Synthesis and biological evaluation of new 1,3-Thiazolidine-4-one Derivatives of 2-(4-Isobutylphenyl)propionic Acid

Article abstract of DOI:10.3390/molecules190915005

New thiazolidine-4-one derivatives of 2-(4-isobutylphenyl)propionic acid (ibuprofen) have been synthesized as potential anti-inflammatory drugs. The structure of the new compounds was proved using spectral methods (FR-IR, 1H-NMR, 13C-NMR, MS). The in vitro antioxidant potential of the synthesized compounds was evaluated according to the total antioxidant activity, the DPPH and ABTS radical scavenging assays. Reactive oxygen species (ROS) and free radicals are considered to be involved in many pathological events like diabetes mellitus, neurodegenerative diseases, cancer, infections and more recently, in inflammation. It is known that overproduction of free radicals may initiate and amplify the inflammatory process via upregulation of genes involved in the production of proinflammatory cytokines and adhesion molecules. The chemical modulation of acyl hydrazones of ibuprofen 3a-l through cyclization to the corresponding thiazolidine-4-ones 4a-n led to increased antioxidant potential, as all thiazolidine-4-ones were more active than their parent acyl hydrazones and also ibuprofen. The most active compounds are the thiazolidine-4-ones 4e, m, which showed the highest DPPH radical scavenging ability, their activity being comparable with vitamin E.

Full text of DOI:10.3390/molecules190915005

Molecules 2014, 19, 15005-15025; doi:10.3390/molecules190915005
OPEN ACCESS
molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
Synthesis and Biological Evaluation of New 1,3-Thiazolidine-4-one
Derivatives of 2-(4-Isobutylphenyl)propionic Acid
Ioana Mirela Vasincu 1, Maria Apotrosoaei 1, Andreea-Teodora Panzariu 1, Frédéric Buron 2,
Sylvain Routier 2,* and Lenuta Profire 1,*
1
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Medicine and
Pharmacy “Grigore T. Popa”, 16 University Street, Iasi 700115, Romania;
E-Mails: ioanageangalau@yahoo.com (I.M.V.); mariasutu@yahoo.com (M.A.);
teutz_panzariu@yahoo.com (A.-T.P.)
2
Institute of Organic and Analytical Chemistry, University of Orléans, Orléans 45076, Cedex 2,
France; E-Mail: frederic.buron@univ-orleans.fr
* Authors to whom correspondence should be addressed;
E-Mails: sylvain.routier@univ-orleans.fr (S.R.); lprofire@mail.umfiasi.ro (L.P.);
Tel.: +40-232-412375 (L.P.); Fax: +40-232-211818 (L.P.).
Received: 3 July 2014; in revised form: 21 August 2014 / Accepted: 10 September 2014 /
Published: 18 September 2014
Abstract: New thiazolidine-4-one derivatives of 2-(4-isobutylphenyl)propionic acid
(ibuprofen) have been synthesized as potential anti-inflammatory drugs. The structure of
the new compounds was proved using spectral methods (FR-IR, 1H-NMR, 13C-NMR, MS).
The in vitro antioxidant potential of the synthesized compounds was evaluated according to
the total antioxidant activity, the DPPH and ABTS radical scavenging assays. Reactive
oxygen species (ROS) and free radicals are considered to be involved in many pathological
events like diabetes mellitus, neurodegenerative diseases, cancer, infections and more
recently, in inflammation. It is known that overproduction of free radicals may initiate and
amplify the inflammatory process via upregulation of genes involved in the production of
proinflammatory cytokines and adhesion molecules. The chemical modulation of acyl
hydrazones of ibuprofen 3a–l through cyclization to the corresponding thiazolidine-4-ones
4a–n led to increased antioxidant potential, as all thiazolidine-4-ones were more active
than their parent acyl hydrazones and also ibuprofen. The most active compounds are the
thiazolidine-4-ones 4e, m, which showed the highest DPPH radical scavenging ability,
their activity being comparable with vitamin E.

Molecules 2014, 19
Keywords: ibuprofen; thiazolidine-4-one; synthesis; spectral methods; antioxidant effect
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1. Introduction
Ibuprofen, a nonsteroidal anti-inflammatory drug (NSAID) with an arylpropionic acid structure is
very useful in therapy for its analgesic, antipyretic and anti-inflammatory effects [1,2]. Long-term use
of this drug, like most NSAIDs, has however been associated with gastro-intestinal (GI) ulceration,
bleeding and nephrotoxicity [3,4]. The anti-inflammatory effects of NSAIDs are related to the
inhibition of prostaglandin synthesis by blocking the activity of cyclooxygenase enzyme (COX) [5]. It
is known that COX exists in two isoforms, constitutive COX-1 that provides cytoprotection in the
gastrointestinal tract and inducible COX-2, which mediates inflammation [5,6]. The GI damage
induced by NSAIDs is generally attributed to two factors, i.e., local irritation caused by the carboxylic
acid moiety common to most NSAIDs (topical effect) and decreased production of tissue-cytoprotective
prostaglandins [7]. Although selective COX-2 inhibitors are very efficient as anti-inflammatory agents
and safer to gastrointestinal tract, recent data showed that therapy with COX-2 selective inhibitors could
be associated with increased cardiovascular risks [8]. In order to improve the anti-inflammatory effect
and safety profile of representative NSAIDs, one research strategy is derivatization of the carboxylic
acid group with various heterocyclic systems (oxazole, izoxazole, pyrazole, oxadiazole, thiazole,
thiadiazole, triazole, etc.) [9,10]. In the past two decades there has been considerable interest in the
role of reactive oxygen species (ROS) in inflammation [11]. ROS mediate the oxidative degradation of
cellular components and alteration of protease/antiprotease balance with damage to the corresponding
tissue. In the early stages of the inflammatory process, ROS exert their actions through activation of
nuclear factors, such as NFkB or AP-1, that induce the synthesis of cytokines. In later stages, endothelial
cells are activated due to the synergy between free radicals and cytokines, promoting the synthesis of
inflammatory mediators and adhesion of molecules. In the last step free radicals react with different
cellular components (trypsin, collagen, LDL, DNA, lipids) inducing the death of cells [12,13].
The thiazolidine-4-one moiety is a heterocycle that has received more attention in the last years due
its important biological properties [14]. Many effects have been found, including anti-inflammatory
and analgesic [15], antitubercular [16], antimicrobial and antifungal [17], antiviral, especially as anti-HIV
agents [18], anticancer, antioxidants [19], anticonvulsants [20] and antidiabetic activity [21]. In the
present study, some new derivatives of ibuprofen that contain thiazolidine-4-one scaffolds were
synthesized in order to obtain compounds with double effect—antioxidant and anti-inflammatory
properties. The structures of the compounds were assigned based on their spectral data (FT-IR,
1H-NMR, 13C-NMR, MS) and the compounds were screened for their in vitro antioxidant potential.
2. Results and Discussion
2.1. Chemistry
The 1,3-thiazolidine-4-one derivatives 4a–m were synthesized in several steps using the method
summarized in Scheme 1 and Table 1. First 2-(4-isobutylphenyl)propionic acid (ibuprofen, 1) was reacted

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with thionyl chloride, followed by treatment with dry ethanol to get 2-(4-isobutylphenyl)propionic acid
ethyl ester, which was turned in 2-(4-isobutylphenyl)propionic acid hydrazide (2) by reaction with
66% hydrazine hydrate [22]. The condensation of compound 2 with various aromatic aldehydes
allowed the preparation of the corresponding hydrazone derivatives 3a–l in satisfactory yields.
Finally, the hydrazone derivatives of ibuprofen upon reaction with mercaptoacetic acid led to the
thiazolidine-4-one derivatives 4a–l in moderate to good yields. By reduction of compound 4g in
presence of tin chloride and few drops of acetic acid in ethanol, the thiazolidine-4-one 4m was obtained
in 90% yield. Acetylation of 4m with acetyl chloride gave thiazolidine-4-one 4n in moderate yield.
Scheme 1. Synthetic procedure of compounds 4a–n.
Reagents and conditions: (a) thionyl chloride, reflux, 4 h; (b) dry ethanol, reflux, 4 h; (c) hydrazine hydrate,
dry ethanol, reflux, 12 h; (d) aromatic aldehyde, dry ethanol, reflux, 4 h; (e) mercaptoacetic acid, heating 2–8 h.
Table 1. Synthesized derivatives 3 and 4.
Entry
Product 3
N°, Yield
Product 4
N°, Yield
1
3a, 76%
4a, 57%
2
3
4
5
6
7
3b, 91%
3c, 93%
3d, 84%
3e, 91%
3f, 85%
3g, 69%
4b, 76%
4c, 77%
4d, 66%
4e, 73%
4f, 62%
4g, 72%

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Table 1. Cont.
Entry
Product 3
N°, Yield
Product 4
N°, Yield
8
3h, 86%
4h, 41%
9
3i, 69%
3j, 69%
3k, 52%
3l, 60%
-
4i, 53%
4j, 38%
4k, 87%
4l, 38%
10
11
12
13
14
-
-
4m, 90%a
4n, 47%b
-
4g, SnCl2, acetic acid, ethyl alcohol, room temperature 14 h; 4m, NaH, acetyl chloride, DMF, reflux, 14 h.
1
The structure of the compounds was assigned on the basis of their spectral data (IR, H-NMR,
13C-NMR, MS) which are provided in the Experimental Section. The spectral data of compound 2 was
in agreement with the literature [23]. The IR spectra of the acyl hydrazone derivatives of ibuprofen
3a–l showed characteristic absorption bands corresponding to their NH, C=O and C=N groups at
3185–3180 cm−1, 1669–1662 cm−1 and 1608–1596 cm−1, respectively. The appearance of the
stretching band of the thiazolidine-4-one C=O at 1710–1721 cm−1, together with the characteristic
C-S absorption band at 656–694 cm−1 confirmed the formation of compounds 4a–n.
In the 1H-NMR spectra of compounds 3a–l all groups exhibited two sets of signals. It is known that
N-acylhydrazones can exist in four possible forms, as geometrical isomers (E/Z) with respect to the
C=N double bond and as rotamers (cis/trans) due to the amide N-C(O) bond [24]. Based on literature
data the N-acylhydrazones derived from aromatic aldehydes are in the E form because the ZN-N
conformer is not formed due to the steric hindrance on the imine bond [25]. All compounds were
found to exist as racemic mixtures of two isomers, as indicated by their 1H-NMR spectra. The two sets
of signals indicate the possibility of equilibrium and interconversion between rotamers (and/or
configurational isomers) in solution. The signals of the azomethine group (N=CH) proton of one form
appeared at δ 8.17–8.61 ppm, while the proton of the other form appeared at δ 7.89–8.30 ppm as a
singlet. The NH proton (CO-NH-N=) of one form also appeared at δ 11.44–11.79 ppm, whereas the

