green synthesis, nmr spectral characterization, dft and...
TRANSCRIPT
Green Synthesis, NMR Spectral Characterization, DFT
and Antibacterial studies of 5-methyl-(2r,6c-diarylthian-
4-ylidene) hydrazono thiazolidin-4-one derivatives
P. Sangeethaa, C. Sankarb, K.Tharinic* and D. Balamurugand
aDepartment of Chemistry, Rajah Serfoji Government College, Thanjavur, India. bDepartment of Chemistry, TRP Engineering College, Irungalur, Tiruchirappalli-26, India
cDepartment of Chemistry, Govt. Arts College Tiruchirappalli - 22, India. dDepartment of Physics, SASTRA University, Tiruchirappalli - 22, India.
Abstract
A novel series of 5-methyl-(2r,6c-diarylthian-4-ylidene)hydrazono)thiazolidin-4-one derivatives (13-
16) were synthesized in excellent yields by green synthetic method under catalytic free conditions in water. The
structure of all the target compounds have been established on the basis of elemental analysis, FT-IR, 1H, 13C,
two dimensional (COSY, NOSEY & HSQC) NMR spectral data. DFT and its time dependent version based
calculations have been carried out to analyze its ground state electronic structure and to interpret the
experimental spectroscopic data. The coupling constants suggested that the cis-thiazolidin-4-ones (13-16),
which have the phenyl groups in cis orientation and largely exists in chair conformations with equatorial
orientation of the phenyl groups 13C. The newly synthesized compounds were screened for their in vitro
antibacterial activity. Amongst the tested compounds, compounds 15 and 16 expressed promising antimicrobial
activity.
Keywords: Thian-4-ones, thiazolidin-4-one, 1H NMR, 13C NMR, conformation, DFT
Introduction
2,6-Diarylthiopyran-4-ones are key building blocks for the synthesis of numerous electron donors [l,2],
sensitizers [3], and dyes [4] used for research on organic conductors and photoconductors. Thian-4-one ring
system is a core structure in various synthetic compounds displaying broad spectrum of biological activities,
such as antimicrobial [5-7] antimalarial [5], antifungal [8] and DNA-PK inhibitor [9]. On the other hand,
Several NMR spectral studies have been reported on 2,6-diarylthian-4-one derivatives [11-14]. In these studies
information has been gained about the conformation of the thian-4-one ring. For the 2r,6c-diarylthian-4-one and
their derivatives are known to exist in chair conformation with equatorial orientations of the phenyl groups. It
* Corresponding author, Tel.; +91-9047030170
E. mail address: [email protected] (Dr. K. Tharini)
* Department of Chemistry, Govt. Arts College, Tiruchirappalli - 22, India.
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has been shown that the substituent in the phenyl ring does not change the conformation of the heterocyclic ring.
From X-ray crystallographic diffraction study [15], it was found that the 2r,6c-diphenythian-4-one adopts chair
conformation with phenyl groups in the equatorial positions.
In view of the increasing demands to develop and implement environmentally benign protocols, chemistry
professionals are on a continuous pursuit to generate ways to reduce or eradicate the risks associated with
chemical processes [16]. In terms of safety, cost and availability, water is one of the greener solvents one can
think of [16, 17]. However, due to the low solubility of majority of organic compounds in water, its use as a
solvent is limited to some extent. Therefore there is a great need for benign and renewable alternative solvents
[18-22] that can be tuned with water to generate different polarity conditions to avoid the solubility problem.
Amid the alternative solvents with sufficient properties, the most promising one is ethyl lactate, a monobasic
ester, which has remarkable solubility in both water and non-polar solvents as well [23]. It is biodegradable, safe
and has negligible harmful effect on air quality. Moreover, ethyl lactate is also used in pharmaceutical
preparation, fragrances, and in food products.
Thiazolidines represent a significant group of compounds among nitrogen and sulfur containing
heterocycles that cover the mainstream of pharmacologically active molecules and natural products [24]. They
are very useful intermediates/ subunits for the development of molecules of pharmaceutical or biological interest
[25-27] including antibacterial [28], anti-inflammatory [29], anti-HIV [30], anticonvulsant [31], and anticancer
[32].
In addition, thiosemicarbazones reacted with cyclization reagents such as ethyl chloroacetate, ethyl-2-
chloroacetoacetate, ethyl-2-bromopropionate and 2-bromo acetophenone to give substituted thiazolidinone and
thiazoline derivatives [20-22, 33-35]. Most of these reports are confined to limited examples. All the above
mentioned procedures have described the use of organic solvents such as methanol [20], acetonitrile [36] and
acetone [24] as reaction media and almost all methods require refluxing conditions with longer reaction times.
Microwave-mediated synthesis of thiazolidinones was also reported [37].
Therefore based on our growing endeavors in investigating novel and eco-friendly green synthetic
protocols, we have developed an alternative route for the generation of thiazolidinones by tuning water with
ethyl lactate (l-form) as a co-solvent. Herein, we report the green synthesis, spectral characterization, DFT study
and antimicrobial activity of the title compounds which was derived from 2r,6c-diarylthian-4-ones (5-7)
(Scheme 1).
