Synthesis and Spectroscopy Characterizations of Some New Bis 1,3-thiazolidin-4-ones Derived from 4-hydroxybenzaldehyde Substrate

Introduction

Heterocyclic compounds have been classified as one of the most significant classes of organic molecules as a result of their use in industrial  and pharmaceutical applications.^1-13 The most significant of them are thiozolidinones (Scheme 1), which are thiazolidine compounds and are described as doubly unsaturated five-membered heterocyclic compounds having an S atom at position 1, an N atom at position 3, and a C=O group at position 2, 4, or 5. ^12-13

Scheme 1: Structures of the Various Thaiazolidinone Derivatives. Click here to View Scheme

The 1,3-thiazolidin-4-one moiety (wonder nucleus) is a magic moiety with a wide range of biological characteristics, including anti-inflammatory ^16-17, oncological activity¹⁸, wound healing ¹⁹, anticonvulsant ²⁰, anti-biofilm ²¹, Tyrosine inhibition ²², antibacterial ²³, anti-HIV ²⁴, etc. In 1961, Brown thoroughly examined the chemistry of 1,3-thiazolidin-1-one.²⁵ The major synthetic pathways for 1,3-thiazolidin-4-one derivatives require 3 components (an aldehyde, an amine, and thioglycolic acid), which are combined in one or two steps.²⁶ Because of the relevance of thiazolidinone derivatives, various helpful synthetic processes for their manufacture have since been devised. ^27–30.

As a result, the production and biological effects of 1,3-thiazolidin-4-one derivatives are receiving a lot of interest, and our present research is a continuation of our ongoing work on the invention, synthesis, and characterization of novel Bis 1,3-thiazolidin-4-one derivatives using three critical approaches.: Etherification ³¹,  condensation ^28,32, and finally cyclization reaction processes ³³ (Scheme 2).

Scheme 2: Synthetiv route of thiazoledenone derivation from 4-hydroxybenzaldehyde. Click here to View Scheme

Results and Discussion

In this approach, we reported a novel synthesis of Bis-1,3-thiazolidin-1-one compounds, which could have significant pharmacological properties. This work’s framework established the etherification of the OH and transformed it into the OR group. This step was done by the reaction of p-hydroxybenzaldehyde with the o-, m-, and p-chloro substituted of benzyl chloride in the presence of anhydrous K₂CO₃ and MeCN as a solvent, at room temperature Typically, after the workup process step, the corresponding 4-((chlorobenzyl)oxy)benzaldehyde products 3(a-c) were prepared with higher yields (98-99%) (Scheme 3, and Table 1). FT-IR for the prepared 3(a-c) compounds exhibit a strong peak at (1255, 1261, 1269) cm^-1 in the fingerprint area for the arC-O-alC group and these indicated the formation of the expected products.

Scheme 3: Synthetic route of 4-((chlorobenzyl)oxy)benzaldehyde derivatives from 4-hydroxybenzaldehyde. Click here to View Scheme

Table 1: The physical properties of 4-((chlorobenzyl)oxy)benzaldehyde products 3(a-c).

Products No.	Chloro Sub.	M. p(oC)	Color	Rf	Yield%
3a	o-Cl	44-48	Pale yellow	0.7	98
3b	m-Cl	50-52	white	0.6	98
3c	p-Cl	64-66	Pale yellow	0.6	98

While the second step involved the synthesis of Bis-Schiff base compounds 7(a-i) through the condensation reaction. This reaction was forwarded by the treatment of 4-((chlorobenzyl)oxy)benzaldehyde 3(a-c) intermediates with aromatic diamines (4-6) with adding afew drops of glacial acetic acid by refluxing reaction in ethanol absolute for 24 hours. This step (Bis-Schiff bases synthesis) showed a prosperous method and awarded the pure desired products (50-95 %) after the purification through the recrystallization from ethanol absolute (Scheme 4 and Tables (2, 3)).The ¹H-NMR spectra of compounds 7(a-i) showed extra protons signal peaks in the aromatic region with the chemical shifts at (7.92-6.94) ppm and a novel imine signal peaks with the chemical shifts at (8.61–8.40) ppm, both of which were consistent with the aromatic structural in these substances.