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13
proton of the other form appeared at δ 11.18–11.55 ppm as a singlet. In the C-NMR spectra of the
compounds 3a–l the azomethine carbon (N=CH) of one form resonated at δ 141.76–146.94 ppm
whereas the carbon of the other form appeared at δ 137.97–142.92 ppm. The formation of the
thiazolidine-4-one heterocyclic system has been proved by the characteristic NMR data. In the
1H-NMR spectra of the compounds 4a–n the CH(SCHN) protons resonate as a singlet between
5.66–6.71 ppm and 5.46–6.57 ppm corresponding to the isomer forms. The protons of the methylene
group (-CH2-S) appears as multiplets or doublets of doublets between 3.61–3.97 ppm and 3.70–3.77 ppm.
The carbons of the thiazolidine-4-one system appear in the 13C-NMR spectra between 55.72–61.80 ppm
and 28.45–29.64 ppm. The proton and carbon signals for other characteristic groups were all observed
according to the expected chemical shift and integral values. The NMR spectral data, coupled with
the mass spectra, strongly support the proposed structures of the all synthesized compounds.
2.2. Biological Evaluation
2.2.1. Total Antioxidant Activity
The total antioxidant activity was determined measuring the phophomolybdenum blue complex
with a maximum absorption at 695 nm [26]. The data, which are presented in Tables 2 and 3, showed
that all the tested compounds are more active than ibuprofen. It was also observed that the total
antioxidant activity of acyl hydrazone derivatives 3a–l (Table 2) was improved by cyclization to the
corresponding thiazolidine-4-ones 4a–l (Table 3) which supports the favorable influence of
thiazolidin-4-one scaffold for antioxidant potential.
Table 2. Total antioxidant activity (EC50 µg/mL) of the acylhydrazone derivatives 3a–l.
Sample
EC50 µg/mL
79.70 ± 0.70
71.96 ± 1.12
96.78 ± 1.22
77.07 ± 0.51
82.39 ± 0.83
73.32 ± 0.32
773.67 ± 3.41
Sample
EC50 µg/mL
78.42 ± 1.34
70.10 ± 1.14
84.57 ± 1.28
106.19 ± 1.64
68.01 ± 1.72
91.64 ± 1.68
26.18 ± 0.51
3a
3b
3c
3d
3e
3g
3h
3i
3j
3k
3f
3l
Ibuprofen
Vitamin E
Data are mean ± SD (n = 3, p < 0.05).
Table 3. Total antioxidant activity (EC50 µg/mL) of the thiazolidine-4-one derivatives 4a–n.
Sample
EC50 µg/mL
73.58 ± 0.96
53.98 ± 1.26
82.26 ± 0.41
74.14 ± 1.39
76.16 ± 1.03
70.04 ± 1.29
53.46 ± 0.90
773.67 ± 3.41
Sample
EC50 µg/mL
74.02 ± 0.97
96.17 ± 1.48
58.84 ± 1.47
74.20 ± 0.50
60.83 ± 0.86
85.10 ± 0.21
109.85 ± 2.56
26.18 ± 0.51
4a
4h
4b
4i
4c
4j
4d
4k
4l
4e
4f
4m
4g
4n
Ibuprofen
Vitamin E
Data are mean ± SD (n = 3, p < 0.05).

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The most active compounds were 4b (EC50 = 53.98 ± 1.26), 4g (EC50 = 53.46 ± 0.90), 4j
(EC50 = 58.84 ± 1.47) and 4l (EC50 = 60.83 ± 0.86) which contain Cl(4), NO2(4), CF3(3) and 2,6-diCl
as substituents on the thiazolidine-4-one aromatic ring. These compounds were about 14 times (4b, 4g)
and 13 times (4j, 4l) more active than ibuprofen (EC50 = 773.67 ± 3.41), respectively. Important
antioxidant activity has also been shown by the compounds 4d (EC50 = 70.04 ± 1.29), 4a
(EC50 = 73.58 ± 0.96), 4h (EC50 = 74.02 ± 0.97), 4d (EC50 = 74.14 ± 1.39), 4k (EC50 = 74.20 ± 0.50)
and 4e (EC50 =76.16 ± 1.03) that are 10–11 times more active than parent compound ibuprofen. The
tested compounds were however less active than vitamin E used as positive control.
2.2.2. DPPH Radical Scavenging Assay
DPPH is a well-known radical used as indicator to evaluate the radical scavenging ability of
antioxidants. In methanol solution DPPH has an intense violet color with a UV-Vis absorption band at
517 nm, and it becomes pale yellow or colorless when neutralized in the presence of proton donating
agents [27]. The DPPH radical scavenging ability (%) of samples at concentrations of 487.8 µg/mL is
presented in Tables 4 and 5. Higher values of scavenging ability indicate a higher radical scavenging
effectiveness potential.
Table 4. The DPPH radical scavenging ability of the acyl hydrazone derivatives 3a–l.
Sample Scavenging Ability (%)
Sample
Scavenging Ability (%)
1.25 ± 0.13
3a
4.19 ± 0.22
5.13 ± 0.61
5.14 ± 0.47
6.27 ± 0.45
17.57 ± 0.21
13.52 ± 0.20
4.15 ± 0.22
3g
3b
3h
6.80 ± 0.55
3c
3i
4.24 ± 0.55
3d
3e
3j
5.57 ± 0.62
3k
3l
2.16 ± 0.15
3f
5.82 ± 0.55
Ibuprofen
Vitamin E *
96.48 ± 0.94
* 0.25 mg/mL stock solution; Data are mean ± SD (n = 3, p < 0.05).
Table 5. The DPPH radical scavenging ability of the thiazolidine-4-one derivatives 4a–n.
Sample Scavenging Ability (%)
Sample
Scavenging Ability (%)
9.89 ± 0.29
4a
59.64 ± 0.28
81.31 ± 0.55
7.98 ± 0.32
11.53 ± 0.18
94.42 ± 0.43
43.33 ± 0.65
67.99 ± 0.60
4.15 ± 0.22
4h
4b
4i
17.85 ± 0.17
3.02 ± 0.09
4c
4j
4d
4k
53.29 ± 0.26
10.62 ± 0.17
94.88 ± 0.57
11.66 ± 0.17
96.48 ± 0.94
4e
4f
4l
4m
4g
4n
Ibuprofen
Vitamin E *
* 0.25 mg/mL stock solution; Data are mean ± SD (n = 3, p < 0.05).
In the acyl hydrazone series most of the the tested compounds showed a radical scavenging ability
comparable with ibuprofen (Table 4). The most active compounds were 3e and 3f which are about
three times and two times more active than their parent compound, respectively. The scavenging ability

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of the acyl hydrazones was improved by cyclization to the corresponding thiazolidine-4-one derivatives,
these compounds all being more active than ibuprofen, except for compound 4j which contains a CF3
group in the meta position of phenyl ring (Table 5). The most active compounds were 4e and 4m
which contain NO2 and NH2 groups in ortho and para position of the phenyl ring, respectively. For
these compounds the radical scavenging ability (%) was 94.42 ± 0.43 and 94.88 ± 0.57, which means
that the compounds are about 23 times more active than ibuprofen (4.15 ± 0.22). The activity of these
compounds is comparable with that of vitamin E used as positive control. Important radical scavenging
ability was also shown by compound 4b (81.31 ± 0.55), which contains a Cl group in the para position
of the phenyl ring, the compound being 20 times more active than ibuprofen.
2.2.3. ABTS Radical Scavenging Assay
The ABTS (2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) radical cation decolorization
assay is based on the ability of hydrogen donating antioxidants to scavenge the long-life radical cation
ABTS+. ABTS+, which is a blue chromophore, is generated by the reaction between 2,2'-azino-bis(3-
ethylbenzothiazoline-6-sulfonic acid) and ammonium persulfate. The antioxidant compound produces
a discoloration of the solution with a decrease in the absorbance measured at 734 nm [28]. The ABTS
radical scavenging ability (%) of samples at concentrations of 200 µg/mL is presented in Tables 6 and
7. Higher values of scavenging ability indicate a higher radical scavenging effectiveness potential.
Table 6. The ABTS radical scavenging ability of the acyl hydrazone derivatives 3a–l.
Sample Scavenging Ability (%)
Sample
Scavenging Ability (%)
1.67 ± 0.35
3a
7.03 ± 0.35
5.44 ± 0.65
3.21 ± 0.18
4.59 ± 0.37
8.19 ± 0.17
3.69 ± 0.07
4.42 ± 0.18
3g
3b
3h
13.31 ± 0.81
5.79 ± 0.48
3c
3i
3d
3e
3j
6.07 ± 0.23
3k
3l
3.79 ± 0.35
3f
3.01 ± 0.27
Ibuprofen
Vitamin E *
96.75 ± 0.40
* 1 mg/mL stock solution; Data are mean ± SD (n = 3, p < 0.05).
Table 7. The ABTS radical scavenging ability of the thiazolidine-4-one derivatives 4a–n.
Sample Scavenging Ability (%)
Sample
Scavenging Ability (%)
7.70 ± 0.57
4a
7.24 ± 0.30
52.17 ± 1.20
4.29 ± 0.21
22.88 ± 0.43
52.79 ± 1.28
10.94 ± 0.51
37.14 ± 1.10
4.42 ± 0.18
4h
4i
4j
4k
4l
4m
4n
4b
4c
4.84 ± 0.43
3.44 ± 0.16
4d
4e
4f
51.53 ± 1.29
2.41 ± 0.30
25.48 ± 0.49
10.08 ± 0.39
96.75 ± 0.40
4g
Ibuprofen
Vitamin E *
* 1 mg/mL stock solution; Data are mean ± SD (n = 3, p < 0.05).
The acyl hydrazone derivatives showed an antioxidant activity comparable with ibuprofen. The
most active compound in this series was 3h, with radical scavenging activity of 13.31 ± 0.81, which