Experimental
Material methods and Physical measurements
Ethyl 2-bromopropionate was purchased from Sigma–Aldrich. All other analytical grade chemicals were
used as purchased without any further purification. Reactions were monitored by TLC. All the reported melting
points were measured in open capillaries and are uncorrected. Elemental analyzes were performed on an
Elementar Vario EL III CHNS analyzer. IR spectra were recorded on an AVATAR 330 FT-IR Thermo Nicolet
spectrometer in KBr pellets.
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NMR measurements were made in CDCl3 for all compounds in 5 mm NMR tubes. 1H NMR
spectra was recorded for 13 on a Bruker DRX-400 NMR spectrometer operating at 400.23 MHz for 1H and
100.63 MHz for 13C. For 14-16 these spectra were recorded on Bruker AMX 400.23 NMR spectrometer
operating at 400.13 MHz for 1H and 100.62 MHz for 13C.
Microwave irradiation was carried out in an open glass vessel. Modified microwave oven (200 W)
was used for the synthesis of compounds. A thermocouple was used to monitor the temperature inside the
vessel of the microwave.
Theoretical calculations
All calculations were carried out using the Gaussian09 program package [38]. The ground-state
structures of the studied compounds have been optimized using the density functional theory with
RB3LYP exchange correlation functional [39,40] and LANL2DZ basis set. The vibrational frequencies and
associated intensities (IR) were computed using RB3LYP/ LANL2DZ level. The computed frequencies
were scaled by a recommended factor 0.9525 [41]. Such a scaling factor was introduced to account for the
anharmonicity effects which are not accounted for in these calculations.
Synthesis of the Compounds
Synthesis of 2r,6c-diarylthian-4-ones (5-8)
The starting compounds 2r,6c-diarylthian-4-ones (5-8) were prepared by the procedure of refluxing
solution of sodium acetate (5 g), 4,4-disubstituted dibenzalacetone (5 g) and ethanol (40 mL), the hydrogen
sulphide gas was passed for 6-8 hours [42]. After the completion of the reaction, the contents were cooled to 0
C and the resinous mass formed was removed from the supernatant liquid by decantation. The supernatant
liquid was kept at 0 C for 1 day when colorless crystals of 2r,6c-diarylthian-4-one separated. The solid was
filtered off and washed with water, dried and recrystallized from pet.ether (b.p 60-80 C) to get the pure
compound.
General procedure for synthesis of 2r,6c-diarylthian-4-one thiosemicarbazone (9-12)
A mixture of 2r,6c-diarylthian-4-one (1 mmol) and thiosemicarbazone (1.5 mmol) in the presence of
hydrochloric acid (0.1 ml) in methanol was refluxed about 2-3 hours. After the completion of reaction the
reaction mixture was cooled and a solid mass was formed. The solid mass was filtered off and thoroughly
washed with cold mixture of ammonia and water. The crude product was recrystallized from ethanol.
General procedure for synthesis of 5-methyl-(2r,6c-diarylthian-4-ylidene)hydrazono)
thiazolidin-4-one derivatives (13-16)
To the boiling solution of thiosemicarbazone (1 mmol) in 50 ml of ethanol, ethyl 2-bromopropionate (1
mmol), and anhydrous sodium acetate (0.15 mmol) were added and refluxed for about 4-5 h. Excess solvent was
removed under reduced pressure. The reaction mixture was poured into crushed ice. The separated solid was
filtered off and purified by recrystallization using ethanol. For some cases, the target compounds could be
purified by column chromatography using mixture of chloroform – ethylacetate (9:1) as eluent.
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General microwave method for synthesis of compound 5-methyl-(2r,6c-diarylthian-4-
ylidene)hydrazono)thiazolidin-4-one derivatives (13-16)
A mixture of thiosemicarbazone (9-12) and ethyl 2-bromopropionate (1:1 mol) were mixed
thoroughly with 5 ml of water and ethyl lactate (40:60) in open glass vessel and subjected to the
microwave irradiation at low power setting (25%, 200 W) for 5-8 minutes, then allowed to cool. The
product was crystalized out from the reaction mixture. Results were given in Table 1.
Antibacterial study
The newly synthesized final compounds were evaluated for their in vitro antibacterial activity against
E. coli (ATCC-25922), S. aureus (ATCC-25923), P. aeruginosa (ATCC-27853), and K. pneumoniae bacterial
strains by serial plate dilution method. The compounds were dissolved in 100% dimethyl sulfoxide (DMSO) and
was diluted further (a twofold serial dilution) using Muller Hinton broth. Serial dilutions of the drug in Muller-
Hinton broth were taken in tubes and their pH was adjusted to 7.2-7.4 using phosphate buffer. A standardized
suspension of the test bacterium (as per the Clinical and Laboratory Standards Institutes (CLSI) guidelines) was
inoculated and incubated for 18-24 h at 37 C [43]. The minimum inhibitory concentration (MIC) was noted by
seeing the lowest concentration of the drug at which there was no visible growth. Activity of each compound
was compared with Ciprofloxacin and Streptomycin as standard [43]. MIC (mg/mL) were determined for 13-16
and the corresponding results are summarized in Table 7.