Scheme 4: Synthesis of Bis-Schiffbases from 4-((chlorobenzyl)oxy)benaldehydes. Click here to View Scheme

Table 2: The physical properties of Bis-Schiff base products 7(a-i). Click here to View Table

Table 3: The physical properties of the synthesizes Bis 1,3-thiazolidin-4-one 9(a-i) From 4-((chlorobenzyl)benzaldehyde susbstitutes. Click here to View Table

Lastly, the Bis 1,3-Thiazolidin-4-ones 9(a-i) products were produced in the final step by refluxing Bis-imines 7(a-i) with thioglycolic acid in dry benzene as solvent. Following the purification approach, this stage (cyclization process) yielded the anticipated products 9(a-i) with good yields (79-97%) (Tables 3, 4 and Scheme 5). The ¹H-NMR spectra revealed a further set of proton signal peaks with the chemical shifts at (3.97-3.07) and (6.68-6.02) ppm, which correspond to the aromatic 4-thiazolidinone framework’s CH₂-S and CH-S, respectively. Furthermore, the formation of new additional carbon signal peaks with the chemical shifts at (173.3-170.82) ppm for C=O of amide, as well as two signals in ¹³C-NMR spectra with the chemical shifts at (71.59-69.25) and (35.6-29.72) ppm attributed to C-C=O and C-S, respectively, supported the structures of the products that were wanted 9(a-i).

Scheme 5: Synthesis of Bis 1,3-thaizolidin-4-one derivatives from Bis Schiff bases 7(a-j). Click here to View Scheme

Table 4: the Bis 1,2-thaizolidin-4-ones 9(a-i) derived from Bis-Schiff bases intermediates. Click here to View Table

Experimental Section

Materials and methods

Table 5: Chemicals used and their suppliers

Chemicals	Companies	Chemicals	Companies
4-Hydroxy benzaldehyde	SIGMA-ALDRICH	Glacial acetic acid.	Hanover Riedel-De Hean AG (99.8%)
4-Chlorobenzayle Chloride.	SIGMA-ALDRICH	Thioglycolic acid	Yaco
3-Chlorobenzayle Chloride.	SIGMA-ALDRICH (99%)	Potassium carbonate	SIGMA-ALDRICH
2-Chlorobenzayle Chloride.	SIGMA-ALDRICH (99%)	Acetonitrile	Sharlau
4,4-Oxydianiline	SIGMA-ALDRICH (97%)	Ethanol absolute.	Sharlau (99.7%)
1,8-Diaminonaphthalane.	SIGMA-ALDRICH (99%)	Benzene.	BDH (99.7%)
2,6-Diaminopyridine	TCI	Dichloromethene.	ReAgent
4,4’-Aminophenyl suifone.	TCI	Petroleu ether.	Roth
4,4’-Diamino diphenyl methane.	Alfa Aesar (97%)	Ethyl acetate.	BDH (99.5%)

All reactions took place in anhydrous, dry conditions with the use of solvents. Commercial reagents weren’t purified before usage. As an absolute solvent, ethanol was utilized. Electrothermal apparatus have been used for melting points determination, which maybe uncorrected. Bruker DPX-300FT-NMR spectrometers have been used to generate ¹H- and ¹³C-NMR spectra at 400 and 100.2 MHz. The Spectrum was recorded in CDCl₃. IR spectra were recorded using a 1710-FTIR Perkin-Elmer spectrometer. Merck Kiese gel 60 F254 Thin Layer Chromatography (TLC) on aluminum foil from Macherey-Nagel. UV light at 254 & 365 nanometers was used for detection.

