facile and green approach for the synthesis of thiazolidine/oxazolidine derivatives 4(a-u) in excellent yields (92-98%) with high purity. The protocol involves a one-pot three-component reaction of substituted 1,3-diketones 1(a-g), cyanates 2(a-c) and ethylchloroacetate (3) in ionic liquid [Et₃NH][HSO₄] under solvent-free conditions. The notable feature of this pathway is that the ionic liquid possesses both catalytic as well as medium engineering capability in this protocol. Use of [Et₃NH][HSO₄] as a catalyst and an environmentally benign solvent eliminates the need for a volatile organic solvent and additional catalyst. This ionic liquid is air and water stable and easy to prepare from cheap amine and acid. The present synthetic route is a green protocol offering several advantages, such as excellent yield of products, mild reaction conditions, minimizing chemical waste, shorter reaction time, simple operational procedure, easy preparation of the catalyst and its recyclability up to five cycles without any noticeable loss in catalytic activity. The protocol is applicable to a broad substrate scope. The optimization of conditions carried out in the present study revealed that 20 mol% of ionic liquid catalyst under solvent-free conditions at 120 °C are the best reaction parameters for the synthesis of thiazolidine/oxazolidine derivatives in excellent yields. This journal is

Full text of DOI:10.1039/c4ra15590d

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Page 1 of 44
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[Et3NH][HSO4]-catalyzed eco-friendly and expeditious synthesis of thiazolidine and
oxazolidine derivatives
Ali Mohammed Malla,a Mehtab Parveen,*a Faheem Ahmad,a Shaista Azaz,a Mahboob Alamb
aDivision of Organic Synthesis, Aligarh Muslim University, Aligarh, 202002, India
bDivision of Bioscience, Dongguk University, Gyeongju 780-714, Republic of Korea
Abstract
The present study reports
a
facile and green approach for the synthesis of
thiazolidine/oxazolidine derivatives 4 (a-u) in excellent yields (92-98%) with high purity. The
protocol involves one-pot three-component reaction of substituted 1,3-diketones 1(a-g), cyanates
2 (a-c) and ethylchloroacetate (3) in ionic liquid [Et3NH][HSO4] under solvent-free condition.
The notable feature of this pathway is that, the ionic liquid possesses both catalytic as well as
medium engineering capability in this protocol. Use of [Et3NH][HSO4] as a catalyst and an
environmentally benign solvent eliminates the need for a volatile organic solvent and additional
catalyst. This ionic liquid is air and water stable and easy to prepare from cheap amine and acid.
The present synthetic route is a green protocol offering several advantages such as, excellent
yield of products, mild reaction conditions, minimizing chemical wastes, shorter reaction time,
simple operational procedure, easy preparation of catalyst and its recyclability up to five cycles
without any noticeable loss in catalytic activity. The protocol is applicable to a broader substrate
scope. The optimization conditions carried out in the present study revealed that 20 mol% of
o
ionic liquid catalyst under solvent-free condition at 120 C are the best reaction parameters for
the synthesis thiazolidine/oxazolidine derivatives in excellent yields.
Keywords: Dimedone, [Et3NH][HSO4], Thiazolidines, Oxazolidines, Solvent-free, Eco-friendly
*Corresponding author: Mehtab Parveen
E-mail: mehtab.organic2009@gmail.com; Tel: +91-9897179498

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Introduction
Over the past 20 years, there has been an upsurge in the field of green chemistry.1 Most of
the efforts in this direction have been focused on replacing the profusely used toxic volatile
organic solvents (VOS) by suitable alternate solvent systems for easy chemical transformations
with the minimum chemical waste and environmental pollution. In this regard, ionic liquids have
engrossed significant research interest in the context of green synthesis due to their adjustable
physical and chemical properties.2 They have been introduced as an alternative green reaction
media due to their exceptional features such as the advantages of optimization of compound
characteristics through a broad choice of anion and cation combinations, low vapor pressure,
non-volatility, low flammability, good solvating ability, high thermal and chemical stability,
controlled miscibility and ease of recyclability.3-12 The report of 1,3-dialkylimidazolium-based
chloroaluminate ionic liquids by Wilkes et al., that possess favorable physical and
electrochemical properties, provided the impetus for a remarkable increase in activity in this
field.13-14 Ionic liquids have been used as environmentally benign solvents or catalysts,15 thermal
fluids,16, sensors,17 fuel cells,18 capacitors,19 lubricants,20 batteries,21 plasticizers,22 and
extractants.23 The first involvement of ionic liquids in 2003 for first industrial process by BASF
(BASIL10 process) opened new avenues for the application of ionic liquids in new chemical
processes.24 A number of ionic liquids (ILs) viz. [BHP-OMe][Br],25 [TMG][Ac],26 1-Ethyl-3-
methylimidazolium hydrogen sulphate,27 [Bmim][PF6],28 [Hbbim][BF4],29 [Bmim][BF4],30 and
[Cmmim][BF4]31 have been documented in the literature employed for the synthesis of
biologically active molecules (Fig. 1).
Although ionic liquids have been used as alternative reaction media and catalyst,15 their
high cost, difficulty in separation and toxicity confine their applicability. Therefore, there is

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[BHP-OMe][Br]25
[TMG][Ac]26
1-Ethyl-3-methyl
imidazolium hydrogen sulphate27
[Bmim][PF6]28
[Hbbim][BF4]29
[Bmim][BF4]30
[Cmmim][BF4]31
Fig. 1 Ionic liquids (ILs) in synthetic transformations
a demand to explore the cheap and easily available ionic liquids in organic synthesis. Bronsted
acid ionic liquids (BAILs) are of exceptional significance as they possess simultaneously the
proton acidity and the characteristic properties of an ionic liquid.32 These ionic liquids have been
proved to be very efficient catalysts as well as solvents for many organic transformations.33-37
It is pertinent to mention that C-N/C-S bond is of significant importance, as it opens new
avenues for the introduction of nitrogen/sulfur in organic molecules. Despite significant
advancement in this field, the construction of the C-N/C-S bond is still a major challenge for
organic chemists, due to the involvement of harsh reaction conditions or the use of expensive
catalysts.38-40 In this regard, thiazolidine/oxazolidine derivatives constitute an important class of
compounds in organic chemistry due to their promising biological activities.41 A plethora of