Results and Discussion
Chemistry
A new series of thiazolidin-4-one derivatives, incorporating important pharmacophores (thiazolidine
and imino/hydrazono group), were synthesized by condensation of thiosemicarbazones with ethyl 2-
bromopropionate. The first step of the synthesis involved the preparation of a series of thiosemicarbazones (9-
12) by acid catalyzed condensation of thiosemicarbazide with a range of substituted 2r,6c-diarylthian-4-ones.
Next, treatment of an equimolar mixture of thiosemicarbazones (9-12) with ethyl 2-bromopropionate in
presence of catalytic amount of anhydrous sodium acetate, afforded thiazolidin-4-ones 13-16 in good to
excellent yields (Scheme 1).
Herein, we report for the first time a catalyst-free reaction for a combinatorial synthesis of novel
thiazolidin-4-one framework in water at microwave irradiation. The reaction was performed by using equimolar
amount of thiosemicarbazones (9-12) and ethyl-2-bromopropionate in water at 200 W microwave irradiation.
Due to the poor solubility problem the reaction proceeded slowly and took longer time for completion and
required further purification steps. Therefore, there is a need for an alternative green solvent which can be co-
tuned with water to overcome the solubility problem.
The reaction was carried out with thiosemicarbazones and ethyl-2-bromopropionate in 5 mL of water
and ethyl lactate (40:60 %) to tests its effectiveness. Surprisingly a solid product was separated out from the
reaction mixture with in 3 min of irradiation. The yield of the product was 95%. The influence of solvent and
percentage of yield was also investigated and the results are given in Table 1.
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Numbering and designing of atoms
The numbering of the carbons of the thiane ring for 13 is shown in Fig.1. The ipso carbons of the aryl
groups at C-2 and C-6 are designated as C-2 and C-6. The other carbons of the aryl group at C-2 are denoted as
o, m and p-carbons and those of the aryl group at C-4 are denoted as o, m and p-carbons. The carbons of the
thiazolidine ring are denoted as C-2', C-4' and C-5'. The protons are denoted accordingly. For example, the
benzylic proton at C-2 is denoted as H-2 that the C-5' is denoted as H-5' and so on. For the compound 13 the
methylene protons at C-3 are denoted as H-3a and H-3e and those at C-5 are denoted as H-5a and H-5e
assuming chair conformation for the thiane ring.
IR spectral studies
The important IR stretching frequencies of 13-16 are given in Table 2. In IR spectra, the presence of
sharp intense bands at 1600 and 1634 cm-1 confirm the C=N stretching frequencies at C-4 and C-2. The bands
observed in the region of 3256–3298 cm-1 are due to N–H stretching frequency of thiazolidine analogues while
the absorption band in the region 3183–2800 cm-1 are ascribed to aromatic and aliphatic C–H stretching
frequencies. The band observed in the region of 1725 – 1735 cm-1 are due to C=O stretching frequency of amide
carbonyl group.
NMR Spectroscopy
Proton and 13C NMR spectral analysis of compound (13)
In order to analysis the spectral assignments of synthesized novel compounds 13-16, we have chosen
compound 13 as the representative compound. The 1H and 13C signals for the remaining compounds were
assigned by comparison with 13 using known effects [44] of the Cl, CH3 and OCH3 substituents in the aryl
rings. In the 1H NMR spectrum of 13 there is a sharp singlet at 7.94 ppm, corresponding to one proton. This
should be due to the thiazolidine NH proton. There are two doublets at 7.42 and 7.40 ppm, each corresponding
to two protons. These signals should be due to the ortho protons (o-H, o'-H). The quartet at 7.34 ppm,
corresponding to four protons, should be due to the meta protons (m-H, m'-H). This quartet has formed by the
overlap of two triplets. There is a multiplet at 7.27 ppm, corresponding to two protons. This signal should be due
to the para protons (p-H, p'-H).
There are two doublet of doublets at 4.25 and 4.13 ppm, each corresponding to one proton. By
comparison with early report [10] the signal at 4.25 ppm is assigned to the benzylic proton H-2a and that at 4.13
ppm is assigned to the benzylic proton H-6a. There is a multiplet at 4.02 ppm, corresponding to one proton.
These signal is due to the thiazolidine proton H-5'. There is a multiplet at 4.05 ppm, corresponding to one
proton. This should be due to H-5e proton. This signal should be a doublet of doublet, but it appeared as
multiplet with overlap of thiazolidine proton H-5'. However, the small vicinal coupling J6a,5e is not resolved.