General procedure for syntheses of 4-((chlorobenzyl)oxy)benzaldehyde Compounds 2(a-c)

In dry acetonitrile (150 ml) chloro substitutions of benzyl chloride 2(a-c) (3.96 gm, 0.025 mol, 1.5 eq.) with anhydrous K₂CO₃ (5.6 gm, 0.04 mol, 2.5 eq.) were added to a solution of p-hydroxy benzaldehyde  (2 gm, 0.016 mol, 1 eq.) The reaction mixture was stirred at ambient temperature for 24 hours. TLC (PE/ EtOAc 80:20) was utilized to track the reaction’s progress. The crude reaction mixture had been concentrated by vacuum. DCM was used to extract the mixture, after which the organic layer was brine-washed and dried on Magnesium sulfate. Then the solvent was vacuum evaporated to generate crude products, which were subsequently refined by recrystallization from ethanol absolute to produce the necessary pure products 5(a-c) (Table 1).³¹

4-((2-chlorobenzyl)oxy)benzaldehyde (3a)

Pall yellow solid, (98%), R_f = 0.7, (44-48) °C. IR ν_max (cm⁻¹): 2924, 2825, 1689, 1255.

4-((3-chlorobenzyl)oxy)benzaldehyde (3b)

White solid, (98%), R_f = 0.6, (50-52) °C. IR ν_max (cm⁻¹): 2924, 2854, 1689, 1269.

4-((4-chlorobenzyl)oxy)benzaldehyde (3c)

Pall yellow solid, (99%), R_f = 0.6, (64-66) °C. IR ν_max (cm⁻¹): 2924, 2850, 1688, 1261.

General procedure for preparation of Bis-Schiff Bases 7(a-i) from 4-((chlorobenzyl)oxy)benzaldehyde 3(a-c)

A solution of 4-((chlorobenzyl)oxy)benzaldehyde substitutes 3(a-c) (2 eq.) was added to a solution of aromatic di-amines (4-6) (1 eq.) with stirring in ethanol absolute (40 ml) at room temperature. The mixture was then treated with some drops of glacial acetic acid and refluxed overnight. TLC (DCM/ MeOH 98:2 and 2 drops of 10% NH₄OH solution) was used to monitor the reaction development. Hot filtration, ethanol washing, and recrystallization by ethanol process were applied to obtain the desired Bis-Schiff products 7(a-i) (Table 2).^34,8

N-(4-(4-((4-((2-chlorobenzyl)oxy)benzylidene)amino)phenoxy)phenyl)-1-(4-((2-chlorobenzyl)oxy)phenyl)methanimine (7a)

Orange solid, (76%), R_f = 0.8, (134–138) °C. ¹H-NMR: δ (ppm)= 8.56 (d, J = 15.2 Hz, 2H, 2(N=CH)), 7.89 (t, J = 8 Hz, 6H, CH_aromatic), 7.64-7.61 (m, 4H, CH_aromatic), 7.55-7.53 (m, 4H, CH_aromatic), 7.33-7.153 (m, 10H, CH_aromatic), 5.24 (d, J = 4 Hz, 4H, 2(O-CH₂)).

N-(4-(4-((4-((3-chlorobenzyl)oxy)benzylidene)amino)phenoxy)phenyl)-1-(4-((3-chlorobenzyl)oxy)phenyl)methanimine (7b)

white solid, (50%), R_f = invisible, (219-220) °C. ¹H-NMR: δ(ppm) = 8.50 (s, 2H, 2(N=CH)), 7.52 (d, J = 6 Hz, 4H, CH_aromatic), 7.44-7.43 (m, 2H, CH_aromatic), 7.27-7.20 (m, 10H, CH_aromatic), 7.00-6.95 (m, 8H, CH_aromatic), 5.23 (s, 4H, 2(O-CH₂)).