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Anti-proliferative42
Analgesic43
Anti-HIV44a
Anti-HIV44b
Anti-malarial45
Anti-convulsant46
7 (a-b) Anti-microbial47
7a: Ar = 2-HOC6H4
7b: Ar = 3-NO2C6H4
COX-2 inhibitory
activity48
Anti-histaminic49
Anti-parasitic50
Anti-oxidant51
Fig. 2 A few examples of pharmacologically active molecules bearing thiazolidine/oxazolidine
moiety in their structural framework

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medicinally important compounds bearing thiazolidine/oxazolidine moiety in their structural
framework have been reported possessing anti-proliferative,42 analgesic,43 anti-HIV,44a-b anti-
malarial,45 anti-convulsant,46 anti-microbial,47 COX-2 inhibitory,48 anti-histaminic,49 Anti-
parasitic50 and anti-oxidant51 activities (Fig. 2). The synthetic efforts for this class of compounds
are very well studied and generally entail the reaction of carbonyl compounds with amine and
mercaptoacetic acid/glycolic acid in organic solvents.52
The catalyst promoted organic synthesis has become one of the hot areas in organic
synthesis in the last few decades. At present, a wide range of methods for synthesizing
thiazolidine/oxazolidine derivatives in the presence of catalysts are available viz. solid-phase/
activation cycloelimination (SP/ACE) process,53 bisphosphine catalyzed,54 Bronsted acids,55 Pd-
catalyzed,56 Zeolite,57 sulfated tungstate,58 ZnCl2,59 SmI2,60 PBu3,61 LiBr,62 PPh3AuNTf2,63
AuPPh3Cl,64 NiI2,65 L-proline66 and PPh3.67 Although, these protocols reported by others find
certain merits of their own, still they suffer from a number of shortcomings including prolonged
reaction times, unsatisfactory yields, harsh reaction conditions, high temperature, use of
hazardous organic solvents and expensive non-reusable catalysts.60,63,68
Thus, it is a challenge to develop alternative greener, milder, cheap and efficient
methodologies for the construction of C-N/C-S bonds. To address the lack of convergent
synthetic methods for the production of desired motifs, in this regard, ionic liquids (ILs) offer
promising efficiency over other catalyzed reactions.69-71 Till now, a very few ionic liquids have
been reported so far for the synthesis of thiazolidine/oxazolidine derivatives such as
[Bmim][PF6],72-73 [TMG][Lac],74 (C3[min]2[Br]2),75 [Bnmim][Cl],76 2-HEAP,77 however these
ionic liquids are of high cost as compared to simple ammonium ionic liquids. The first report
documented so far for the synthesis of thiazolidinones involving [Et3NH][HSO4] was recently

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published by Maryam Kalantari78 involving reaction between thiosemicarbazide,
dimethylacetylene dicarboxylate (DMAD) and carbonyl compounds (scheme 1).
Scheme: 1 Strategy for the synthesis of C-N/C-X (O, S) bonds
In continuation of our previous work on the progress of designing green synthetic
methodologies for organic transformations,79-80 herein we report for the first time the
development of an efficient, economical and recyclable Bronsted acid ionic liquid,
[Et3NH][HSO4] promoted synthesis of thiazolidine/oxazolidine derivatives in excellent yields.
The notable feature of this pathway is that, the ionic liquid possesses both catalytic as well as
medium engineering capability in this protocol. In comparison with the current methods of
thiazolidine/oxazolidine formation, our approach displays specific advantages: (i) it proceeds
faster and gives excellent yields (92-98%); (ii) it requires an inexpensive catalyst; (iii) gives
cleaner reaction profile with high purity (iv) it is applicable to a broader substrate scope
(electron-rich and electron-deficient).

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Results and discussions
Characterization of ionic liquid [Et3NH][HSO4]
The ionic liquid [Et3NH][HSO4] employed in the present study has been characterized on the
basis of 1H NMR and 13C NMR spectral analysis. 1H NMR spectrum displayed a triplet at around
δ 1.29 integrating for nine protons has been attributed to methyl group (3×CH3) protons.
Similarly a multiplet resonating at δ 3.13 for six protons has been assigned to methylene
(3×CH2) protons. A sharp singlet at δ 8.85 for one proton has been assigned to -NH (D2O-
exchangeable) proton (Fig. S1). 13C NMR spectrum of the [Et3NH][HSO4] showed a pair of
signals resonating at around δ 10.27 and 52.09 assigned to methyl (CH3) and methylene (CH2)
carbons, respectively (Fig. S2). These spectral analysis suggested the formation of desired ionic
liquid (IL) [Et3NH][HSO4].
Chemistry
The synthetic pathway for the synthesis of thiazolidine/oxazolidine derivatives 4 (a-u) has been
depicted in Table 1. Herein, a series was typically accessed via a facile condensation reaction
between appropriately substituted 1,3-diketones 1(a-g), cyanates 2 (a-c) and ethylchloroacetate
(3) in [Et3NH][HSO4]. The present “one-pot synthesis” protocol provides easy access to the
synthesis of desired products in excellent yields (92-98%) with high purity and was investigated
to establish the feasibility and scope for broader substrate choice.
The structural elucidation of the synthesized compounds 4 (a-u) has been established on
1
13
the basis of elemental analysis, IR, H NMR, C NMR and mass spectral study. The analytical
results for C, H and N were within ±0.3% of the theoretical values and were found to be in
conformity with the proposed molecular structures. IR spectrum of all the synthesized

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Table 1 Synthetic pathway for the synthesis of of thiazolidine/oxazolidine derivatives 4 (a-u)
Products
Substituents
R1
R2
R3
X
-CH3
-CH3
S
4a
4b
-CH3
-CH3
-CH3
O
-CH3
H
CH2=CH-CH2-
CH2=CH-CH2-
S
S
4c
4d
H
H
H
O
S
S
4e
4f
4g
H
H
O
S
4h
4i
CH2=CH-CH2-
H
H
S
4j
O
4k