There is one triplet at 2.51 ppm corresponding to one proton. This must be due to H-5a. The doublet of doublet
at 3.10 ppm is due to H-3e. There is signal at 1.65 ppm, corresponding to three protons. This is due to the
methyl protons at C-5'. The proton chemical shifts are given in Table 3. For confirming these assignments 1H-
1H COSY spectrum was recorded and the observed correlations are given in Table 4. In the 1H-1H COSY the
signal at 4.02 ppm shows correlation with the signal at 1.65 ppm. This correlation suggest that the signal at 4.02
ppm due to the H-5 and that at 1.65 ppm is due to the CH3 at C-5. Also, there is correlation between the signals
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at 4.13 ppm and that at 2.51 and 4.05 ppm. These correlations suggest that the signals at 4.13 ppm is due to H-
6a and that at 4.05 and 2.51 ppm are respectively, due to H-5e and H-5a.
It is seen that the ortho protons show correlation with the signal at 7.42. The ortho protons can couple
with only meta protons obviously, the signal at 7.42 ppm is due to o-H, o'-H and that at 7.34 ppm is due to m-H
and m'-H. In 14-16, assignments of the individual protons were made based on their multiplicities, position,
integral values of the signals and by comparison with 13. The 1H chemical shifts of the compounds 14-16 are
given in Table 3.
In order to assign the 13C signals unambiguously HSQC spectrum has been recorded for 13. The
observed correlations in the HSQC spectrum are given in Table 5. There are two weak signals at 175.3 and
167.7 ppm have no correlation in the HSQC spectrum. Obviously, the signal at 167.7 ppm is due to C-4 and that
at 175.3 ppm is due to the carbonyl carbon at C-4. There is a weak signal at 140.2 ppm. This signal has no
correlation in the HSQC spectrum. These signal is due to the ipso carbons of the phenyl groups. The signals in
the range 30–50 ppm could be assigned to the heterocyclic ring carbons. Among the four signals for the
heterocyclic ring carbons, two upfield signals could be assigned to the -carbons (carbons to the C=N-
N=C groups). Among these two signals, the upfield signal could be assigned to the syn -carbon [45, 46].
The other signals are confirmed based on the observed HSQC correlations. The observed 13C chemical shifts of
13 are given in Table 6. The 13C signals for 14-16, were assigned based on their multiplicities, position,
intensity and comparison with 13. The observed chemical shifts of 14-16 are given in Table 6.
Analysis of coupling constants
In compound 13 the Protons H-3a, H-3e and H-2a form an ABX system and protons H-5a, H-5e and H-
6a form an AMX system. The various coupling constants involving them could be determined directly from the
spectral data. The coupling constants J2a,3a and J2a,3e are calculated using second-order [47] analysis. The
conformation of the thiane ring can be deduced from the vicinal coupling constants. The coupling constants of
13 are as follows;
J2a,3a = 12.00 Hz; J2a,3e = 3.00 Hz; J6a,5e = 3.0 Hz; J6a,5a 12.00 Hz; J5a,5e = 13.0 Hz
The coupling constant values and position of the chemical shifts were used to predict the conformation
of the compound. The observations of large vicinal coupling constant values between 12.00 Hz (3J2a,3a) and
12.00 Hz (3J6a,5a) and of the vicinal coupling constant 3.0 Hz (J6a,5e) and 3.0 Hz (J2a,3e) for the protons of C-6 and
C-2 of compound 13 should largely exist in chair cornformation 13C with equatorial orientations of phenyl
groups at C-2 and C-6 Fig.1.
Configuration about C(4)꞊N bond
In all compounds the chemical shift of H-5e is greater than that of H-5a by about 1.0 ppm. Also, C-5 as
a much lower chemical shifts than C-3. Those observations suggest that the configuration about C4=N bond is E.
There are two isomers E and Z formed in this reaction about C2'=N bond. In such a configuration the C-5 – H-5e
bond will be polarized by γ-syn effect, so that H-5e gets a partial positive charge and C-5 gets a partial negative
charge. The partial positive charge on H-5e Deshields, if whereas the partial negative charge on C-5 shields it
and H-5a.
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HOMO, LUMO analysis
Highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) are
very important parameters for chemical reactions and quantum chemistry. It determines the way the molecule
interacts with other species; hence, they are called the frontier orbitals. HOMO is the outermost orbital
containing electrons which is ready to give these electrons and hence can act as electron donor. On the other
hand; LUMO is the innermost orbital containing free places to accept electrons [48] and hence act as electron
acceptor. The gap between HOMO and LUMO characterizes the molecular chemical stability [49]. The frontier
orbital gap helps to identify the chemical reactivity and kinetic stability of the molecule. A molecule with a
small frontier orbital gap is more polarizable and is generally associated with high chemical reactivity, low
kinetic stability and is also termed as soft molecule [50-52]. The lower value of frontier orbital gap in case of 13
makes it more reactive and less stable. The HOMO and LUMO energy is calculated by RB3LYP method using
LANL2DZ basis set. This electronic transition absorption corresponds to the transition from the ground to the
first excited state and is mainly described by an electron excitation from the HOMO to the LUMO. The HOMO
is located over the N–N and C꞊N of 8, the HOMO LUMO transition implies an electron density transfer to
ring. The optimized structure and atomic compositions of the frontier molecular orbital are shown in Fig. 2 and
Fig. 3. The calculated self-consistent field (SCF) energy of 13 is -1072.3723 au. The density of state spectra
were drawn by convolution the molecular orbital information with GAUSSIN curve of unit height as shown in
Fig. 4. The most important application of the DOS plot is to demonstrate molecular orbital compositions and
their contribution to chemical bonding. The energy gap between HOMO–LUMO explains the eventual charge
transfer interaction Fig. 5. The calculated MEP within the molecule. The frontier orbital energy gap in case of
13 is found to be 4.53 a.u.