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means that this compound is three times more active than ibuprofen (4.42 ± 0.18). In the
thiazolidine-4-one series the most active compounds were 4b, 4e and 4k, which contain Cl(4), NO2(2)
and CN(4), respectively, as substituents on the phenyl ring. These compounds, which showed a
scavenging ability of around 50%, are 12 times more active than ibuprofen. In comparison with the
corresponding acyl hydrazones 3b, 3e and 3k the thiazolidine-4-ones were 10 times (4b), seven times
(4e) and 13 times (3k) more active. The improved antiradical activity of acyl hydrazones by
cyclization to form thiazolidine-4-ones was also observed for compounds 3d, 3f and 3g. The most
favorable influence was observed for acyl hydrazone 4g, which contains a NO2 in the para position of
the phenyl ring. The corresponding thiazolidine-4-one (4g, 37.14 ± 1.10) is 22 times more active than
3g (1.67 ± 0.35). These data strongly support the favorable influence of the thiazolidine-4-one ring on
the antioxidant potential of these compounds. The tested compounds were less active than vitamin E.
3. Experimental Section
3.1. General Procedures
The melting points were measured using a Buchi Melting Point B-540 apparatus and they are
uncorrected. The FT-IR spectra were recorded on Horizon MBTM FT-IR, over a 500–4000 cm−1 range,
after 32 scans at a resolution of 4 cm−1. The spectra processing was carried out with the Horizon MBTM
FTIR Software. The 1H-NMR (400 MHz) and 13C-NMR (101 MHz) spectra were obtained on a Bruker
Avance 400 MHz spectrometer using tetramethylsilane as internal standard and DMSO-d6 as solvent.
The chemical shifts were shown in δ values (ppm). The mass spectra were registered using a Bruker
MaXis Ultra-High Resolution Quadrupole Time-of-Flight Mass Spectrometer. The progress of the
reaction was monitored on TLC, using pre-coated Kieselgel 60 F254 plates (Merck, Whitehouse
Station, NJ, USA) and the compounds were visualized using UV light. E-factor and material efficiency
(ME) have been selected to evaluate the greenness of the synthetic procedures. E-factor is a very useful
metric tool that is defined as E-Factor = mass of wastes/mass of product [29,30]. The E-factor can be
used to calculate the material efficiency of the process according to the equation: ME = 1/E-factor +1 [30].
3.2. Synthetic Procedures
3.2.1. Preparation of the Acyl Hydrazones 3a–l
Preparation of the acyl hydrazones 3a–l was realized according to a conventional method from the
literature [31]. To a solution of 2-(4-isobutylphenyl)propionic acid hydrazide 5 (13.6 mmol) in dry
ethanol (50 mL) aromatic aldehydes (13.6 mmol) were added. The reaction mixtures were heated at
90–95 °C until completion of the reaction (TLC monitoring using dichloromethane-methanol, 9.8:0.2,
v/v, UV light at 254 nm). The mixture was cooled to room temperature and the solvent was removed
by rotary evaporator. The residue was purified on a silica gel column using dichloromethane-methanol
(9.8:0.2, v/v) as eluent system. FT-IR and physical data for 3a–g were reported in our previous paper [22].
1
2-(4-Isobutylphenyl)propionic acid (benzylidene)hydrazide (3a). 50/50 racemic mixture. H-NMR
(δ ppm): 11.50/11.25 (s, 1H, -NH-N=), 8.21/7.92 (s, 1H, -N=CH-), 7.76–7.56 (m, 2H, Ar-H ), 7.41 (d,
J = 6.9 Hz, 3H, Ar-H), 7.27 (dd, J = 8.0, 4.8 Hz, 2H, Ar-H), 7.08 (dd, J = 14.6, 8.0 Hz, 2H, Ar-H),

Molecules 2014, 19
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4.65/3.67 (q, J = 6.9 Hz, 1H, -CH-CH3), 2.38 (dd, J = 13.8, 6.6 Hz, 2H, -CH2-CH(CH3)2), 1.85–1.69
(m, -CH2-CH(CH3)2), 1.39 (t, J = 6.9 Hz, 3H, -CH-CH3), 0.83 (dd, J = 11.5, 6.6 Hz, 6H, -CH2
CH(CH3)2); 13C-NMR (δ ppm): 175.48/170.27 (Cq), 146.94/142.92 (N=CH), 139.95/139.20 (Cq),
139.58 (Cq), 134.71 (Cq), 130.30/130.02 (CHAr), 129.23 (CHAr), 127.67 (CHAr), 127.38 (CHAr), 127.06
(CHAr), 44.63 (-CH2-CH(CH3)2), 44.05 (-CH-CH3)/40.59 (-CH-CH3), 29.99 (-CH(CH3)2), 22.56
(-CH(CH3)2), 18.87 (-CH-CH3); HRMS (EI-MS): m/z calculated 309.196140; [M+H]+ found
309.196400; Green chemistry metrics: E-factor 16.001, ME 0.059.
2-(4-Isobutylphenyl)propionic acid (4-chlorobenzylidene)hydrazide (3b). 50/50 racemic mixture.
1H-NMR (δ ppm): 11.57/11.31 (s, 1H, -NH-N=), 8.20/7.91 (s, 1H, -N=CH), 7.79–7.59 (m, 2H, Ar-H),
7.46 (d, J = 8.4 Hz, 2H, Ar-H), 7.26 (t, J = 7.6 Hz, 2H, Ar-H), 7.07 (dd, J = 14.9, 7.6 Hz, 2H, Ar-H),
4.63/3.67 (q, J = 7.0 Hz, 1H, -CH-CH3), 2.37 (dd, J = 13.6, 6.9 Hz, 2H, -CH2-CH(CH3)2), 1.84–1.69
(m, 1H, -CH2-CH(CH3)2), 1.38 (t, J = 7.0 Hz, 3H, -CH-CH3), 0.81 (dd, J = 11.5, 6.9 Hz, 6H,
-CH2-CH(CH3)2); 13C-NMR (δ ppm): 175.59/170.41 (Cq), 145.68/141.68 (-N=CH-), 140.02/139.20
(Cq), 139.62 (Cq), 134.81/134.52 (Cq), 133.73 (Cq), 129.33 (2CHAr), 129.02/128.74 (CHAr),
127.72/127.47 (CHAr), 44.69 (-CH2-CH(CH3)2, 44.11 (-CH-CH3)/40.59 (-CH-CH3), 29.99
(-CH-(CH3)2), 22.60 (-CH(CH3)2), 18.85 (-CH-CH3); HRMS (EI-MS): m/z calculated 343.157167;
[M+H]+ found 343.157343; Green chemistry metrics: E-factor 11.942, ME 0.077.
2-(4-Isobutylphenyl)propionic acid (4-bromobenzylidene)hydrazide (3c). 50/50 racemic mixture.
1H-NMR (δ ppm): 11.57/11.32 (s, 1H, -NH-N=), 8.18/7.89 (s, 1H, -N=CH), 7.60 (d, J = 2.2 Hz, 4H,
Ar-H), 7.26 (t, J = 7.6 Hz, 2H, Ar-H), 7.07 (dd, J = 15.1, 7.6 Hz, 2H, Ar-H), 4.63/3.67 (q, J = 6.9 Hz,
1H, -CH-CH3), 2.37 (dd, J = 13.0, 6.8 Hz, 2H, -CH2-CH-(CH3)2), 1.77 (dq, J = 20.3, 6.8 Hz, 1H,
-CH2-CH-(CH3)2), 1.38 (t, J = 6.9 Hz, 3H, -CH-CH3), 0.81 (dd, J = 13.0, 6.8 Hz, 6H,
-CH2-CH-(CH3)2); 13C-NMR (δ ppm): 175.11/169.93 (Cq), 145.27/141.29 (-N=CH-), 139.53/138.70
(Cq), 139.12 (Cq), 133.59 (Cq), 131.72 (CHAr), 128.85 (CHAr), 128.50 (CHAr), 127.24/126.98 (CHAr),
123.10/122.77 (Cq), 44.21 (-CH2-CH(CH3)2), 43.64 (-CH-CH3)/40.18 (-CH-CH3), 29.56 (-CH-(CH3)2),
22.13 (-CH-(CH3)2), 18.43 (-CH-CH3); HRMS (EI-MS): m/z calculated 387.106652; [M+H]+ found
387.106804; Green chemistry metrics: E-factor 10.341, ME 0.088.
2-(4-Isobutylphenyl)propionic acid (4-fluorobenzylidene)hydrazide (3d). 50/50 racemic mixture. 1H-NMR
(δ ppm): 11.50/11.25 (s, 1H, -NH-N=), 8.20/7.91 (s, 1H, -N=CH), 7.70 (dt, J = 9.0, 5.9 Hz, 2H, Ar-H),
7.27–7.23 (m, 4H, Ar-H), 7.08 (dd, J = 14.2, 9.0 Hz, 2H, Ar-H), 4.63/3.65 (q, J = 7.0 Hz, 1H, -CH-CH3),
2.38 (dd, J = 13.3, 6.7 Hz, 2H,-CH2-CH(CH3)2), 1.85–1.70 (m, 1H, -CH2-CH(CH3)2), 1.38 (t, J = 7.0 Hz,
3H, -CH-CH3), 0.82 (dd, J = 10.7, 6.7 Hz, 6H, -CH2-CH(CH3)2); 13C-NMR (δ ppm): 175.06/169.86 (Cq),
164.14/161.04 (Cq), 145.42/141.36 (-N=CH-), 139.54/138.78 (Cq), 139.17 (Cq), 131.32 (Cq), 129.09
(CHAr), 128.83 (CHAr), 127.25/126.99 (CHAr), 115.91/115.69 (CHAr), 44.63 (-CH2-CH(CH3)2), 44.02/40.58
(-CH-CH3), 30.00 (-CH(CH3)2), 22.56 (-CH(CH3)2), 18.87 (-CH-CH3); HRMS (EI-MS): m/z calculated
327.186718; [M+H]+ found 327.186906; Green chemistry metrics: E-factor 13.705, ME 0.068.
2-(4-Isobutylphenyl)propionic acid (2-nitrobenzylidene)hydrazide (3e). 50/50 racemic mixture. 1H-NMR
(δ ppm): 11.69 (s, 1H, -NH-N=), 8.61/8.30 (s, 1H, -N=CH), 8.01 (td, J = 14.3, 7.7 Hz, 2H, Ar-H), 7.76
(t, J = 7.7 Hz, 1H, Ar-H), 7.63 (q, J = 7.7 Hz, 1H, Ar-H), 7.31–7.20 (m, 2H, Ar-H), 7.09 (dd, J = 12.0,