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H
H
CH2=CH-CH2-
S
S
4l
4m
H
H
O
S
4n
4o
CH2=CH-CH2-
H
H
H
H
H
H
S
O
S
4p
4q
4r
4s
4t
CH2=CH-CH2-
S
O
S
CH2=CH-CH2-
4u
compounds displayed characteristic signals for carbonyl (C=O) and lactam (CO-N) linkage at
1
around 1730-1749 and 1622-1647 cm-1, respectively. H NMR spectrum (see supplementary
information) of each compound exhibited a sharp singlet resonating at around δ 2.65-4.93 for
two protons, has been assigned to methylene (H-5′) protons of the thiazolidine/oxazolidine ring.
This downfield shift is attributed to the electron withdrawing nature of the adjacent carbonyl
group. 13C NMR spectrum (see supplementary information) was also in good agreement with the
proposed structures displaying characteristic signals for carbonyl and lactam carbonyl at around
δ 189.5-199.6 and 155.7-178.9, respectively. Similarly signals resonating at around δ 32.6-74.9
have been assigned to methylene carbon (-CH2) of the thiazolidine/oxazolidine ring. Moreover

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characteristic signals for aromatic ring carbons have been discussed in experimental section. The
mass spectral analysis of the synthesized compounds was also in good conformity with the
proposed structures.
In our present study, a series of thiazolidine/oxazolidine derivatives 4 (a-u) of substituted
1,3-diketones were synthesized by reaction between substituted 1,3-diketones 1 (a-g), cyanates
2 (a-c) and ethylchloacetate (3) in DMF in the absence of ionic liquid [Et3NH][HSO4]. The
reaction took stretched time period (5-7 hours) for completion with a moderate yield (65-75%) of
the products (Table 2). The use of DMF as a solvent of choice for the comparative studies
(Table 2) has been selected in view of its aprotic nature. Since, we believe that using common
protic solvents (EtOH, MeOH) may react with the reactants in the reaction media that will
eventually affect our reaction in terms of yield as there is the probability of by-product
formation.81-82 Moreover, there are reports in the literature where almost analogues of
thiazolidine/oxazolidine compounds have been synthesized in excellent yields using DMF as a
solvent of choice.83-84
In order to develop an eco-friendly and efficient approach for the synthesis of
biologically active thiazolidine/oxazolidine derivatives, we explored the efficiency of ionic
liquid [Et3NH][HSO4] by carrying out one-pot condensation reaction of appropriately substituted
1,3-diketones, cyanates and ethylchloroacetate in equimolar ratio (2 mmol each). To explore the
generality and scope of this reaction, different 1,3-diketones were examined under the optimized
conditions and the results are summarized in Table 2. To our delight, this method was found to
be very general for a wide range of 1,3-diketones with various substituents on the aromatic ring.
In our experiments, we investigated the optimum reaction conditions regarding the choice of

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Table 2 [Et3NH][HSO4] catalyzed synthesis of thiazolidine/oxazolidine derivatives 4 (a-u)
Products
Structure
Reaction in presence Reaction in presence
of DMF of [Et3NH][HSO4]
M.P
(oC)
Time
(hrs)
Yield
(%)
Time
(min)
Yield
(%)
5
74
25
98
128-
129
4a
4b
5.5
70
28
95
125-
126
5
72
73
69
71
26
30
28
35
96
94
97
92
145-
146
4c
4d
4e
4f
6
198
175
182
5.3
5.5

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6
68
73
70
35
32
29
93
96
94
201
4g
4h
4i
5.7
6.5
215
173
7
5
65
75
71
34
27
30
92
98
95
156
167
163
4j
4k
4l
5.8
6
73
28
96
204
4m

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6.4
6.2
68
71
27
32
93
97
219
4n
4o
196
5.8
5.5
5.2
5.0
68
66
72
74
35
28
26
27
93
95
97
98
137
147
153
186
4p
4q
4r
4s
5.8
6.0
70
68
32
34
93
95
171
167
4t
4u

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solvent, temperature of reaction and loading of catalyst on a model reaction using 5,5-dimethyl-
cyclohexane-1,3-dione (1a), phenylisothiocyanate (2a) and ethylchloroacetate (3) to establish
best reaction conditions in terms of yield and reaction time.
To achieve the optimum concentration of [Et3NH][HSO4], the model reaction was
investigated initially in absence of [Et3NH][HSO4], it was found that reaction took prolonged
time period (8 hrs) with impure products (Table 3, entry 1). The model reaction was then
subsequently tested for different concentrations 5, 10, 15, 20 and 25 mol% (Table 3, entries 2-6)
o
of [Et3NH][HSO4] at 120 C under solvent-free condition. It is evident from (Table 3, entry 5)
that 20 mol% of the [Et3NH][HSO4] is adequate to gain the optimum yield in the shortest
reaction time (25 min). Using less than 20 mol% of catalyst, moderate yields of the product (57-
85%) were obtained with extended reaction times, while with an excess mol% of catalyst (25
mol%) there was no further increase in the yield of the product, possibly due to the saturation of
the [Et3NH][HSO4]. The above results signify that 20 mol% of [Et3NH][HSO4] is optimum dose
in terms of efficient yield and reduced reaction time.
In order to study the effect of solvents, the model reaction was carried out in various
conventional organic solvent systems. The model reaction was first investigated in DMSO and
EtOH (Table 4, entries 1-2) the reaction took a longer time period (6-7 hrs) with moderate yields
of 55% and 52%, respectively, whereas in DMF (Table 4, entry 3), the product 4a was obtained
in better yield (74%) after refluxing for 4 hrs. In CH3CN and CH3NO2, moderate yields (61%
and 63%) of the product 4a were obtained after a stretched reaction periods (Table 4, entries 4-
5). On the other hand, toluene (C6H5CH3) gave comparable results in terms of yield 85% (Table
4, entry 6) with drop in reaction time (4 hrs). It is quite evident from the data reported in Table
4, that nature of solvent has a prominent effect on the kinetics as well as on the yield of the