Antibacterial activity
Antibacterial activity of title compounds were investigated against four different bacterial strains viz, S.
aureus, P. aeruginosa, K. pneumonia, S. typhi and E. coli using Streptomycin and ciprofloxacin as reference, by
serial dilution method. Results of antibacterial screening of compounds 13-16 are shown in Table 7. It indicate
that the compounds showed MIC values between 12.5 and 100 g/mL concentrations. It has been observed that
the compounds 15 and 16 displayed substantial activity against S. aureus and K. pneumonia. Amongst them,
compound 15 showed better activity at 12.5 g/mL against K. pneumonia which is more potent than the
reference compound. It is interesting to note that the activity decreased by two fold when 4-chloro (15) was
replaced by 4-methyl group (14). The promising activity of the compounds is mainly attributed to the presence
of chloro substitution in piperidine ring.
4. Conclusion
In this study, a solvent tuning green approach have been illustrated for the generation of 5-methyl-(2,6-
diarylthian-4-ylidene)hydrazono)thiazolidin-4-one (13-16) derivatives by tuning water with environmentally
benign ethyl lactate as a co-solvent. The reaction were rapid and good yield. All the compounds were
characterized by FT-IR, 1H, 13C NMR spectral data and elemental analyses. Based on the observed chemical
shifts and 2D correlations the thiane ring adopts chair conformation 13C with equatorial orientations of the
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phenyl groups. HOMO–LUMO calculations were performed on the stable molecule of 13. HOMO–LUMO
energy gap explains eventual charge transfer interactions taking place within the compound. All the newly
synthesized compounds were screened for their antibacterial activity. Among the synthesized compound, 15
exhibited good activity against all the bacterial strains.
Acknowledgements
The authors are thankful to SIF, Indian Institute of Science, Bangalore and to SAIF IIT Chennai for
recording NMR spectra. We also thankful to CECRI, Karaikudi for elemental analysis.
References
[1] C.H. Chen, G.A. Reynolds, J. Org. Chem. 45 (1980) 2453.
[2] G.A. Reynolds, C.H. Chen, J. Heterocycl. Chem. 18 (1981) 1235.
[3] C.J. Fox, W.A. Light, W. A. US Patent (1972) 3 706 504, 1972.
[4] J.R. Wilt, G.A. Reynolds, J.A. Van Allan, Tetrahedron 29 (1973) 795.
[5] M. Chaykovsky, M. Lin, A. Rosowsky, E. Modest, J. Med. Chem. 16 (1973) 188.
[6] J. Jayabharathi, Thanikachalam, A.Thangamani, M. Padmavathi, Med. Chem. Res. 16 (2007) 266.
[7] M. Gopalakrishnan, J. Thanusu, V. Kanagarajan, J. Enzy. Inhi. Medi. Chem. 24 (2009) 669.
[8] P. Parthiban, G. Aridoss, P. Rathika, V. Ramkumar, S. Kabilan, Bioorg. Med. Chem. Letts. 19 (2009)
2981
[9] J.J. Hollick, B.T. Golding, I.R. Hardcastle, N. Martin, C. Richardson, L.J.M. Rigoreau, G.C.M. Smith,
R.J. Griffina, Bioorg. Med. Chem. Letts. 13 (2003) 3083
[10] V. Gurumani, K. Pandiarajan, M. Swaminathan, Bull. Chem. Soc. Japan. 70 (1997) 29.
[11] K. Pandiarajan, J. Christophor Newton Benny, Indian J. Chem. 42B (2003) 1711.
[12] C. Sankar, S. Umamatheswari, K. Pandiarajan. J. Mol. Struct. 1076 (2014) 554.
[13] N.W. Boaz, K.M. Fox, J.Org.Chem. 58 (1993) 9042.
[14] D. Devanathan, K. Pandiarajan, Spectrosc. Lett. 42 (2009) 147.
[15] K. Pandiarajan, R. Sekar, T. Rangarajan, R. Sarumathi, Indian J. Chem. 32B (1993) 535.
[16] T. Narasimhamurthy, R.V. Krishnakumar, J.C.N. Benny, K. Pandiarajan, M.A. Viswamitra, Acta
Cryst. C56 (2000) 870.
[17] L.H. Keith, L.U. Gron, J.L. Young, Chem. Rev. 107 (2007) 2695.
[18] J.F. Jenck, F. Agterberg, M.J. Droescherc, J. Green Chem. 6 (2004) 544.
[19] http://www.medscape.com/.