Molecules 2014, 19
15014
8.6 Hz, 2H, Ar-H), 4.59/3.68 (q, J = 8.0 Hz, 1H, -CH-CH3), 2.44–2.33 (m, 2H, -CH2-CH(CH3)2), 1.79
(m, 1H, -CH2-CH(CH3)2), 1.45–1.32 (m, 3H, -CH-CH3), 0.82 (dd, J = 11.3, 7.2 Hz, 6H, -CH2-CH(CH3)2);
13C-NMR (δ ppm): 175.40/170.20 (Cq), 148.01 (Cq), 141.76/138.62 (-N=CH-), 139.63/139.27 (Cq),
139.00/137.87 (Cq), 133.54 (CHAr), 130.34 (CHAr), 128.94 (CHAr), 128.75/128.40 (Cq), 127.86 (CHAr),
127.13 (CHAr), 124.56 (CHAr), 44.22 (-CH2-CH-(CH3)2), 43.71 (-CH-CH3)/40.24 (-CH-CH3), 29.58
(-CH(CH3)2), 22.14 (-CH(CH3)2), 18.52 (-CH-CH3); HRMS (EI-MS): m/z calculated 354.181218;
[M+H]+ found 354.181363; Green chemistry metrics: E-factor 14.772, ME 0.063.
2-(4-Isobutylphenyl)propionic acid (3-nitrobenzylidene)hydrazide (3f). 50/50 racemic mixture. 1H-NMR
(δ ppm): 11.75/11.48 (s, 1H, -NH-N=), 8.45 (d, J = 22.9 Hz, 1H, Ar-H), 8.31/8.00 (s, 1H, -N=CH),
8.20 (t, J = 8.0 Hz, 1H, Ar-H), 8.06 (dd, J = 11.2, 8.0 Hz, 1H, Ar-H), 7.78–7.60 (m, 1H, Ar-H), 7.27 (t,
J = 7.5 Hz, 2H, Ar-H), 7.08 (dd, J = 12.9, 7.5 Hz, 2H, Ar-H), 4.60/3.70 (q, J = 6.9 Hz, 1H, -CH-CH3),
2.37 (dd, J = 17.0, 6.7 Hz, 2H, -CH2-CH-(CH3)2), 1.83–1.69 (m, 1H, -CH2-CH(CH3)2), 1.39 (dd,
13
J = 9.1, 6.9 Hz, 3H, -CH-CH3), 0.80 (dd, J = 20.5, 6.7 Hz, 6H, -CH2-CH(CH3)2); C-NMR (δ ppm):
175.27/170.21 (Cq), 148.16 (Cq), 144.10/140.08 (-N=CH-), 139.60/139.20 (Cq), 138.62 (Cq), 136.20
(Cq), 133.13/132.79 (CHAr), 130.33 (CHAr), 128.93 (CHAr), 127.07 (CHAr ), 124.06/123.74 (CHAr),
120.90/120.67 (CHAr), 44.20 (-CH2-CH(CH3)2), 43.63/40.66 (-CH-CH3), 29.57 (-CH(CH3)2), 22.09
(-CH(CH3)2), 18.51 (-CH-CH3); HRMS (EI-MS): m/z calculated 354.181218; [M+H]+ found
354.181401; Green chemistry metrics: E-factor 14.123, ME 0.066.
2-(4-Isobutylphenyl)propionic acid (4-nitrobenzylidene)hydrazide (3g). 50/50 racemic mixture. 1H-NMR
(δ ppm): 11.79/11.55 (s, 1H, -NH-N=), 8.30/8.00 (s, 1H, -N=CH), 8.25 (dd, J = 8.6, 3.5 Hz, 2H,
Ar-H), 7.90 (dd, J = 8.6, 6.4 Hz, 2H, Ar-H), 7.27 (dd, J = 7.9, 1.8 Hz, 2H, Ar-H), 7.08 (dd, J = 13.2,
7.9 Hz, 2H, Ar-H), 4.65/3.70 (q, J = 6.9 Hz, 1H, -CH-CH3), 2.37 (dd, J = 15.1, 7.1 Hz, 2H,
-CH2-CH(CH3)2), 1.88–1.66 (m, 1H, -CH2-CH(CH3)2), 1.39 (t, J = 6.9 Hz, 3H, -CH-CH3), 0.81 (dd,
13
J = 14.2, 6.6 Hz, 6H, -CH2-CH(CH3)2); C-NMR (δ ppm): 175.44/170.27 (Cq), 147.73/147.51 (Cq),
144.07/140.64 (-N=CH-), 140.15 (Cq), 139.63/139.28 (Cq), 138.95/138.54 (Cq), 128.94 (CHAr),
127.84/127.55 (CHAr), 127.24/127.01 (CHAr), 123.97 (CHAr), 44.20 (-CH2-CH(CH3)2), 43.70/40.35
(-CH-CH3), 29.56 (-CH(CH3)2), 22.12 (-CH(CH3)2), 18.44 (-CH-CH3); HRMS (EI-MS): m/z calculated
354.181218; [M+H]+ found 354.181362; Green chemistry metrics: E-factor 15.231, ME 0.062.
2-(4-Isobutylphenyl)propionic acid (4-methylbenzylidene)hydrazide (3h). 50/50 racemic mixture.
Yield: 81%, m.p. 145–147 °C; IR (ZnSe crystal, cm−1): 3181 (-NH-), 2953 (CHAr), 1666 (-CO-NH-),
1608 (-CH=N-); 1H-NMR (δ ppm): 11.44/11.18 (s, 1H, -NH-N=), 8.17/7.89 (s, 1H, -N=CH-), 7.54 (dd,
J = 7.3, 5.2, 2H, Ar-H), 7.36–7.16 (m, 4H, Ar-H), 7.07 (dd, J = 15.5, 7.8 Hz, 2H, Ar-H), 4.64/3.66 (q,
J = 6.8 Hz, 1H, -CH-CH3), 2.38 (dd, J = 13.8, 6.6 Hz, 2H, -CH2-CH(CH3)2), 2.31 (s, 3H, Ar-CH3),
1.77 (dd, J = 6.6, 3.6 Hz, 1H, -CH2-CH(CH3)2), 1.38 (t, J = 6.8 Hz, 3H, -CH-CH3), 0.82 (dd, J = 10.4,
6.6 Hz, 6H, -CH2-CH(CH3)2); 13C-NMR (δ ppm): 174.94/169.73 (Cq), 146.54/142.56 (-N=CH-),
139.66/139.49 (Cq), 139.33/138.83 (Cq), 139.16 (Cq), 131.60 (Cq), 129.35 (CHAr), 128.84 (CHAr),
127.26/126.61 (CHAr), 126.94 (CHAr), 44.22 (-CH2-CH(CH3)2), 43.62/40.13 (-CH(CH3), 29.58
(-CH(CH3)2), 22.14 (-CH(CH3)2), 20.97 (Ar-CH3), 18.43 (-CH-CH3); HRMS (EI-MS): m/z calculated
323.211790; [M+H]+ found 323.212005; Green chemistry metrics: E-factor 14.262, ME 0.065.

Molecules 2014, 19
15015
2-(4-Isobutylphenyl)propionic acid (3-trifluoromethylbenzylidene)hydrazide (3i). 50/50 racemic
mixture. Yield: 69%, m.p. 120–123 °C; IR (ZnSe crystal, cm−1): 3180 (-NH-), 2956 (CHAr), 1668
1
(-CO-NH-), 1602 (-CH=N-), 1070 (C-F); H-NMR (δ ppm): 11.70/11.42 (s, 1H, -NH-N=), 8.28/7.99
(s, 1H, -N=CH-), 7.97–7.89 (m, 2 H, Ar-H), 7.74–7.61 (m, 2H, Ar-H), 7.25 (dd, J = 16.3, 7.6, 2H, Ar-H),
7.06 (dd, J = 19.3, 7.6 Hz, 2H, Ar-H), 4.58/3.69 (q, J = 6.9 Hz, 1H, -CH-CH3), 2.36 (dd, J = 17.9,
6.5 Hz, 2H, -CH2-CH(CH3)2), 1.85–1.66 (m, 1H, -CH2-CH(CH3)2), 1.38 (dd, J = 13.0, 6.9 Hz,
13
3H, -CH-CH3), 0.80 (dd, J = 20.8, 6.5 Hz, 6H, -CH2-CH(CH3)2); C-NMR (δ ppm): 175.27/170.21
(Cq), 144.81/140.72 (-N=CH-), 139.63 (Cq), 139.28 (Cq), 138.69 (Cq), 135.52 (Cq), 130.87/130.55
(CHAr), 129.91 (CHAr), 128.93 (CHAr), 127.08 (CHAr), 126.12/125.78 (CHAr), 125.38(Cq),
122.98/122.70 (CHAr), 44.24 (-CH2-CH(CH3)2), 43.65/40.78 (-CH-CH3), 29.60 (-CH(CH3)2), 22.11
(-CH(CH3)2), 18.54 (-CH-CH3); HRMS (EI-MS): m/z calculated 377.183524; [M+H]+ found
377.183680; Green chemistry metrics: E-factor 14.641, ME 0.064.
2-(4-Isobutylphenyl)propionic acid (4-trifluoromethylbenzylidene)hydrazide (3j). 50/50 racemic mixture.
Yield: 69%, m.p. 160–162 °C; IR (ZnSe crystal, cm−1): 3185 (-NH-), 2957 (CHAr), 1669 (-CO-NH-),
1604 (-CH=N-), 1064 (C-F); 1H-NMR (δ ppm): 11.69/11.45 (s, 1H, -NH-N=), 8.28/7.98 (s, 1H, -N=CH-),
7.86 (t, J = 8.2 Hz, 2H, Ar-H), 7.75 (dd, J = 8.2, 2.4 Hz, 2H, Ar-H), 7.27 (dd, J = 7.9, 6.2, 2H, Ar-H),
7.07 (dd, J = 15.6, 7.9 Hz, 2H, Ar-H), 4.65/3.69 (q, J = 6.9 Hz, 1H, -CH-CH3), 2.37 (dd, J = 16.0, 6.7
Hz, 2H, -CH2-CH(CH3)2), 1.76 (m, 1H, -CH2-CH(CH3)2), 1.39 (t, J = 6.9 Hz, 3H, -CH-CH3), 0.81 (dd,
J = 16.6, 6.7 Hz, 6H, -CH2-CH(CH3)2); 13C-NMR (δ ppm): 175.31/170.15 (Cq), 144.79/140.81
(-N=CH-), 139.60 (Cq), 139.14 (Cq), 138.64 (Cq), 138.29 (Cq), 128.91 (CHAr), 127.50/127.01 (CHAr),
127.22 (CHAr), 125.60 (CHAr), 122.73 (Cq) 44.21 (-CH2-CH(CH3)2), 43.68/40.33 (-CH-CH3), 29.57
(-CH(CH3)2), 22.09 (-CH(CH3)2), 18.43 (-CH-CH3); HRMS (EI-MS): m/z calculated 377.183524;
[M+H]+ found 377.183689; Green chemistry metrics: E-factor 14.822, ME 0.063.
2-(4-Isobutylphenyl)propionic acid (4-cianobenzylidene)hydrazide (3k). 50/50 racemic mixture. Yield:
52%, m.p. 179–180 °C; IR (ZnSe crystal, cm−1): 3180 (-NH-), 2954 (CHAr), 2227 (C≡N), 1666
1
(-CO-NH-), 1596 (-CH=N-); H-NMR (δ ppm): 11.75/11.47 (s, 1H, -NH-N=), 8.25/7.95 (s, 1H,
-N=CH-), 7.92–7.73 (m, 4H, Ar-H), 7.26 (t, J = 7.4, 2H, Ar-H), 7.07 (dd, J = 15.2, 7.4 Hz, 2H,
Ar-H), 4.64/3.68 (q, J = 7.1 Hz, 1H, -CH-CH3), 2.37 (dd, J = 14.4, 6.8 Hz, 2H, -CH2-CH(CH3)2), 1.76
(dd, J = 12.5, 6.8 Hz, 1H, -CH2-CH(CH3)2), 1.38 (t, J = 7.1 Hz, 3H, -CH-CH3), 0.81 (dd, J = 13.8,
6.8 Hz, 6H, -CH2-CH(CH3)2); 13C-NMR (δ ppm): 175.45/170.29 (Cq), 144.67/140.69 (-N=CH-),
139.68/139.32 (Cq), 139.03/138.60 (Cq), 138.80 (Cq), 132.70 (CHAr), 128.98 (CHAr), 127.54/127.05
(CHAr), 127.27 (CHAr), 118.69 (Cq), 111.79/111.51 (Cq), 44.24 (-CH2-CH(CH3)2), 43.72/40.34
(-CH-CH3), 29.61 (-CH(CH3)2), 22.17 (-CH(CH3)2), 18.48 (-CH-CH3); HRMS (EI-MS): m/z calculated
334.191389; [M+H]+ found 334.191499; Green chemistry metrics: E-factor 22.513, ME 0.042.
2-(4-Isobutylphenyl)propionic acid (2,6-dichlorobenzylidene)hydrazide (3l). 60/40 racemic mixture.
Yield: 60%, m.p. 151–153 °C; IR (ZnSe crystal, cm−1): 3185 (-NH-), 2951 (CHAr), 1662 (-CO-NH-),
1605 (-CH=N-), 776 (C-Cl); 1H-NMR (δ ppm): 11.77/11.52 (s, 1H, -NH-N=), 8.41/8.22 (s, 1H, -N=CH-),
7.51 (d, J = 7.9 Hz, 2H, Ar-H), 7.43–7.34 (m, 1H, Ar-H), 7.24 (dd, J =29.5, 8.0 Hz, 2H, Ar-H), 7.07
(dd, J = 29.5, 8.0, 2H, Ar-H), 4.59/3.67 (q, J = 7.0 Hz, 1H, -CH-CH3), 2.37 (dd, J = 14.8, 6.8 Hz, 2H,

