green synthesis, nmr spectral characterization, dft and...

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: tharinilenin@gmail.com (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

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.

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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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[41] A. P. Scott, L.Radom J. Phys. Chem. 100 (1996) 16502.

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[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:

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Compounds; 6th ed, Wiley: New York, 1998; 234 pp.

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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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H3C CH3

EtOH / NaOH

String

1 - 4 5-8

Com. No. R

13 H14 p-CH315 p-Cl16 p-OCH3

H2S / Warm EtOH

MeOH / 0.5 mLCon. HCl

NH2NHCSNH2

ref lux

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

2' 3'4'

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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

No Compounds

Micro Wave Irradiation Conventional Method

Solvent

Composition

(Water: EL)

Reaction Time

Solvent

Composition

Reaction

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.

C) Elemental analysis IR stretching frequencies (cm1)

Calculated (%) Found (%)

(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 -

14 C23H25N3OS2

235 65.21 5.95 9.92 65.28 5.90 9.95 1735 1637 1600 1427 3183-

15 C21H19Cl2N3OS2

227 54.31 4.12 9.05 54.27 4.18 9.10

1731 1624 1630 1389 3170-

16 C23H25N3O2S2

248 60.63 5.53 9.22 60.59 5.57 9.28

1732 1610 1648 1373 3054 -

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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