[20] J.W. Lown, J.C.N. Ma, Can. J. Chem. 45 (1967) 939.
[21] J.B. Hendrickson, R. Rees, J.F. Templeton, J. Am. Chem. Soc. 86 (1964) 107.
ADALYA JOURNAL
Volume 9, Issue 2, February 2020
ISSN NO: 1301-2746
http://adalyajournal.com/774
[22] A.F. Cameron, N.J. Hair, N.F. Elmore, P. Taylor, J. Chem. Commun. 1970, 890.
[23] U. Vogeli, W. Von Philipsborn, K. Nagarajan, M.D. Nair, Helv. Chim. Acta 61 (1978) 607.
[24] A. Ramazani, A. Morsali, A.A. Soudi, A. Souldozi, Z.A. Starikova, A.Z. Yanovsky, Kristallographie
218 (2003) 33.
[25] M.H. Gonbaria, A. Ramazania, A. Souldozia, Phosphorus, Sulfur Silicon 184 (2009) 309.
[26] I. Hutchinson, S. A. Jennings, B. R. Vishnuvajjala, A. D. Westwell, M. F. Stevens, J. Med. Chem. 45
(2002) 744.
[27] J. L. Kane, B. H. Hirth, B. Liang, B. B. Gourlie, S. Nahill, G. Barsomian, Bioorg. Med. Chem. Lett. 13
(2003) 4463.
[28] A. C. L. Leite, L. M. F. Santos, D. Rde. M. Moreira, D. J. Brondani, Quím. Nova 30 (2007) 284.
[29] D.P. Gouvea, F.A. Vasconcellos, G.A. Berwaldt, A.C.P.S. Neto, G. Fischer, R.P. Sakata, W.P.
Almeida, W. Cunico, Eur. J.Med. Chem. 118 (2016) 259
[30] H. Chen, T. Yang, S. Wei, H. Zhang, R. Li, Z. Qin, X. Li, Bioorg. Med. Chem. Letts. 22 (2012) 7041.
[31] A. Pratima G. Nikalje, A.N. Shaikh, S.I. Shaikh, F.A. Kalam Khan, J.N. Sangshetti, D.B. Shinde,
Bioorg. Med. Chem. Letts. 24 (2014) 5558
[32] D.D. Subhedar, M.H. Shaikh, F.A. Kalam Khan, J.N. Sangshetti, V.M. Khedkar, B.B. Shingate, New
J. Chem. 40 (2016) 3047.
[33] A. Cukurovali, I. Yilmaz, S. Gur, C. Kazaz, Eur. J. Med. Chem. 41 (2006) 201.
[34] M. Gruttadauria, F. Buccheri, G. Cusmano, P. L. Meo, R. Noto, G. Werber, J. Heterocycl. Chem. 30
(1993) 765.
[35] A. M. M. E. Omar, I. C. Ahmed, O. M. Aboul Wafa, A. M. Hassan, H. Abuo-Shleib, K. A. Ismail,
Alex. J. Pharm. Sci. 3 (1989) 211.
[36] D. Gautam, P. Gautam, R. P. Chaudhary, Heterocycl. Commun. 17 (2011) 147.
[37] R.M. Achenson, J.D. Wallis, J Chem. Soc., Perkin Trans. 1 (1981) 415.
[38] M. J. Frisch, G. W. Trucks, H. B. Schlegel, G. E. Scuseria, M. A. Robb, J. R. Cheeseman, G. Scalmani,
V. Barone, B. Mennucci, G. A. Petersson, H. Nakatsuji, M. Caricato, X. Li, H. P. Hratchian, A. F.
Izmaylov, J. Bloino, G. Zheng, J. L. Sonnenberg, M. Hada, M. Ehara, K. Toyota, R. Fukuda, J.
Hasegawa, M. Ishida, T. Nakajima, Y. Honda, O. Kitao, H. Nakai, T. Vreven, J. A. Montgomery, Jr., J.
E. Peralta, F. Ogliaro, M. Bearpark, J. J. Heyd, E. Brothers, K. N. Kudin, V. N. Staroverov, R.
Kobayashi, J. Normand, K. Raghavachari, A. Rendell, J. C. Burant, S. S. Iyengar, J. Tomasi, M. Cossi,
N. Rega, J. M. Millam, M. Klene, J. E. Knox, J. B. Cross, V. Bakken, C. Adamo, J. Jaramillo, R.
Gomperts, R. E. Stratmann, O. Yazyev, A. J. Austin, R. Cammi, C. Pomelli, J. W. Ochterski, R. L.
Martin, K. Morokuma, V. G. Zakrzewski, G. A. Voth, P. Salvador, J. J. Dannenberg, S. Dapprich, A.
D. Daniels, Ö. Farkas, J. B. Foresman, J. V. Ortiz, J. Cioslowski, and D. J. Fox, Gaussian, Inc.,
Wallingford CT, 2009.
[39] CA.D. Becke, J. Chem. Phys, 98 (1993) 5652.