Molecules 2014, 19
15016
-CH2-CH(CH3)2), 1.86–1.67 (m, 1H, -CH2-CH(CH3)2), 1.38 (dd, J = 15.8, 7.0 Hz, 3H, -CH-CH3), 0.82
13
(dd, J = 10.2, 6.8 Hz, 6H, -CH2-CH(CH3)2); C-NMR (δ ppm): 175.55/170.12 (Cq), 141.97/137.97
(-N=CH-), 139.70/139.29 (Cq), 138.76/138.61 (Cq), 133.88 (Cq), 131.07/130.87 (CHAr), 130.47 (Cq),
129.74 (Cq), 129.34 (CHAr), 128.93 (CHAr), 127.20 (CHAr), 44.26 (-CH2-CH(CH3)2), 43.78/39.85
(-CH-CH3), 29.62 (-CH(CH3)2), 22.16 (-CH(CH3)2), 18.64 (-CH-CH3); HRMS (EI-MS): m/z calculated
377.118195; [M+H]+ found 377.118261; Green chemistry metrics: E-factor 16.891, ME 0.056.
3.2.2. Preparation of the Acetamidothiazolidin-4-One Derivatives 4a–l
The acyl hydrazones of ibuprofen 3a–l (3.2 mmol) were reacted with mercaptoacetic acid
(14.4 mmol) and the reaction mixtures was heated at 80–85 °C for 2–8 h using an oil bath, according
to a procedure described for other compounds [32]. After the completion of the reaction (TLC
monitoring using dichloromethane-methanol, 9.8:0.2, v/v, UV light at 254 nm), the mixture was
diluted with ethyl acetate (200 mL) and then neutralized with a saturated solution of sodium carbonate.
After stirring for 3–4 h the organic layer was separated and washed with saturated solution of sodium
bicarbonate, then with saturated solution of sodium chloride and finally with water. The organic layers
were collected, dried with MgSO4 and concentrated by rotary evaporator. The residue was purified on
a silica gel column using dichloromethane-methanol (9.8:0.2, v/v) as the eluent system.
2-(Phenyl)-3-[2-(4-(isobutyl)phenyl)-2-methyl]acetamidothiazolidine-4-one (4a). 60/40 racemic
mixture. Yield: 57%, m.p. 125 °C; IR (ZnSe crystal, cm−1): 3243 (-NH-), 2959 (CHAr), 1716 (C=O,
1
thiazolidine-4-one), 1666 (-CO-NH-), 1203 (C-N), 694 (C-S); H-NMR (δ ppm): 10.26 (d,
J = 3.1 Hz, 1H, -NH-), 7.50–7.35 (m, 2H, Ar-H), 7.34–7.21 (m, 3H, Ar-H), 7.11 (d, J = 7.6 Hz, 1H,
Ar-H), 7.01 (dd, J = 14.8, 7.6 Hz, 3H, Ar-H), 5.82/5.67 (s, 1H, CH thiazolidine-4-one), 3.86 (t,
J = 14.9 Hz, 1H, CH2 thiazolidine-4-one), 3.72 (dd, J = 14.9, 9.0 Hz, 1H, CH2 thiazolidine-4-one),
3.61–3.47 (m, 1H, -CH-CH3), 2.39 (d, J = 6.7 Hz, 2H, -CH2-CH(CH3)2), 1.79 (dt, J = 13.4, 6.7 Hz, 1H,
-CH2-CH(CH3)2), 1.25 (dd, J = 24.2, 7.0 Hz, 3H, -CH-CH3), 0.85 (d, J = 6.7 Hz, 6H, -CH2-CH(CH3)2);
13C-NMR (δ ppm): 172.23 (Cq), 168.85/168.69 (Cq), 139.31 (Cq), 138.15 (Cq), 137.95 (Cq),
128.98/128.88 (CHAr), 128.69 (CHAr), 128.54/128.39 (CHAr), 127.80 (CHAr), 127.01/126.73 (CHAr),
61.43 (CH thiazolidine-4-one), 44.22 (-CH2-CH(CH3)2), 42.12 (-CH-CH3), 29.62 (-CH(CH3)2), 29.27
(CH2 thiazolidine-4-one), 22.13 (-CH(CH3)2), 18.81/17.90 (-CH-CH3); HRMS (EI-MS): m/z calculated
383.178776; [M+H]+ found 383.178716; Green chemistry metrics: E-factor 2.361, ME 0.297.
2-(4-Chlorophenyl)-3-[2-(4-(isobutyl)phenyl)-2-methyl]acetamidothiazolidine-4-one
(4b).
50/50
racemic mixture. Yield: 76%, m.p. 80 °C; IR (ZnSe crystal, cm−1): 3238 (-NH-), 2954 (CHAr), 1718
1
(C=O, thiazolidine-4-one), 1672 (-CO-NH-), 1215 (C-N), 810 (C-Cl), 656 (C-S); H-NMR (δ ppm):
10.23 (d, J = 7.1 Hz, 1H, -NH-), 7.43 (q, J = 8.6 Hz, 2H, Ar-H), 7.28 (dd, J = 18.7, 8.6 Hz, 2H, Ar-H),
7.16–6.88 (m, 4H, Ar-H), 5.80/5.71 (s, 1H, CH thiazolidine-4-one), 3.87 (dd, J = 15.8, 8.3, 1H, CH2
thiazolidine-4-one), 3.72 (dd, J = 15.8, 8.3 Hz, 1H, CH2 thiazolidine-4-one), 3.52 (dq, J = 14.1, 7.0 Hz,
1H, -CH-CH3), 2.46–2.33 (m, 2H, -CH2-CH(CH3)2), 1.79 (dt, J = 13.5, 6.7 Hz, 1H, -CH2-CH(CH3)2),
1.25 (dd, J = 17.9, 7.0 Hz, 3H, -CH-CH3), 0.85 (d, J = 6.7 Hz, 6H, -CH2-CH(CH3)2); 13C-NMR (δ ppm):
172.17 (Cq), 168.70/168.45 (Cq), 139.36 (Cq), 138.17/137.94 (Cq), 137.25/137.07 (Cq), 133.56/133.44
(Cq), 129.77 (CHAr), 128.70 (CHAr), 128.49/128.38 (CHAr), 126.92/126.71 (CHAr), 60.86/60.50