N-(4-(4-((4-((4-chlorobenzyl)oxy)benzylidene)amino)phenoxy)phenyl)-1-(4-((4-chlorobenzyl)oxy)phenyl)methanimine (7c)

white solid, (75%), R_f = 0.9, (250-254) °C. ¹H-NMR : δ(ppm) = 8.61 (s, 2H, 2(N=CH)), 7.57 (d, J = 6 Hz, 4H, CH_aromatic), 7.32-730 (m, 4H, CH_aromatic), 7.21 (d, J = 6 Hz, 4H, CH_aromatic), 7.02 (d, J = 6 Hz, 4H, CH_aromatic), 6.95 (d, J = 6Hz, 6H, CH_aromatic), 5.20 (s, 4H, 2(O-CH₂)).

N-(4-(4-((4-((2-chlorobenzyl)oxy)benzylidene)amino)benzyl)phenyl)-1-(4-((2-chlorobenzyl)oxy)phenyl)methanimine (7d)

Yellow solid, (85%), R_f = 0.8, (114-118) °C.¹H-NMR : δ(ppm) = 8.50 (s, 2H, 2(N=CH)), 7.54 (d, J = 6.1 Hz, 4H, CH_aromatic), 7.31-7.14 (m, 16H, CH_aromatic), 6.94 (d, J = 6.4 Hz, 4H, CH_aromatic), 5.23 (s, 4H, 2(O-CH₂)), 3.82 (s, 2H, -CH₂-).

N-(4-(4-((4-((3-chlorobenzyl)oxy)benzylidene)amino)benzyl)phenyl)-1-(4-((3-chlorobenzyl)oxy)phenyl)methanimine (7e)

White solid, (56%), R_f = invisible, (158-160) °C. ¹H-NMR : δ(ppm) = 8.40 (s, 2H, 2(N=CH)), 7.45 (d, J = 4.5 Hz, 4H, CH_aromatic), 7.36-7.33 (m, 6H, CH_aromatic), 7.23-7.18 (m, 8H, CH_aromatic), 7.14-7.12 (m, 2H, CH_aromatic), 7.00 (d, J = 4.5 Hz, 4H, CH_aromatic), 5.20 (s, 4H, 2(O-CH₂)), 3.74 (s, 2H, -CH₂-).

N-(4-(4-((4-((4-chlorobenzyl)oxy)benzylidene)amino)benzyl)phenyl)-1-(4-((4-chlorobenzyl)oxy)phenyl)methanimine (7f)

White solid, (60%), R_f = 0.9, (220-222) °C. ¹H-NMR : δ(ppm) = 8.54 (s, 2H, 2(N=CH)), 7.56 (d, J = 6.4 Hz, 4H, CH_aromatic), 7.31-7.20 (m, 16H, CH_aromatic), 6.98 (d, J = 6 Hz, 4H, CH_aromatic), 5.19 (s, 4H, 2(O-CH₂)), 3.81 (s, 2H, -CH₂-).

N-(4-((4-((4-((2-chlorobenzyl)oxy)benzylidene)amino)phenyl)sulfonyl)phenyl)-1-(4-((2-chlorobenzyl)oxy)phenyl)methanimine (7g)

Yellow solid, (95%), R_f = 0.8, (170-172) °C. ¹H-NMR : δ(ppm) 9.90 (s, 2H, 2(N=CH)), 7.96 (d, J = 8.8 Hz, 4H, CH_aromatic), 7.86 (d, J = 8.8 Hz, 4H, CH_aromatic), 7.66 (d, J = 8.4 Hz, 2H, CH_aromatic), 7.55-7.52 (m, 4H, CH_aromatic), 7.44-7.41 (m, 4H, CH_aromatic), 7.11-7.09 (m, 6H, CH_aromatic), 5.26 (s, 4H, 2(O-CH₂)).