[40] C. Lee, W. Yang, R.G. Parr, Phys. Rev. B 37 (1988) 789.
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ISSN NO: 1301-2746
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[41] A. P. Scott, L.Radom J. Phys. Chem. 100 (1996) 16502.
[42] F. Arndt, P. Nachtwey, J. Chem. Ber. 58 (1925) 1633.
[43] M.H. Dhar, M.M. Dhar, B.N. Dhawan, B.N. Mehrotra, C. Ray Indian J Exp Biol. 6 (1968) 232.
[44] (a) R.M. Silverstein, F.X. Webster, Spectrometric Identification of Organic Compounds; 6th ed, Wiley:
New York, 1998; 229 pp. (b) R.M. Silverstein, F.X. Webster, Spectrometric Identification of Organic
Compounds; 6th ed, Wiley: New York, 1998; 234 pp.
[45] P. Geneste, R. Durand, J.M. Kamenka, H. Beierbeck, R. Marino, J.K. Saundes, Can. J. Chem. 56
(1978) 1940.
[46] G.E. Hawkes, K. Herwig, J.D. Roberts. J. Org. Chem. 39 (1974) 1017.
[47] P. Laszlo and P.R. Schleyer, Bull. Soc. Chim. Fr., (1964) 87.
[48] D.F.V. Lewis, C. Ioannides, D.V. Parke, Xenobiotica 24 (1994) 401.
[49] N.B. Colthup, L.H. Daly, S.E. Wiberley, Introduction to Infrared and Raman Spectroscopy, Academic
Press, New York, 1975.
[50] G. Socrates, Infrared Characteristic Group Frequencies, Wiley Inter science Publication, New York,
1980.
[51] A. Nataraj, V. Balachandran, T. Karthick, J. Mol. Struct. 1031 (2013) 221–233.
[52] G. Gece, Corros. Sci. 50 (2008) 2981.
FIGURE CAPTIONS
Scheme 1. Schematic diagram showing the synthesis of title compounds 13-16.
Figure 1. Numbering pattern followed for compounds 13-16 to explain NMR spectra and Conformation (13C)
of the compound 13.
Figure 2. Optimized structure of compound 13.
Figure 3 The total electron density mapped with electrostatic potential of compound 13.
Figure 4: Density of state (DOS) spectrum of Compound 13.
Figure 5. The calculated frontiers energies of compound 13.
Table 1. Synthesis of thiazolidinones in Microwave irradiation (water tuned with ethyl lactate as a co-solvent)
and conventional method.
Table 2.Characteristic FT-IR stretching frequencies (cm-1) and analytical data of 13- 16.
Table 3. 1H Chemical Shifts (ppm) of compounds 13-16.
Table 4. Correlations in the COSY and NOESY spectra of 13.
Table 5. Correlations in the HSQC spectrum of 13.
Table 6. 13C Chemical Shifts (ppm) of compounds 13-16.
Table 7. In vitro antibacterial activity of compounds 13-16.
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HHO O
R R
H3C CH3
O
EtOH / NaOH
String
O
R R
O
R R
S
1 - 4 5-8
Com. No. R
13 H14 p-CH315 p-Cl16 p-OCH3
H2S / Warm EtOH
S
N
HNC S
MeOH / 0.5 mLCon. HCl
NH2NHCSNH2
ref lux
R R
Br O
ONH2
S
N
RR
N
SN
O
H
CH3
H
a
b
9-1213-16
Scheme 1. Reagents and conditions: (a) Thermal method: EtOH, anhy. NaOAc; reflux (b) Green synthesis:
water and ethyl lactate (1:1 v/v), Microwave (25%, 200 W) for 5–8 mins
o'
o
m
m'
p'
p
S
NH
H H
H
H
H
65
4
312
N NH
S
H
CH3
O
2''
6''
1'
2' 3'4'
5'
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Figure 1. Numbering pattern followed for compounds 13-16 to explain NMR spectra and Conformation
(13C) of the compound 13
Figure 2. Optimized structure of compound 13
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Figure 3. The total electron density mapped with electrostatic potential of compound 13
Figure 4. Density of state (DOS) spectrum of Compound 13
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Figure 5. The calculated frontiers energies of compound 13.
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Table 1. Synthesis of thiazolidinones in Microwave irradiation (water tuned with ethyl lactate as a co-solvent)
and conventional method
S.
No Compounds
Micro Wave Irradiation Conventional Method
Solvent
Composition
(Water: EL)
Reaction Time
(Min)
Yield
(%)
Solvent
Composition
Reaction
Time
(Hrs)
Yield
(%)
1 13 100:00 10 20 Ethanol 6 90
2 13 50:50 5 50
3 13 40:60 3 95
4 14 40:60 5 93 Ethanol 7 85
5 15 40:60 5 90 Ethanol 7 85
6 16 40:60 6 89 Ethanol 7 78
Table 2.Characteristic IR stretching frequencies (cm-1) and analytical data of compounds 13- 16.