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Table 3 Effect of catalyst loading on the yield and time period of model reaction (4a)a
Entry
Catalyst (mol %)
Time (hrs)b
Yield (%)c
No Catalyst
8
4
Impure
57
1
2
3
4
5
6
5
10
15
20
25
2.5
1
72
85
25d
25d
98
98
aReaction conditions: 5,5-dimethylcyclohexane-1,3-dione (1a, 2 mmol), phenylisothiocyanate
(2a, 2 mmol) and ethylchloroacetate (3, 2 mmol), solvent free, 120 oC
bReaction progress monitored by TLC (entry 1-4, hrs)
cIsolated yield of products
dReaction progress monitored by TLC (entry 5-6, min)
products. This variation in results (% yield of products) is believed to be due to polar/protic
nature of the solvent systems used in the study. The results justify that nonpolar solvents such as
toluene endowed excellent selectivity about 85% yield of the desired product 4a (Table 4, entry
6) with substantial dip in reaction time. However, toluene is not a solvent of choice for
sustainable chemistry as it poses a serious threat to the environment.85 The variation of solvent
system from nonpolar to polar (DMF, CH3NO2, CH3CN, DMSO and EtOH) endorses a

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Table 4 Effect of various solvents and temperature on the model reactiona
Entry
Solvent
DMSO
Temp (oC)
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Room Temp.
60
Time (hrs)b
Yield (%)c
6
7
55
52
74
61
63
85
82
85
88
90
98
98
1
2
EtOH
DMF
5
3
CH3CN
6.5
6.5
4
4
CH3NO2
5
Toluene
6
[Et3NH][HSO4]
[Et3NH][HSO4]
[Et3NH][HSO4]
[Et3NH][HSO4]
[Et3NH][HSO4]
[Et3NH][HSO4]
4
7
3
8
80
2
9
100
1.5
25d
25d
10
11
12
120
140
aReaction conditions: 5,5-dimethylcyclohexane-1,3-dione (1a, 2 mmol), phenylisothiocyanate
(2a, 2 mmol) and ethylchloroacetate (3, 2 mmol), Different solvents (20 mL, entry 1-6, refluxing
temperature), [Et3NH][HSO4] (20 mol%, entry 7-12, temperature 25-140 oC)
bReaction progress monitored by TLC (entry 1-10, hrs)
cIsolated yield of products
dReaction progress monitored by TLC (entry 11-12, min)

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reasonable fall in selectivity of product 4a as well as stretched reaction times (Table 4, entry 1-
5). The resuts suggest that the yield of product 4a in different solvent systems follow the order
as: Nonpolar solvent (85%) ˃ Polar-aprotic solvent (55-74%) ˃ Polar-protic solvent (52%). The
significant dip in the yield of product 4a (52%) (Table 4, entry 2) in polar-protic solvent (EtOH)
is believed to be its protic nature that may react with the phenylisothiocyanate, rendering it
unavailable (by-product) for the reaction with 1,3-diketones eventually will lower the yield of
product.81 The selectivity would decrease largely, because of the formation of by-product O-
Ethyl phenylcarbamothioate. The percent of by-product formation can be minimized by choosing
nonpolar solvent as a reaction media. However, toluene being environmentally toxic can allocate
DMF as an optional solvent in the present study in absence of ionic liquid. On the basis of these
findings it can be concluded that [Et3NH][HSO4] is the solvent of choice in comparison to
conventional solvent systems.
To optimize the reaction temperature, the model reaction was carried out at different
temperatures in ionic liquid [Et3NH][HSO4] (Table 4, entries 7-12). It was observed that the
o
o
increase in temperature from 25 C to 120 C, has a noteworthy effect on the model reaction in
terms of yield and reaction time. The yield of the product increased from 82-98% during the
course of reaction (Table 4, entries 7-11). However, no further enhancement in the yield of
o
o
product 4a was observed when the reaction temperature was raised from 120 C to 140 C
(Table 4, entry 12). In view of the above results, it was concluded that 20 mol% of ionic liquid
o
[Et3NH][HSO4] mediated synthesis of 4a at 120 C are the best reaction paramaters for the
synthesis of present thiazolidine/oxazolidine derivatives in excellent yields.
A comparative study of a variety of other Bronsted acid ionic liquid catalysts was
conducted to probe the superiority of [Et3NH][HSO4]. It is apparent from (Table 5) that the

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Table 5 Comparison of the efficiency of [Et3NH][HSO4] for the synthesis of (4a)a
Entry
Catalyst
Time (min)b
Yield (%)c
[Et3NH][HSO4]
[Me3NH][HSO4]
[Et2NH2][HSO4]
[Et3NH][H2PO4]
[Me3NH][H2PO4]
[Et2NH2][H2PO4]
[Et3NH][CH3COO]
[Me3NH][CH3COO]
25
48
43
51
55
49
54
59
98
89
93
85
81
76
78
74
1
2
3
4
5
6
7
8
aReaction conditions: 5,5-dimethylcyclohexane-1,3-dione (1a, 2 mmol), phenylisothiocyanate
o
(2a, 2 mmol) and ethylchloroacetate (3, 2 mmol), Solvent free, 120 C, Different ionic liquids
(20 mol%)
bReaction progress monitored by TLC
cIsolated yield of products.
catalytic activity was strongly affected by the anionic part of the ionic liquids. In case of [HSO4]
anion, higher yields were obtained (Table 5, entries 1-3). However, when [H2PO4] and
[CH3COO] anions were probed for their efficiency, lower yields (74-85%) were obtained as
compared to [HSO4] anion (89-98%), probably due to the weaker acidity of the phosphate and
acetate anions in comparison to [HSO4] anion. The results obtained in Table 5 validate that the
anions of the ionic liquid (IL) have a notable effect than the cations on the reaction rates and