Molecules 2014, 19
15017
(CH thiazolidine-4-one), 44.22 (-CH2-CH(CH3)2), 42.21 (-CH-CH3), 29.61 (-CH(CH3)2), 29.21
(CH2 thiazolidine-4-one), 22.15 (-CH(CH3)2), 18.76/17.89 (-CH-CH3); HRMS (EI-MS): m/z calculated
417.139803; [M+H]+ found 417.139745; Green chemistry metrics: E-factor 1.423, ME 0.413.
2-(4-Bromophenyl)-3-[2-(4-(isobutyl)phenyl)-2-methyl]acetamidothiazolidine-4-one (4c). 50/50 racemic
mixture. Yield: 77%, m.p. 70–72 °C; IR (ZnSe crystal, cm−1): 3238 (-NH), 2954 (CHAr), 1718 (C=O,
thiazolidine-4-one), 1672 (-CO-NH-), 1215 (C-N), 810 (C-Cl), 656 (C-S); 1H-NMR (δ ppm): 10.23 (d,
J = 8.1 Hz, 1H, -NH-), 7.55 (d, J = 8.4 Hz, 1H, Ar-H), 7.41 (dd, J = 21.1, 8.4 Hz, 2H, Ar-H), 7.19 (d,
J = 8.4 Hz, 1H, Ar-H), 7.11–6.93 (m, 4H, Ar-H), 5.79/5.70 (s, 1H, CH thiazolidine-4-one), 3.87 (dd,
J = 15.8, 8.4 Hz, 1H, CH2 thiazolidine-4-one), 3.72 (dd, J = 15.8, 8.4 Hz, 1H, CH2 thiazolidine-4-one),
3.52 (dq, J = 14.1, 7.0 Hz, 1H, -CH-CH3), 2.40 (dd, J = 6.9, 2.3 Hz, 2H, -CH2-CH(CH3)2), 1.79 (td,
J = 13.4, 6.9 Hz, 1H, -CH2-CH(CH3)2), 1.25 (dd, J = 18.2, 7.0 Hz, 3H, -CH-CH3), 0.85 (d, J = 6.9 Hz,
6H, -CH2-CH(CH3)2); 13C-NMR (δ ppm): 172.16 (Cq), 168.71/168.46 (Cq), 139.35 (Cq), 138.16/137.95
(Cq), 137.68/137.48 (Cq), 131.36 (CHAr), 130.06 (CHAr), 128.70 (CHAr), 126.91/126.71 (CHAr),
122.22/122/08 (Cq), 60.94/60.56 (CH thiazolidine-4-one), 44.24 (-CH2-CH(CH3)2), 42.21 (-CH-CH3),
29.62 (-CH(CH3)2), 29.22 (CH2 thiazolidine-4-one), 22.19 (-CH(CH3)2), 18.77/17.89 (-CH-CH3);
HRMS (EI-MS): m/z calculated 461.089288; [M+H]+ found 461.089204; Green chemistry metrics:
E-factor 1.122, ME 0.471.
2-(4-Fluorophenyl)-3-[2-(4-(isobutyl)phenyl)-2-methyl]acetamidothiazolidine-4-one (4d). 50/50 racemic
mixture. Yield: 66%, m.p. 72 °C; IR (ZnSe crystal, cm−1): 3252 (-NH-), 2954 (CHAr), 1716 (C=O,
thiazolidine-4-one), 1672 (-CO-NH-), 1224 (C-N), 1095 (C-F), 659 (C-S); 1H-NMR (δ ppm): 10.22 (d,
J = 4.4 Hz, 1H, -NH-), 7.48 (dd, J = 8.8, 5.5 Hz, 1H, Ar-H), 7.28 (dd, J = 8.6, 5.5 Hz, 1H, Ar-H), 7.18
(t, J = 8.8 Hz, 1H, Ar-H), 7.14–6.90 (m, 5H, Ar-H), 5.82/5.71 (s, 1H, CH thiazolidine-4-one), 3.86 (dd,
J = 15.8, 8.6, 1.4 Hz, 1H, CH2 thiazolidine-4-one), 3.72 (dd, J = 15.8, 8.6 Hz, 1H, CH2 thiazolidine-4-one),
3.52 (dq, J = 14.1, 7.0 Hz, 1H, -CH-CH3), 2.39 (dd, J = 6.7, 1.2 Hz, 2H, -CH2-CH(CH3)2), 1.79 (dt,
J = 13.5, 6.7 Hz, 1H, -CH2-CH(CH3)2), 1.25 (dd, J = 17.2, 7.0 Hz, 3H, -CH-CH3), 0.85 (d, J = 6.7 Hz,
6H, -CH2-CH(CH3)2); 13C-NMR (δ ppm): 172.18 (Cq), 168.70/168.47 (Cq), 163.54/161.10 (Cq), 139.35
(Cq), 138.19/137.95 (Cq), 134.21(Cq), 130.16 (CHAr), 128.70 (CHAr), 126.85 (CHAr), 115.27 (CHAr),
60.90/60.59 (CH thiazolidine-4-one), 44.22 (-CH2-CH(CH3)2), 42.21 (-CH-CH3), 29.62 (-CH(CH3)2),
29.26 (CH2 thiazolidine-4-one), 22.15 (CH(CH3)2), 18.76/17.89 (-CH-CH3); HRMS (EI-MS): m/z
calculated 401.169354; [M+H]+ found 401.169387; Green chemistry metrics: E-factor 1.821, ME 0.354.
2-(2-Nitrophenyl)-3-[2-(4-(isobutyl)phenyl)-2-methyl]acetamidothiazolidine-4-one (4e). 70/30 racemic
mixture. Yield: 73%, m.p. 69–71 °C; IR (ZnSe crystal, cm−1): 3246 (-NH), 2953 (CHAr), 1721 (C=O,
1
thiazolidine-4-one), 1674 (-CO-NH-), 1216 (C-N), 661 (C-S); H-NMR (δ ppm): 10.45/10.38 (d, 1H,
-NH-), 8.05/7.96 (d, J = 8.2 Hz, 1H, Ar-H), 7.90–7.49 (m, 3H, Ar-H), 7.12/7.03 (d, J = 8.1 Hz, 3H,
Ar-H), 6.90 (d, J = 6.5 Hz, 1H, Ar-H), 6.14/6.02 (d, J = 1.4 Hz, 1H, CH thiazolidine-4-one), 3.93–3.86
(m, 1H, CH2 thiazolidine-4-one), 3.70 (dd, J = 20.0, 15.8, 1H, CH2 thiazolidine-4-one), 3.57–3.48 (m,
1H, -CH-CH3), 2.37 (dd, J = 20.3, 6.8 Hz, 2H, -CH2-CH(CH3)2), 1.84–1.69 (m, 1H, -CH2-CH(CH3)2),
1.24 (dd, J = 23.1, 7.0 Hz, 3H, -CH-CH3), 0.83 (dd, J = 13.4, 6.8 Hz, 6H, -CH2-CH(CH3)2); 13C-NMR
(δ ppm): 172.38 (Cq), 169.07/168.89 (Cq), 147.67/147.45 (Cq), 139.38/139.31 (Cq), 138.01/137.92

Molecules 2014, 19
15018
(Cq), 134.55 (CHAr), 134.33 (Cq), 129.75 (CHAr), 128.72 (CHAr), 128.16/127.94 (CHAr), 126.93
(CHAr), 126.35 (CHAr), 124.79 (CHAr), 56.98/56.48 (CH thiazolidine-4-one), 44.19 (-CH2-CH(CH3)2),
42.26 (-CH-CH3), 29.57 (-CH(CH3)2), 28.45 (-CH2 thiazolidine-4-one), 22.14 (-CH(CH3)2),
18.68/17.83 (-CH-CH3); HRMS (EI-MS): m/z calculated 428.163854; [M+H]+ found 428.163864;
Green chemistry metrics: E-factor 1.503, ME 0.405.
2-(3-Nitrophenyl)-3-[2-(4-(isobutyl)phenyl)-2-methyl]acetamidothiazolidine-4-one (4f). 50/50 racemic
mixture. Yield: 62%, m.p. 70–72 °C; IR (ZnSe crystal, cm−1): 3247 (-NH-), 2953 (CHAr), 1721 (C=O,
1
thiazolidine-4-one), 1674 (-CO-NH-), 1216 (C-N), 679 (C-S); H-NMR (δ ppm): 10.31/10.25 (d, 1H,
-NH-), 8.37–8.04 (m, 2H, Ar-H), 7.91/7.72 (d, J = 7.7 Hz, 1H, Ar-H), 7.60 (dt, J = 29.4, 7.7 Hz, 1H,
Ar-H), 7.16–6.76 (m, 4H, Ar-H), 5.96/5.90 (s, 1H, CH thiazolidine-4-one), 3.97–3.92 (m, 1H, CH2
thiazolidine-4-one), 3.77 (dd, J = 15.8, 8.3, 1H, CH2 thiazolidine-4-one), 3.49 (dq, J = 14.1, 6.9 Hz,
1H, -CH-CH3), 2.35 (t, J = 7.5 Hz, 2H, -CH2-CH(CH3)2), 1.83–1.67 (m, 1H, -CH2-CH(CH3)2), 1.23
13
(dd, J = 20.2, 6.9 Hz, 3H, -CH-CH3), 0.81 (t, J = 7.1 Hz, 6H, -CH2-CH(CH3)2); C-NMR (δ ppm):
172.16 (Cq), 168.71/168.39 (Cq), 147.66 (Cq), 140.70 (Cq), 139.37 (Cq), 138.01 (Cq), 134.80/134.55
(CHAr), 130.08 (CHAr), 128.65 (CHAr), 126.71 (CHAr), 123.82/122.69 (CHAr), 60.66/60.20 (CH
thiazolidine-4-one), 44.17 (-CH2-CH(CH3)2), 42.29 (-CH-CH3), 29.56 (-CH(CH3)2), 29.21 (CH2
thiazolidine-4-one), 22.15 (-CH(CH3)2), 18.70/17.76 (-CH-CH3); HRMS (EI-MS): m/z calculated
428.163854; [M+H]+ found 428.163708; Green chemistry metrics: E-factor 1.874, ME 0.352.
2-(4-Nitrophenyl)-3-[2-(4-(isobutyl)phenyl)-2-methyl]acetamidothiazolidine-4-one (4g). 50/50 racemic
mixture. Yield: 72%, m.p. 70–72 °C; IR (ZnSe crystal, cm−1): 3233 (-NH-), 2955 (CHAr), 1716 (C=O,
thiazolidine-4-one), 1672 (-CO-NH-), 1217 (C-N), 692 (C-S); 1H-NMR (δ ppm): 10.31 (d, J = 11.5 Hz,
1H, -NH-), 8.17 (d, J = 8.4 Hz, 1H, Ar-H), 8.09 (d, J = 8.6 Hz, 1H, Ar-H), 7.70 (d, J = 8.4 Hz, 1H, Ar-H),
7.53 (d, J = 8.6 Hz, 1H, Ar-H), 7.16–6.82 (m, 4H, Ar-H), 5.93/5.89 (s, 1H, CH thiazolidine-4-one),
3.93 (d, J = 15.8, 1H, CH2 thiazolidine-4-one), 3.76 (dd, J = 15.8, 10.4, 1H, CH2 thiazolidine-4-one),
3.60–3.42 (m, 1H, -CH-CH3), 2.37 (d, J = 7.0 Hz, 2H, -CH2-CH(CH3)2), 1.82–1.69 (m, 1H,
-CH2-CH(CH3)2), 1.24 (dd, J = 17.2, 6.9 Hz, 3H, -CH-CH3), 0.82 (t, J = 7.0 Hz, 6H, -CH2-CH(CH3)2);
13C-NMR (δ ppm): 172.20 (Cq), 168.74/168.44 (Cq), 147.64/147.50 (Cq), 145.88 (Cq), 139.38 (Cq),
138.19/137.91 (Cq), 129.06 (CHAr), 128.66 (CHAr), 126.77 (CHAr), 123.53 (CHAr), 60.55/60.01 (CH
thiazolidine-4-one), 44.15 (-CH2-CH(CH3)2), 42.28 (-CH-CH3), 29.58 (-CH(CH3)2), 29.14 (CH2
thiazolidine-4-one), 22.13 (-CH(CH3)2), 18.60/17.91 (-CH-CH3); HRMS (EI-MS): m/z calculated
428.163854; [M+H]+ found 428.163805; Green chemistry metrics: E-factor 1.506, ME 0.403.
2-(4-Methylphenyl)-3-[2-(4-(isobutyl)phenyl)-2-methyl]acetamidothiazolidine-4-one
(4h).
50/50
racemic mixture. Yield: 41%, m.p. 67 °C; IR (ZnSe crystal, cm−1): 3254 (-NH-), 2953 (CHAr), 1715
1
(C=O thiazolidine-4-one), 1673 (-CO-NH-), 1213 (C-N), 659 (C-S); H-NMR (δ ppm): 10.21 (d,
J = 4.0 Hz, 1H, -NH-), 7.31 (d, J = 7.9 Hz, 1H, Ar-H), 7.19 (d, J = 7.9 Hz, 1H, Ar-H), 7.16–7.05 (m,
3H, Ar-H), 7.05–6.96 (m, 3H, Ar-H), 5.78/5.64 (s, 1H, CH thiazolidine-4-one), 3.92–3.77 (m, 1H, CH2
thiazolidine-4-one), 3.71 (dd, J = 15.8, 9.0, 1H, CH2 thiazolidine-4-one), 3.53 (dq, J = 20.4, 7.0 Hz,
1H, -CH-CH3), 2.40 (dd, J = 7.0, 2.0 Hz, 2H, -CH2-CH(CH3)2), 2.30 (d, J = 21.4 Hz, 3H, Ar-CH3),
1.85–1.75 (m, 1H, -CH2-CH(CH3)2), 1.25 (dd, J = 20.4, 7.0 Hz, 3H, -CH-CH3), 0.85 (dd, J = 7.0,