Co
mp
ou
n
ds M
ole
cula
r
Fo
rmu
la
m.p
. (
C) Elemental analysis IR stretching frequencies (cm1)
Calculated (%) Found (%)
C
=O
C2
'=N
C4
=N
N
-H
C-H
(Aliphatic
&
Aromatic) C H N C H N
13 C21H21N3OS2
219 63.77 5.35 10.62 63.70 5.32 10.65 1729 1608 1640 1386 3183 -
2917
14 C23H25N3OS2
235 65.21 5.95 9.92 65.28 5.90 9.95 1735 1637 1600 1427 3183-
2900
15 C21H19Cl2N3OS2
227 54.31 4.12 9.05 54.27 4.18 9.10
1731 1624 1630 1389 3170-
2890
16 C23H25N3O2S2
248 60.63 5.53 9.22 60.59 5.57 9.28
1732 1610 1648 1373 3054 -
2895
Table 3 1H. Chemical Shifts (ppm) of compounds 13-16.
Protons Compounds
Parent 13 14 15 16
H2a 4.84 4.25 4.22 4.20 4.23
H3a 2.73 2.91 2.93 2.92 2.90
H3e 2.69 3.10 3.11 3.09 3.11
H5a 2.73 2.51 2.53 2.52 2.59
H5e 2.69 4.05 4.07 3.99 4.05
H6 4.84 4.13 4.12 4.13 4.15
H5 - 4.02 4.03 4.01 4.02
CH3C5 - 1.65 1.67 1.66 1.65
o-H, o'-H 7.46 7.42, 7.40 7.21, 7.35 7.51, 7.51 7.43
m-H, m'-H 7.32 7.34 7.05,7.09 7.41 6.90
p-H, p'-H 7.27
p-OCH3 3.73
p-CH3 2.30
-NH- 9.51 9.59 9.57 9.56
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Table 4. Correlations in the COSY and NOESY spectra of 13.
Protons Correlations in the
COSY spectrum
Correlations in the
NOESY spectrum
9.51 (NH) - 3.05( H-5e)
7.42, 7.40(o-H, o'-H) 7.34 (m-H, m'-H) 4.25 (H-2), 4.13 (H-6)
2.91 (H-3a), 2.51 (H-5a)
7.34(m-H, m'-H) 7.42, 7.40(o-H, o'-H),
7.27(p-H, p'-H) -
7.27 (p-H, p'-H) 7.34 (m-H, m'-H) -
4.25 (H-2a) 2.91 (H-3a) 3.10 (H-3e), 7.42 (o-H)
3.10 (H-3e) 4.25 (H-2a) 2.51 (H-5a), 4.25(H-2a), 7.40 (o'-H)
2.91 (H-3a) 3.10 (H-3e) -
2.51 (H-5a) 4.05 (H-5e), 4.13 (H-6) 3.10 (H-3e), 4.05 (H-5e),
7.40 (o'-H)
4.05 (H-5e) 2.51 (H-5a) 2.51 (H-5a), 4.13 (H-6), 9.51 (NH)
4.13 (H-6) 2.51 (H-5a) 4.05 (H-5e), 7.40 (o'-H)
1.65 (CH3 – C5) 4.02 (H-5) 4.05 (H-5e)
Table 5. Correlations in the HSQC spectrum of 13.
Carbons (ppm) Correlations in the
HSQC spectrum
175.3 -
167.74 -
140.2 -
127.4 7.42, 7.40 (o-H)
128.8 7.34 (m-H, m'-H)
127.9 7.27 (p-H, p'-H)
49.6 4.25 (H-2a)
48.4 4.13 (H-6a)
44.2 3.10 (H-3e), 2.91 (H-3a)
37.1 2.51 (H-5a), 4.05 (H-5e)
42.3 4.02(H-5)
19.2 1.65 CH3-C5
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Table 6. 13C Chemical Shifts (ppm) of hydrazones 13-16.
Carbons
Compounds
13 14 15 16
C=O 175.3 175.2 175.4 175.3
C2 49.6 49.1 49.2 49.5
C3 44.2 40.9 40.9 44.3
C4 167.7 160.5 161.3 166.6
C5 37.1 33.9 33.9 36.8
C6 48.4 47.9 47.8 48.4
C5 42.5 41.7 42.5 42.4
CH3 – C5 19.2 19.1 19.2 19.3
C-2', C-6' 140.2 136.9 138.5 135.0
o-C, o'-C 127.4 126.6 129.6, 128.5 129.2, 129.1
m-C, m'-C 128.8 127.8 128.1 114.4, 114.3
p-C, p'-C 127.9 128.7 131.6, 131.5 159.1 158.8
p-OCH3 - 55.5
p-CH3 21.03
Table 7. In vitro antibacterial activity of compounds 13-16.
Compounds Minimum inhibitory concentration (MIC) in g/mL
R S. aureus K. pneumonia E. coli P. aeruginosa S. typhi
13 H 100 50 100 100 100
14 p-CH3 50 50 100 100 100
15 p-Cl 25 12.5 50 50 50
16 p-OCH3 25 25 100 50 50
Streptomycin - 25 25 25 50 50
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