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selectivity. This can be presumably attributed to the pKa values (acid dissociation constant) of
their respective anions (HSO4, H2PO4 and CH3COO) which offers a quantitative measurement of
the strength of an acid, smaller the pKa value, stronger is the acid. The results (% yield of
products) obtained in Table 5 are in good agreement with the pKa values of their respective
anions which follow the order as: HSO4 (pKa = -3) ˃ H2PO4 (pKa = 2.15) ˃ CH3COO (pKa = 4).
The size of the alkyl chain tethered to the cationic part of ionic liquid (IL) endorse no significant
effect on the yield and selectivity of the model reaction in the present study (Table 5). However,
triethylammonium cation [Et3NH]+ in each respective series i.e., [Et3NH][HSO4],
[Et3NH][H2PO4] and [Et3NH][CH3COO] enhances the yield of the desired product 4a to a
reasonable extent. Tuning the ionic liquid in a particular series in the present study, by replacing
ethyl group‟s by methyl group‟s results in a modest decrease in the yield of the desired product
4a. This fluctuation in yield can be presumably attributed to the extent of stabilization of
ammonium cation by the attached electron releasing alkyl groups (+ Inductive effect), the more
stabilization effect being offered by ethyl moiety followed by methyl group. It is obvious that
tuning of triethylammonium cation by HSO4 anion in the present study provides excellent yields
(92-98 %) of the desired products. These results imply that [Et3NH][HSO4] is the best ionic
liquid catalyst/promoter for the synthesis of present thiazolidine/oxazolidine derivatives.
The reusability of the catalyst was also explored for the selected model reaction. The
catalyst was reused five times and the results demonstrate that the catalyst can be reused without
a significant reduction in the yield (Table 6). After the first fresh run with 98% yield, cold water
was added to the reaction mixture and the products were isolated by filtration. The ionic liquid
was recovered from the filtrate by removing the water under reduced pressure. The recovered
ionic liquid was further tested up to four more reaction cycles. Recycling and reuse of the ionic

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Table 6 Reusability of [Et3NH] [HSO4] in the synthesis of (4a)a
Entry
Reaction cycle
1st (fresh run)
2nd cycle
Isolated yield (%)b
98
92
89
85
80
1
2
3
4
5
3rd cycle
4th cycle
5th cycle
aReaction conditions: 5,5-dimethylcyclohexane-1,3-dione (1a, 2 mmol), phenylisothiocyanate
(2a, 2 mmol) and ethylchloroacetate (3, 2 mmol), [Et3NH][HSO4] (20 mol%), 120 oC
bIsolated yield of products
liquid showed minimal decreases in yields. The product 4a was obtained in 92%, 89%, 85%,
80% yields after successive cycles. (Table 6, entries 2-5), thus proving the catalyst‟s reusability.
The results demonstrate that our ionic liquid is almost stable towards moisture. Although the
reaction rate get decreased gradually with repetition of the reaction cycle, however we succeeded
in getting the desired product 4a in satisfactory yield (80%) even after 5th repetition of the model
reaction without any addition of the fresh catalyst (Table 6, entry 5). This gradual but consistent
dip in reaction rate is assumed to be due to remains of traces of water in ionic liquid during
reaction work-up process. The traces of water in the ionic liquid is believed to react with active

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reaction reactants (phenylisothiocyanate) leading to by-product formation, consequently
lowering the yields of desired product 4a in the subsequent cycles.86
To ascertain the intermediate involved in the reaction pathway, the reaction of 5,5-
dimethyl-cyclohexane-1,3-dione (1a) and phenylisothiocyanate (2a) was ceased without the
addition of ethylchloroacetate (3) (scheme 2).
Scheme: 2 Synthetic route for the synthesis of intermediate compound 5
Water was added and the reaction mixture was further stirred for 5 min. The solid obtained was
removed by filtration, washed with appropriate solvents and then crystallized from methanol to
yield block shaped crystals of intermediate compound 5 (Fig. S3). The structural authentication
1
13
of intermediate compound 5 was confirmed on the basis of H and C NMR spectral analysis
(Fig. S4-S5), finally verified by single crystal X-ray crystallographic studies (Fig. 3). Pertinent
crystallographic data for compound 5 is summarized in Table S1 (see supplementary
information).
In light of the above results, a plausible mechanistic pathway (scheme 3) is proposed to
illustrate the synthesis of thiazolidine/oxazolidine derivatives catalyzed by [Et3NH][HSO4]. The
initial step is believed to be the protonation of the cyanates (I) by protic ionic liquid
[Et3NH][HSO4] to form intermediate (II), which facilitates the nucleophilic attack of substituted
1,3-diketone to promote the formation of C-C bond to yield intermediate (III). The subsequent
elimination of HCl by the reaction of intermediate (III) with ethylchloroacetate expedite the

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(a)
(b)
Fig. 3 Asymmetric unit showing (a) Thermal ellipsoid (50%) plot and (b) Ball and stick model
of intermediate compound (5)
formation of C-X bond to yield compound (IV). The final step involves the sequential expulsion
of ethanol (EtOH) molecule by the nucleophilic attack of nitrogen to the carbonyl group to
promote C-N bond formation, accelerated by ionic liquid [Et3NH][HSO4] eventually leads to the
formation of cyclized target products 4 (a-u).
Experimental section
Materials and general methods
Chemicals and reagents were purchased from Merck and Sigma-Aldrich (India) as „synthesis
grade‟ and used without further purification. Melting points were determined on a Kofler
apparatus and are uncorrected. Elemental analysis (C, H, N) was conducted using Carlo Erba
analyzer model 1108. The IR spectra were recorded with a Shimadzu IR-408 Perkin-Elmer1800
1
13
instrument (FTIR) and the values are given in cm-1. H NMR and C NMR spectra were run in
DMSO-d6 on a Bruker Avance-II 400 MHz instrument with TMS as an internal standard and J

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Scheme: 3 Plausible mechanistic catalytic cycle for the synthesis of target
thiazolidine/oxazolidine derivatives 4 (a-u)