N-(4-((4-((4-((3-chlorobenzyl)oxy)benzylidene)amino)phenyl)sulfonyl)phenyl)-1-(4-((3-chlorobenzyl)oxy)phenyl)methanimine (7h)

Red solid, (58%), R_f = invisible, (98-100) °C. ¹H-NMR : δ(ppm) = 8.53 (s, 2H, 2(N=CH)), 7.92 (d, J = 6 Hz, 4H, CH_aromatic), 7.53 (d, J = 6 Hz, 4H, CH_aromatic), 7.48 (d, J = 6 Hz, 4H, CH_aromatic), 7.21 (m, 8H, CH_aromatic), 6.95 (s, 4H, CH_aromatic), 5.22 (s, 4H, 2(O-CH₂)).

N-(4-((4-((4-((4-chlorobenzyl)oxy)benzylidene)amino)phenyl)sulfonyl)phenyl)-1-(4-((4-chlorobenzyl)oxy)phenyl)methanimine (7i)

Pale-yellow solid, (50%), R_f = 0.9, (252-255) °C. ¹H-NMR : δ(ppm) = 8.53 (s, 2H, 2(N=CH)), 7.92 (d, J = 5.6 Hz, 4H, CH_aromatic), 7.86 (d, J = 8.8 Hz, 4H, CH_aromatic), 7.66 (d, J = 8.4 Hz, 2H, CH_aromatic), 7.55-7.52 (m, 4H, CH_aromatic), 7.44-7.41 (m, 4H, CH_aromatic), 6.95 (m, 4H, CH_aromatic), 5.22 (s, 4H, 2(O-CH₂)).

General procedure for preparation of Synthesis of Bis 1,3-thiazolidin-4-ones 9(a-i) from Bis Iimine 7(a-i)

A dropwise addition of thioglycolic acid 8 (10 mg, 2 eq.) have been added to a (1eq.) of Bis-Schiff Bases 7(a-i) solution in present of dry benzene (30 ml) with  refluxing the mixture for twenty-four hours. TLC was used to monitor the reaction progress (DCM/ MeOH 98:02 and 2 drops of 10% NH₄OH solution). Rotary evaporation was used to evaporate the extra solvent. The solid chemicals that remained were neutralized through the addition of a cold 10% NaHCO₃ solution till CO₂ bubbles were evaluated and left to stand overnight. The solid products have been separated through filtration, water cold washing, dried, and recrystallized twice using EtOH absolute. The physical characteristics of Bis 1,3-thiazolidin-4-ones 9(a-i) are synthesized in (Table 3).^{[35], [36]}

3,3′-(oxybis(4,1-phenylene))bis(2-(4-((2-chlorobenzyl)oxy)phenyl) thiazolidin-4-one) (9a)

Pale-yellow solid, (96%), R_f = 0.3, (145-147) °C. ¹H-NMR : δ(ppm) = 7.59 (m, 4H, CH_aromatic), 7.46-7.41 (m, 4H, CH_aromatic), 7.32 (d, J = 3.6 Hz, 2H, CH_aromatic), 7.13-7.06 (m, 8H, CH_aromatic), 7.02 (d, J = 8.8 Hz, 2H, CH_aromatic), 6.95- 6.90 (m, 4H, CH_aromatic), 6.02 (d, J = 6.8 Hz, 2H, 2(CH-S)), 5.28 (d, J = 2.4 Hz, 4H, (O-CH₂)), 3.92 (d, J = 5.2 Hz,  2H, (CH₂-S)), 3.98 (dd, J = 1.6 and 6.8 Hz,  2H, (CH₂-S)).

¹³C-NMR : δ (ppm)= 171.05 (2C=O), 158.98 (2C_ar), 153.92 (2C_ar), 134.32 (2C_ar), 132.70 (2C_ar), 131.09 (2C_ar),129.57 (2C_ar), 129.25 (4C_ar), 128.81 (4C_ar), 127.64 ( 2C_ar), 127.06 (2C_ar), 122.37 (4C_ar),117.26 (4C_ar), 115.16 ( 4C_ar), 67.21 (2C-C=O), 61.32 (2O-C), 29.72 (2C-S).