Molecules 2014, 19
15019
2.9 Hz, 6H, -CH2-CH(CH3)2); 13C-NMR (δ ppm): 172.19 (Cq), 168.82/168.63 (Cq), 139.30 (Cq),
138.46/138.31 (Cq), 138.19.137.93 (Cq), 135.05/134.88 (Cq), 129.02 (CHAr), 128.68 (CHAr), 127.82
(CHAr), 127.02/126.75 (CHAr), 61.39/61.21 (CH thiazolidine-4-one), 44.22 (-CH2-CH(CH3)2), 42.11
(-CH-CH3), 29.63 (-CH(CH3)2), 29.28 (CH2 thiazolidine-4-one), 22.13 (-CH(CH3)2), 20.77 (Ar-CH3),
18.81/17.99 (-CH-CH3); HRMS (EI-MS): m/z calculated 397.194426; [M+H]+ found 397.194552;
Green chemistry metrics: E-factor 3.767, ME 0.213.
2-(3-trifluoromethylphenyl)-3-[2-(4-(isobutyl)phenyl)-2-methyl]acetamidothiazolidine-4-one (4i). 50/50
racemic mixture. Yield: 53%, m.p. 68 °C; IR (ZnSe crystal, cm−1): 3233 (-NH-), 2955 (CHAr), 1720
1
(C=O, thiazolidine-4-one), 1673 (-CO-NH-), 1216 (C-N), 1071 (C-F), 656 (C-S); H-NMR (δ ppm):
10.32 (d, J = 19.4 Hz, 1H, -NH-), 7.88–7.46 (m, 4H, Ar-H), 7.20–6.86 (m, 4H, Ar-H), 5.96/5.86 (s,
1H, CH thiazolidine-4-one), 3.96–3.90 (m, 1H, CH2 thiazolidine-4-one), 3.76 (dd, J = 15.8, 8.2, 1H,
CH2 thiazolidine-4-one), 3.60–3.48 (m, 1H, -CH-CH3), 2.37 (dd, J = 6.8, 3.5 Hz, 2H, -CH2-CH(CH3)2),
1.85–1.70 (m, 1H, -CH2-CH(CH3)2), 1.26 (dd, J = 18.7, 7.0 Hz, 3H, -CH-CH3), 0.83 (dd, J = 6.8, 3.5
13
Hz, 6H, -CH2-CH(CH3)2); C-NMR (δ ppm): 172.33 (Cq), 168.88/.16862 (Cq), 139.86 (Cq), 139.38
(Cq), 138.07 (Cq), 132.06 (CHAr), 129.61 (CHAr), 128.71 (CHAr), 126.92/126.68 (CHAr), 125.72/124.55
(CHAr), 125.36 (Cq), 122.66 (Cq), 61.01/60.77 (CH thiazolidine-4-one), 44.29 (-CH2-CH(CH3)2, 42.33
(-CH-CH3), 29.62 (-CH(CH3)2), 29.32 (CH2 thiazolidine-4-one), 22.13 (-CH(CH3)2), 18.80/17.87
(-CH-CH3); HRMS (EI-MS): m/z calculated 451.166160; [M+H]+ found 451.166296; Green chemistry
metrics: E-factor 2.079, ME 0.325.
2-(4-Trifluoromethylphenyl)-3-[2-(4-(isobutyl)phenyl)-2-methyl]acetamidothiazolidine-4-one
(4j).
50/50 racemic mixture. Yield: 38%, m.p. 74–75 °C; IR (ZnSe crystal, cm−1): 3246 (-NH-), 2956
(CHAr), 1721 (C=O, thiazolidine-4-one), 1673 (-CO-NH-), 1217 (C-N), 1066 (C-F), 664 (C-S);
1H-NMR (δ ppm): 10.28 (d, J = 9.6 Hz, 1H, -NH-), 7.77–7.54 (m, 3H, Ar-H), 7.48 (d, J = 8.1 Hz, 1H,
Ar-H), 7.14‒6.89 (m, 4H, Ar-H), 5.89/5.82 (s, 1H, CH thiazolidine-4-one), 3.91 (dd, J = 15.7, 5.5 Hz,
1H, CH2 thiazolidine-4-one), 3.75 (dd, J = 15.7, 10.6, 1H, CH2 thiazolidine-4-one), 3.53 (dq, J =13.9,
7.0 Hz, 1H, -CH-CH3), 2.38 (d, J = 6.8 Hz, 2H, -CH2-CH(CH3)2), 1.85–1.69 (m, 1H, -CH2-CH(CH3)2),
13
1.25 (dd, J = 17.5, 7.0 Hz, 3H, -CH-CH3), 0.83 (dd, J = 6.8, 3.9 Hz, 6H, -CH2-CH(CH3)2); C-NMR
(δ ppm): 172.22 (Cq), 168.81/168.56 (Cq), 143.19 (Cq), 142.95 (Cq), 139.34 (Cq), 138.21 (Cq), 137.97
(Cq), 128.66 (CHAr), 126.90 (CHAr), 126.69 (CHAr), 125.35 (CHAr), 60.86/60.41 (CH thiazolidine-4-one),
44.20 (-CH2-CH(CH3)2), 42.24 (-CH-CH3), 29.58 (-CH(CH3)2), 29.19 (CH2 thiazolidine-4-one), 22.13
(-CH(CH3)2), 18.72/17.88 (-CH-CH3); HRMS (EI-MS): m/z calculated 451.166160; [M+H]+ found
451.166066; Green chemistry metrics: E-factor 3.687, ME 0.2134.
2-(4-Cyanophenyl)-3-[2-(4-(isobutyl)phenyl)-2-methyl]acetamidothiazolidine-4-one (4k). 50/50 racemic
mixture. Yield: 87%, m.p. 75 °C; IR (ZnSe crystal, cm−1): 3256 (-NH-), 2953 (CHAr), 2230 (C≡N),
1720 (C=O, thiazolidine-4-one), 1677 (-CO-NH-), 1204 (C-N), 661 (C-S); 1H-NMR (δ ppm): 10.28 (d,
J = 10.7 Hz, 1H, -NH-), 7.81 (d, J = 8.0 Hz, 1H, Ar-H), 7.72 (d, J = 8.2 Hz, 1H, Ar-H), 7.61 (d, J = 8.2 Hz,
1H, Ar-H), 7.45 (d, J = 8.0 Hz, 1H, Ar-H), 7.11–6.90 (m, 4H, Ar-H), 5.87/5.81 (s, 1H, CH
thiazolidine-4-one), 3.91 (dd, J = 15.8, 4.4 Hz, 1H, CH2 thiazolidine-4-one), 3.73 (dd, J = 15.8, 10.1,
1H, CH2 thiazolidine-4-one), 3.50 (dq, J = 14.1, 7.0 Hz, 1H, -CH-CH3), 2.39 (dd, J = 6.8, 2.5 Hz, 2H,

Molecules 2014, 19
15020
-CH2-CH(CH3)2), 1.84–1.71 (m, 1H, -CH2-CH(CH3)2), 1.24 (dd, J = 16.6, 7.0 Hz, 3H, -CH-CH3), 0.83
(dd, J = 6.8, 2.5 Hz, 6H, -CH2-CH(CH3)2); 13C-NMR (δ ppm): 172.23 (Cq), 168.77/168.49 (Cq),
144.02/143.87 (Cq), 139.40 (Cq), 138.15/137.92 (Cq), 132.41 (CHAr), 128.69 (CHAr), 126.90 (CHAr),
126.68 (CHAr), 118.48 (Cq), 111.52 (Cq), 60.85/60.39 (CH thiazolidine-4-one), 44.20 (-CH2-CH(CH3)2),
42.27 (-CH-CH3), 29.62 (-CH(CH3)2), 29.14 (CH2 thiazolidine-4-one), 22.15 (-CH(CH3)2), 18.68/17.91
(-CH-CH3); HRMS (EI-MS): m/z calculated 408.174025; [M+H]+ found 408.173935; Green chemistry
metrics: E-factor 1.218, ME 0.452.
2-(2,6-Dichlorophenyl)-3-[2-(4-(isobutyl)phenyl)-2-methyl]acetamidothiazolidine-4-one (4l). 60/40
racemic mixture. Yield: 38%, m.p. 74 °C; IR (ZnSe crystal, cm−1): 3239 (-NH), 2953 (CHAr), 1716
1
(C=O, thiazolidine-4-one), 1673 (-CO-NH-), 1218 (C-N), 778 (C-Cl), 663 (C-S); H-NMR (δ ppm):
10.38 (d, J = 10.9 Hz, 1H, -NH-), 7.61–7.24 (m, 3H, Ar-H), 7.22–6.89 (m, 4H, Ar-H), 6.71/6.57 (s,
1H, CH thiazolidine-4-one), 3.96–3.71 (m, 2H, CH2 thiazolidine-4-one), 3.68–3.50 (m, 1H, -CH-CH3),
2.38 (dd, J = 10.5, 6.5 Hz, 2H, -CH2-CH(CH3)2), 1.88–1.67 (m, 1H, -CH2-CH(CH3)2), 1.26 (dd,
13
J = 22.0, 6.9 Hz, 3H, -CH-CH3), 0.84 (dd, J = 6.5, 2.8 Hz, 6H, -CH2-CH(CH3)2); C-NMR (δ ppm):
172.84/172.68 (Cq), 168.19/168.01 (Cq), 139.48/138.25 (Cq), 138.06/137.74 (Cq), 135.58/135.48 (Cq),
135.25/134.72 (Cq), 130.96 (Cq), 131.38 (CHAr), 131.14 (CHAr), 130.89 (CHAr), 128.68 (CHAr),
127.08/126.46 (CHAr), 55.87/55.72 (CH thiazolidine-4-one), 44.23 (-CH2-CH(CH3)2), 41.90 (-CH-CH3),
30.27 (-CH(CH3)2), 29.64 (CH2 thiazolidine-4-one), 22.18 (-CH(CH3)2), 18.84/17.49 (-CH-CH3);
HRMS (EI-MS): m/z calculated 451.100831; [M+H]+ found 451.100760; Green chemistry metrics:
E-factor 3.418, ME 0.226.
3.2.3. Preparation of 2-(4-Aminophenyl)-3-[2-(4-(isobutyl)phenyl)-2-methyl]acetamidothiazolidine-4-
one (4m)
To a solution of 2-(4-nitrophenyl)-3-[2-(4-(isobutyl)phenyl)-2-methyl]acetamidothiazolidine-4-one
(4g, 1.6 mmol) in ethyl alcohol (20 mL) there were added SnCl2 (10 mmol) and 3–4 drops of acetic
acid and the mixture of reaction was stirred at room temperature under argon atmosphere for 14 h,
according to the procedure described for other compounds [33]. After the completion of the reaction
(TLC monitoring using dichloromethane-methanol, 9.5:0.5, v/v, UV light at 254 nm) the mixture was
neutralized with saturated solution of sodium carbonate, diluted with dichloromethane and then
filtered. The organic layer was dried with MgSO4, filtered and concentrated at rotary evaporator. The
residue was precipitated with ethyl ether. 50/50 racemic mixture. Yield: 90%, m.p. 165–167 °C; IR
(ZnSe crystal, cm−1): 3362 (NH2), 3224 (-NH-), 2953 (CHAr), 1710 (C=O, thiazolidine-4-one), 1672
(-CO-NH-), 1214 (C-N), 658 (C-S); 1H-NMR (δ ppm): 10.13 (brs, 1H, -NH-), 7.12 (d, J =7.8 Hz, 1H,
Ar-H), 7.09–7.00 (m, 4H, Ar-H), 6.86 (d, J = 8.4 Hz, 1H, Ar-H), 6.55 (d, J = 7.8 Hz, 1H, Ar-H), 6.44
(d, J = 8.4 Hz, 1H, Ar-H), 5.66/5.46 (s, 1H, CH thiazolidine-4-one), 5.26 (d, J = 22.10 Hz, 2H, -NH2),
3.86–3.61 (m, 2H, CH2 thiazolidine-4-one), 3.60–3.48 (m, 1H, -CH-CH3), 2.41 (t, J = 6.8 Hz,
2H, -CH2-CH(CH3)2), 1.90–1.72 (m, 1H, -CH2-CH(CH3)2), 1.26 (dd, J = 22.4, 7.0 Hz, 3H, -CH-CH3),
0.86 (t, J = 6.0 Hz, 6H, -CH2-CH(CH3)2); 13C-NMR (δ ppm): 172.12 (Cq), 168.69/168.47 (Cq),
149.68/149.56 (Cq), 138.10/137.97 (Cq), 129.03 (CHAr), 128.69 (CHAr), 127.07/126.81 (CHAr), 123.58
(Cq), 113.49/113.36 (Cq), 61.80 (CH thiazolidine-4-one), 44.25 (-CH2-CH(CH3)2), 42.09/41.97 (-CH-CH3),