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values were measured in Hertz (Hz). Chemical shifts are reported in ppm (δ) relative to TMS.
Mass spectra were recorded on a JEOL D-300 mass spectrometer. Thin layer chromatography
(TLC) glass plates (20×5 cm) were coated with silica gel G (Merck) and exposed to iodine
vapors to check the homogeneity as well as the progress of the reaction.
Synthesis of ionic liquids
The simple ammonium ionic liquids of general type [amine] [HSO4] were synthesized by the
known standard literature methods87 in the following way:
Triethylammonium sulfate [Et3NH] [HSO4]
The synthesis of ionic liquid was carried out in a 250 mL round-bottomed flask, which was
immersed in a recirculating heated water-bath and fitted with a reflux condenser. Sulfuric acid
(49 g, 0.5 mol) 98% solution in water was added drop wise into triethylamine (50.5 g, 0.5 mol) at
60 oC for 1 hour. After the addition, the reaction mixture was stirred for an additional period of 1
o
hour at 70 C to ensure the reaction had proceeded to completion. The traces of water were
o
removed by heating the residue at 80 C in high vacuum (5 mm Hg) until the weight of the
1
residue remained constant. The yield of [Et3NH] [HSO4] was 95%. H NMR (400 MHz, DMSO-
13
d6, δ, ppm): 1.29 (t, 9H), 3.13 (m, 6H), 8.85 (s, 1H, D2O exchangeable). C NMR (100 MHz,
DMSO-d6, δ, ppm): 10.27 (CH3), 52.09 (CH2).
The following ionic liquids were synthesized by the same procedure.87
Trimethylammonium sulfate [Me3NH] [HSO4]
1H NMR (400 MHz, DMSO-d6, δ, ppm): 2.52 (s, 9H), 2.70 (s, 1H, D2O exchangeable).

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Diethylammonium sulfate [Et2NH2] [HSO4]
1H NMR (400 MHz, DMSO-d6, δ, ppm): 1.13 (t, 6H), 2.97 (m, 4H), 8.24 (s, 2H, D2O
exchangeable).
Triethylammonium dihydrogen phosphate [Et3NH] [H2PO4]
1H NMR (400 MHz, DMSO-d6, δ, ppm): 1.16 (t, 9H), 3.23 (m, 6H), 8.73 (s, 1H, D2O
exchangeable).
Trimethylammonium dihydrogen phosphate [Me3NH] [H2PO4]
1H NMR (400 MHz, DMSO-d6, δ, ppm): 2.51 (s, 9H), 2.73 (s, 1H, D2O exchangeable).
Diethylammonium dihydrogen phosphate [Et2NH2] [H2PO4]
1H NMR (400 MHz, DMSO-d6, δ, ppm): 1.15 (t, 6H), 2.94 (m, 3H), 8.11 (s, 2H, D2O
exchangeable).
Triethylammonium Acetate [Et3NH] [CH3COO]
1H NMR (400 MHz, DMSO-d6, δ, ppm): 1.12 (t, 9H), 2.10 (s, 3H), 3.14 (m, 6H), 8.81 (s, 1H,
D2O exchangeable).
Trimethylammonium Acetate [Me3NH] [CH3COO]
1H NMR (400 MHz, DMSO-d6, δ, ppm): 2.57 (s, 9H), 2.15 (s, 3H), 2.73 (s, 1H, D2O
exchangeable).
General procedure for the synthesis of thiazolidine/oxazolidine derivatives
To a mixture of substituted 1,3-diketone 1 (a-g) (2 mmol) and cyanate 2 (a-c) (2 mmol), 20 mol
% of [Et3NH][HSO4] was added and the reaction mixture was allowed to stir at room
temperature for 5 min. After 5 min, ethylchloroacetate (2 mmol) was added and the reaction
o
mixture was heated at 120 C with stirring. During the reaction process, the reaction mixture

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spontaneously solidified. After completion of the reaction as evident from thin layer
chromatography (TLC), the reaction mixture was allowed to cool at room temperature. Water
was added and the reaction mixture was further stirred for 5 min. The solid obtained was
removed by filtration, washed with appropriate solvents and then recrystallized from ethanol.
The water was removed from filtrate under reduced pressure to recover [Et3NH] [HSO4], which
was then reused in subsequent cycles.
Spectral characterization
5,5-dimethyl-2-(4-oxo-3-phenyl-thiazolidin-2-yl)-cyclohexane-1,3-dione (4a)
Compound 4a crystallized from CHCl3-MeOH as colorless solid; Yield: 98%; m.p. 128-129 oC;
Anal. Calc. for C17H17NO3S: C, 64.74; H, 5.43; N, 4.44; Found: C, 64.70; H, 5.41; N, 4.39. IR ν
cm-1: 1744 (C=O), 1640 (-CON), 1613 (C=C), 2874 (CH2 Str.). 1H NMR (400 MHz, DMSO-
KBr
max
d6, δ, ppm): 1.12 (s, 6H, 2×CH3), 1.57 (s, 2H, CH2), 2.48 (s, 2H, CH2), 2.65 (s, 2H, CH2,
thiazolidine ring), 7.26-7.47 (m, 5H, phenyl ring). 13C NMR (100 MHz, DMSO-d6, δ, ppm): 27.9
(2×CH3), 30.22 (C-5), 46.9 (C-5'), 52.5 (C-4 and C-6), 108 (C-2), 125.7, 127.3, 128.9, 131.5
(phenyl ring), 137.0 (C-2'), 180.0 (C=O, C-4'), 191.5 (C=O), 199.3 (C=O). MS (ESI) m/z: 315
[M+H] +•
5,5-dimethyl-2-(4-oxo-3-phenyl-oxazolidin-2-yl)-cyclohexane-1,3-dione (4b)
Compound 4b crystallized from CHCl3-EtOH as white solid; Yield: 95%; m.p 125-126 oC; Anal.
Calc. for C17H17NO4: C, 68.21; H, 5.72; N, 4.68; Found: C, 68.24; H, 5.70; N, 4.63. IR ν KBr cm-
max
1
1: 2945 (CH2 Str.), 1744 (C=O), 1649 (-CON), 1597 (C=C). H NMR (400 MHz, DMSO-d6, δ,
ppm): 1.12 (s, 6H, 2×CH3), 1.57 (s, 2H, CH2), 2.48 (s, 2H, CH2), 2.65 (s, 2H, CH2, oxazolidine
ring), 7.0-7.38 (m, 5H, phenyl ring). 13C NMR (100 MHz, DMSO-d6, δ, ppm): 22.2 (2×CH3),

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29.9 (C-5), 36.4 (C-5'), 48.3 (C-4 and C-6), 108 (C-2), 119.8, 121.9, 128.8, 131.5 (phenyl ring),
139.1 (C-2'), 155.7 (C=O, C-4'), 192.2 (C=O), 195.5 (C=O). MS (ESI) m/z: 299 [M+H] +•.
2-(3-allyl-4-oxo-thiazolidin-2-yl)-5,5-dimethyl-cyclohexane-1,3-dione (4c)
Compound 4c crystallized from CHCl3-MeOH as brownish solid; Yield: 96%; m.p. 145-146 oC.
Anal. Calc. for C14H17NO3S: C, 60.19; H, 6.13; N, 5.01; Found: C, 60.15; H, 6.15; N, 5.04. IR ν
1
cm-1: 1739 (C=O), 1645 (-CON), 1592 (C=C), 29631 (CH2 Str.). H NMR (400 MHz,
KBr
max
DMSO-d6, δ, ppm): 1.07 (s, 6H, 2×CH3), 1.59 (s, 2H, CH2), 2.57 (s, 2H, CH2), 2.70 (s, 2H, CH2,
thiazolidine ring), 2.98 (d, 2H, N-CH2), 4.53 (dd, 2H, =CH2), 6.03 (m, 1H, =CH-). 13C NMR
(100 MHz, DMSO-d6, δ, ppm): 26.5 (2×CH3), 31.6 (C-5), 46.9 (N-CH2), 52.5 (C-4 and C-6),
105.2 (C-2), 116.4 (=CH2), 137 (C-2'), 139.2 (=CH-), 172.3 (C=O, C-4'), 189.5 (C=O), 190.1
(C=O). MS (ESI) m/z: 279 [M+H] +•.
5-(4-chlorophenyl)-2-(4-oxo-3-phenylthiazolidin-2-ylidene)-cyclohexane-1,3-dione (4d)
o
Compound 4d crystallized from CHCl3-MeOH as colorless solid; Yield: 94%; m.p. 198 C;
Anal. Calc. for C21H16ClNO3S: C, 63.39; H, 4.05; N, 3.52; found: C, 63.37; H, 4.06; N, 3.53. IR
1
cm-1: 1746 (C=O), 1630 (-CON), 1611 (C=C), 2870 (CH2 str.). H NMR (400 MHz,
KBr
max
ν
DMSO-d6, δ, ppm): 3.20 (m, 1H, C-5), 3.38 (m, 4H, C-4 and C-6), 4.20 (s, 2H, C-5ʹ thiazolidine
ring), 7.10-7.45 (m, 9H, phenyl ring). 13C NMR (100 MHz, DMSO-d6, δ, ppm): 31.9 (C-5), 33.9
(C-2ʹ), 43.9 (C-5ʹ), 46.8 (C-4 and C-6), 106.3 (C-2), 126.5 (C-2ʹʹ and C-6ʹʹ), 129.5 (C-3ʹʹ and C-
5ʹʹ), 132.1 (C-4ʹʹ), 133.5, 127.8, 124.9, 118.8 (phenyl ring), 140.5 (C-1ʹʹ), 166.6 (C-4ʹ), 199.0 (C-
1 and C-3). MS (ESI) m/z: 397.05 [M+H] +•.
5-(4-chlorophenyl)-2-(4-oxo-3-phenyloxazolidin-2-ylidene)-cyclohexane-1,3-dione (4e)
o
Compound 4e crystallized from CHCl3-acetone as orange solid; Yield: 97%; m.p. 175 C; Anal.
Calc. for C21H16ClNO4: C, 66.06; H, 4.22; N, 3.67; found: C, 66.01; H, 4.25; N, 3.69. IR ν mKBaxr