Molecules 2014, 19
15021
29.62 (-CH(CH3)2), 29.39 (CH2 thiazolidine-4-one), 22.18 (-CH(CH3)2), 18.89/17.80 (-CH-CH3);
HRMS (EI-MS): m/z calculated 398.189675; [M+H]+ found 398.189802; Green chemistry metrics:
E-factor 38.478 ME 0.025.
3.2.4. Preparation of 2-(4-Acetamidophenyl)-3-[2-(4-(isobutyl)phenyl)-2-methyl]acetamidothiazol-
idine-4-one (4n)
To a solution of 2-(4-aminophenyl)-3-[2-(4-(isobutyl)phenyl)-2-methyl]acetamidothiazolidine-4-one
(4m, 0.8 mmol) in DMF (5 mL) which was cooled at 0 °C there was added sodium hydride (0.96 mmol,
60% dispersion in mineral oil), according to the procedure described for other compounds [34]. After
the mixture of reaction was stirred 1 h at room temperature under argon atmosphere, acetyl chloride
(1.6 mmol) was added under low temperature (0 °C), and then the mixture was heated under reflux for
14 h. After the completion of reaction (TLC monitoring using dichloromethane-methanol, 9.5:0.5, v/v,
UV light at 254 nm) the solvent was removed under reduced pressure and the residue was treated with
dichloromethane and washed three times with distilled water. The organic layer was dried with
MgSO4, filtered and concentrated at rotary evaporator. The residue was precipitated with ethyl ether.
50/50 racemic mixture. Yield: 47%, m.p. 230 °C; IR (ZnSe crystal, cm−1): 3340, 3206 (-NH-), 2955
1
(CHAr), 1715 (C=O, thiazolidine-4-one), 1672 (-CO-NH-), 1212 (C-N), 659 (C-S); H-NMR (δ ppm):
10.19 (brs, 1H, -NH-), 10.01 (d, J = 23.2 Hz, 1H, -NH-CO-CH3), 7.59 (d, J = 8.5 Hz, 1H, Ar-H), 7.49 (d,
J = 8.4 Hz, 1H, Ar-H), 7.34 (d, J = 8.5 Hz, 1H, Ar-H), 7.13 (d, J = 8.4 Hz, 1H, Ar-H), 7.07 (d,
J = 7.9 Hz, 1H, Ar-H), 7.00 (dd, J = 11.4, 7.9 Hz, 3H, Ar-H), 5.75/5.60 (s, 1H, CH thiazolidine-4-one),
3.89–3.76 (m, 1H, CH2 thiazolidine-4-one), 3.70 (dd, J = 15.9, 7.0 Hz, 1H, CH2 thiazolidine-4-one),
3.59–3.45 (m, 1H, -CH-CH3), 2.39 (dd, J = 7.0, 3.7 Hz, 2H, -CH2-CH(CH3)2), 2.05 (d, J = 7.1 Hz, 3H,
-NH-CO-CH3), 1.85–1.73 (m, 1H, -CH2-CH(CH3)2), 1.24 (dd, J = 22.3, 7.0 Hz, 3H, -CH-CH3), 0.84
(d, J = 6.6 Hz, 6H, -CH2-CH(CH3)2); 13C-NMR (δ ppm): 172.16 (Cq), 168.75/168.52 (Cq), 168.33 (Cq),
140.01/139.92 (Cq), 139.32 (Cq), 138.09/137.93 (Cq), 132.08/131.91 (Cq), 128.70 (CHAr), 128.43 (CHAr),
126.98/126.74 (CHAr), 118.79 (CHAr), 61.30/61.12 (CH thiazolidine-4-one), 44.24 (-CH2-CH(CH3)2),
42.12 (-CH-CH3), 29.59 (-CH(CH3)2), 29.31 (CH2 thiazolidine-4-one), 24.01 (-NH-CO-CH3) 22.17
(-CH(CH3)2), 18.80/17.79 (-CH-CH3); HRMS (EI-MS): m/z calculated 440.200239; [M+H]+ found
440.200178; Green chemistry metrics: E-factor 33.52, ME 0.029.
3.3. Biological Evaluation
The antioxidant activity was estimated using the following in vitro tests: total antioxidant activity,
DPPH and ABTS radical scavenging assays.
3.3.1. Total Antioxidant Activity
The total antioxidant activity of the tested compounds was evaluated using the phosphomolybdenum
method according to the procedure in [26] with minor modifications. The method is based on the
reduction of Mo(VI) to Mo(V) by the tested compounds followed by the formation of a green
phosphate/Mo(V) complex at acid pH. Samples of different concentrations in DMSO (2.5, 1.25, 0.625,
0.3125 mg/mL) have been used. The samples (200 µL) were mixed with the reagent solution (2 mL,

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28 mM sodium phosphate; 4 mM ammonium molybdate; 0.6 M sulphuric acid), incubated at 95 °C for
90 min, cooled at room temperature. The absorbance of the samples was measured at 695 nm against a
blank solution (DMSO mixed with the reagents). For each sample the effective concentration (EC50)
was calculated. Ibuprofen and vitamin E (α-tocopherol) were used as reference and positive control,
respectively. All tests were performed in triplicate.
3.3.2. DPPH Radical Scavenging Assay
The radical scavenging activity of the tested compounds towards the radical 1,1-diphenyl-2-
picrylhydrazyl (DPPH) was measured as described in [27] with slight modifications. DPPH in
methanol (4 mL, 15 µM) was added to the test compounds (100 µL) prepared from stock solution
(20 mg/mL). The concentration of the tested compounds in the sample was 487.8 µg/mL. The mixture
was left for 1 h at room temperature in the dark and after that, the absorbance was measured at 517 nm
against a blank solution (methanol). The radical scavenging capacity was calculated according to the
following equation: Scavenging activity % = (Acontrol − Asample/Acontrol) × 100. Asample is the absorbance
of the sample after 1 h. Acontrol is the absorbance of mixture of 100 µL DMSO and 4 mL DPPH). The
ibuprofen and vitamin E (α-tocopherol) were used as reference and positive control, respectively. All
tests were performed in triplicate.
3.3.3. ABTS Radical Scavenging Assay
The ABTS+ radicals were activated by reacting of ABTS (2,2'-azino-bis(3-ethylbenzthiazoline-6-
sulphonic acid) (7 mM) with ammonium persulphate (2.45 mM). The mixture was left at room temperature
for 16 h in the dark as described in [28]. The intensely colored ABTS+ radical cation solution was
diluted with ethanol to obtain an absorbance value of 0.7 ± 0.02 at 734 nm. To test compound solutions
(20 µL) prepared from stock solution (20 mg/mL) ABTS solution (1980 µL) was added. The
concentration of the tested compounds in the sample was 200 µg/mL. After 6 min the absorbance was
measured and the radical scavenging capacity was calculated according to the following equation:
Scavenging activity % = (At = 0 − At = 6min/At = 0) × 100. At = 0 is the absorbance before adding the
sample. At=6 min is the absorbance after 6 min of reaction. The ibuprofen and vitamin E (α-tocopherol)
were used as reference and positive control respectively. All tests were performed in triplicate.
3.3.4. Statistical Analysis
All antioxidant assays were carried out in triplicate. Data were analyzed by an analysis of variance
(ANOVA) (p < 0.05) and were expressed as means ± SD. The EC50 values were calculated by linear
interpolation between the values registered above and below 50% activity.
4. Conclusions
In this study new heterocyclic compounds that combine the thiazolidine-4-one structure with the
arylpropionic acid one have been synthesized. The structure of the new compounds was proved using
1
13
spectral methods (IR, H-NMR, C-NMR, MS). The compounds were evaluated for their antioxidant
effects using in vitro assays: total antioxidant activity, DPPH and ABTS radical scavenging ability. All

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thiazolidin-4-one derivatives 4a–n showed improved antioxidant effects in comparison with the
corresponding acyl hydrazones 3a–l and ibuprofen, the parent compound. The encouraging
preliminary results illustrate the antioxidant potential of the synthesized compounds and motivate our
next research focused on their anti-inflammatory effects in chronic and acute inflammation models.
Acknowledgments
This work was supported by the project “Inter-university partnership for increasing the medical
doctoral research quality and interdisciplinarity through doctoral scholarships–DocMed.net”
(POSDRU/107/1.5/S/78702).
Author Contributions
IMG, FB, SR and LP designed research; IMG, MA and ATP performed research; IMG, FB, SR and
LP analyzed the data; LP, FB, SR wrote the paper. All authors read and approved the final manuscript
Conflicts of Interest
The authors declare no conflict of interest.
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