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1
cm-1: 1736 (C=O), 1635 (-CON), 1619 (C=C), 2878 (CH2 str.). H NMR (400 MHz, DMSO-d6,
δ, ppm): 3.24 (m, 1H, C-5), 3.31 (m, 4H, C-4 and C-6), 4.82 (s, 2H, C-5ʹ oxazolidine ring), 7.22-
7.40 (m, 9H, phenyl ring). 13C NMR (100 MHz, DMSO-d6, δ, ppm): 33.5 (C-5), 46.82 (C-4 and
C-6), 48.9 (C-2ʹ), 73.5 (C-5ʹ), 106.7 (C-2), 126.2 (C-2ʹʹ and C-6ʹʹ), 128.8 (C-3ʹʹ and C-5ʹʹ), 131.5
(C-4ʹʹ), 133.1, 126.8, 125.9, 117.8 (phenyl ring), 140.7 (C-1ʹʹ), 165.6 (C-4ʹ), 197.8 (C-1 and C-3).
MS (ESI) m/z: 381.08 [M+H] +•.
2-(3-allyl-4-oxothiazolidin-2-ylidene)-5-(4-chlorophenyl)-cyclohexane-1,3-dione (4f)
o
Compound 4f crystallized from CHCl3-MeOH as white solid; Yield: 92%; m.p. 182 C; Anal.
Calc. for C18H16ClNO3S: C, 59.75; H, 4.46; N, 3.87; found: C, 59.72; H, 4.47; N, 3.89. IR ν mKBaxr
1
cm-1: 1746 (C=O), 1639 (-CON), 1616 (C=C), 2870 (CH2 str.). H NMR (400 MHz, DMSO-d6,
δ, ppm): 3.22 (m, 1H, C-5), 3.35 (m, 4H, C-4 and C-6), 3.98 (d, 2H, N-CH2), 4.13 (dd, 2H,
=CH2), 4.89 (s, 2H, C-5ʹ thiazolidine ring), 6.13 (m, 1H, =CH-), 7.27 (d, 2H, C-2ʹʹ and C-6ʹʹ),
13
7.36 (d, 2H, C-3ʹʹ and C-5ʹʹ). C NMR (100 MHz, DMSO-d6, δ, ppm): 14.5 (C-4ʹʹ), 31.9 (C-5),
33.8 (C-5ʹ), 45.5 (C-2ʹ), 46.8 (C-4 and C-6), 46.9 (N-CH2), 106.1 (C-2), 116.4 (=CH2), 126.9 (C-
2ʹʹ and C-6ʹʹ), 127.8 (C-3ʹʹ and C-5ʹʹ), 139.2 (=CH-), 141.7 (C-1ʹʹ), 166.6 (C-4ʹ), 197.6 (C-1 and
C-3). MS (ESI) m/z: 361.05 [M+H] +•.
5-(3,4-dimethoxyphenyl)-2-(4-oxo-3-phenylthiazolidin-2-ylidene)-cyclohexane-1,3-dione
(4g)
o
Compound 4g crystallized from CHCl3-EtOH as reddish solid; Yield: 93%; m.p. 201 C; Anal.
Calc. for C23H21NO5S: C, 65.23; H, 5.00; N, 3.3; found: C, 65.20; H, 5.03; N, 3.3. IR ν KBr cm-1:
max
1
1732 (C=O), 1639 (-CON), 1620 (C=C), 2888 (CH2 str.). H NMR (400 MHz, DMSO-d6, δ,
ppm): 3.11 (m, 4H, C-4 and C-6), 3.20 (m, 1H, C-5), 3.53 (s, 6H, 2×-OCH3), 4.72 (s, 2H, C-5ʹ
thiazolidine ring), 7.12-7.70 (m, 8H, phenyl ring). 13C NMR (100 MHz, DMSO-d6, δ, ppm): 31.9

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(C-5), 33.5 (C-5ʹ), 46.62 (C-4 and C-6), 57.0 (2×-OCH3), 106.9 (C-2), 112.0 (C-6ʹʹ), 113.8 (C-
3ʹʹ), 121.2 (C-2ʹʹ), 133.8, 126.2, 124.9, 118.8 (phenyl ring), 143.5 (C-4ʹʹ), 145.7 (C-1ʹʹ), 149.6 (C-
5ʹʹ), 165.7 (C-2ʹ), 178.9 (C-4ʹ), 196.8 (C-1 and C-3). MS (ESI) m/z: 423.11 [M+H] +•.
5-(3,4-dimethoxyphenyl)-2-(4-oxo-3-phenyloxazolidin-2-ylidene)-cyclohexane-1,3-dione
(4h)
o
Compound 4h crystallized from CHCl3-acetone as white solid; Yield: 96%; m.p. 215 C; Anal.
Calc. for C23H21NO6: C, 67.80; H, 5.20; N, 3.44; found: C, 67.80; H, 5.22; N, 3.42. IR ν KBr cm-1:
max
1
1733 (C=O), 1632 (-CON), 1614 (C=C), 2858 (CH2 str.). H NMR (400 MHz, DMSO-d6, δ,
ppm): 3.10 (m, 1H, C-5), 3.21 (m, 4H, C-4 and C-6), 3.69 (s, 6H, 2×-OCH3), 4.79 (s, 2H, C-5ʹ
oxazolidine ring), 7.32-7.72 (m, 8H, phenyl ring). 13C NMR (100 MHz, DMSO-d6, δ, ppm):
31.54 (C-5), 46.35 (C-4 and C-6), 56.2 (2×-OCH3), 73.5 (C-5ʹ), 104.9 (C-2), 112.1 (C-3ʹʹ), 112.5
(C-6ʹʹ), 120.6 (C-2ʹʹ), 132.9, 126.8, 124.1, 118.5 (phenyl ring), 143.0 (C-4ʹʹ), 147.1 (C-1ʹʹ), 147.9
(C-2ʹ), 148.2 (C-5ʹʹ), 165.1 (C-4ʹ), 195.1 (C-1 and C-3). MS (ESI) m/z: 407.14 [M+H] +•.
2-(3-allyl-4-oxothiazolidin-2-ylidene)-5-(3,4-dimethoxyphenyl)-cyclohexane-1,3-dione (4i)
o
Compound 4i crystallized from CHCl3-MeOH as yellowish solid; Yield: 94%; m.p. 173 C;
Anal. Calc. for C20H21NO5S: C, 62.00; H, 5.46; N, 3.62; found: C, 62.04; H, 5.42; N, 3.60. IR ν
cm-1: 1738 (C=O), 1622 (-CON), 1620 (C=C), 2852 (CH2 str.). 1H NMR (400 MHz, DMSO-
KBr
max
d6, δ, ppm): 3.14 (m, 1H, C-5), 3.26 (m, 4H, C-4 and C-6), 3.79 (s, 6H, 2×-OCH3), 4.21 (s, 2H,
C-5ʹ thiazolidine ring), 4.93 (dd, 2H, =CH2), 4.98 (d, 2H, N-CH2), 6.03 (m, 1H, =CH-), 6.13 (d,
1H, C-2ʹʹ), 7.17 (s,1H, C-6ʹʹ), 7.37 (d, 1H, C-3ʹʹ). 13C NMR (100 MHz, DMSO-d6, δ, ppm): 31.59
(C-5), 32.6 (C-5ʹ), 45.1 (N-CH2), 46.31 (C-4 and C-6), 56.4 (2×-OCH3), 108.9 (C-2), 112.4 (C-
3ʹʹ), 112.8 (C-6ʹʹ), 116.8 (=CH2), 120.9 (C-2ʹʹ), 135.2 (=CH-), 143.6 (C-4ʹʹ), 146.7 (C-2ʹ), 147.8
(C-1ʹʹ), 148.7 (C-5ʹʹ), 165.6 (C-4ʹ), 193.9 (C-1 and C-3). MS (ESI) m/z: 387.11 [M+H] +•.