3,3′-(oxybis(4,1-phenylene))bis(2-(4-((3-chlorobenzyl)oxy)phenyl) thiazolidin-4-one) (9b)

yellow solid, (80%), R_f = 0.2, (198-200) °C; ¹H-NMR : δ(ppm)= 7.34 (s, 2H, CH_aromatic), 7.29-7.24 (m, 8H, CH_aromatic), 7.11-7.06 (m, 10H, CH_aromatic), 6.98 (d, J = 6 Hz, 4H, CH_aromatic), 6.68 (s, 2H, 2(CH-S)), 5.13 (s, 4H, (O-CH₂)), 3.77 (dd, J = 15.6 and 15. 3, 4H, 2(CH₂-S)).

¹³C-NMR : δ (ppm)= 173.3 (2C=O), 160.4 (2C_ar), 154.5 (2C_ar), 140.4 (2C_ar), 135.1 (2C_ar), 134.1 (2C_ar), 133.0 (2C_ar), 128.8 (4C_ar), 128.6 (4C_ar), 128.0 (2C_ar), 126.7 (2C_ar), 126.6 (2C_ar), 124.6 (2C_ar), 122.6 (2C_ar), 116.1 (2C_ar), 71.5 (2C-C=O), 66.9 (2O-C), 35.6 (2C-S).

3,3′-(oxybis(4,1-phenylene))bis(2-(4-((4-chlorobenzyl)oxy)phenyl) thiazolidin-4-one) (9c)

White solid, (82%), R_f = 0.2, (258-260) °C; ¹H-NMR : δ(ppm)= 7.87 (d, J = 8.8 Hz, 2H, CH_aromatic), 7.49-7.43 (m, 10H, CH_aromatic), 7.27 (m,4H, CH_aromatic), 6.99 (d, J = 8.4 Hz, 2H, CH_aromatic), 6.91 (appearant t, J = 8.8 and 6.8 Hz, 4H, CH_aromatic), 6.84 (d, J = 9.2 Hz, 2H, CH_aromatic), 6.39 (d, J = 6.4 Hz, 2H, 2(CH-S)), 5.03 (d, J = 5.2 Hz, 4H, (O-CH₂)), 3.92 (dd, J = 5.2 and 4 Hz,  4H, 2(CH₂-S)).

¹³C-NMR : δ (ppm)= 170.85 (2C=O), 158.64 (2C_ar), 148.00 (2C_ar), 132.92 (4C_ar), 132.48 (2C_ar), 132.40 (2C_ar), 128.96 (4C_ar), 128.90 (8C_ar), 120.32 (4C_ar), 115.58 (4C_ar), 115.25 (4C_ar), 68.82 (2C-C=O), 63.80 (2O-C), 33.15 (2C-S).

3,3′-(methylenebis(4,1-phenylene))bis(2-(4-((2-chlorobenzyl)oxy)phenyl) thiazolidin-4-one) (9d)

Dark-yellow solid, (97%), R_f = 0.2, (98-100) °C; ¹H-NMR : δ(ppm)= 7.91-7.86 (m, 4H, CH_aromatic), 7.57-7.56 (m, 2H, CH_aromatic), 7.32-7.29 (m, 6H, CH_aromatic), 7.24-7.20 (m, 4H, CH_aromatic) ,7.14-7.07 (m, 8H, CH_aromatic), 6.62 (dd, J = 8.4 and 18.4 Hz, 2H, 2(CH-S)), 5.26 (d, J = 6 Hz, 4H, (O-CH₂)), 4.02 (s, 2H,-CH₂-), 3.90 ( d, J = 6.4 Hz, 2H, (CH₂-S)),3.79 ( d, J = 7.2 Hz, 2H, (CH₂-S)).

¹³C-NMR : δ (ppm)= 170.99 (2C=O), 159.19 (2C_ar), 138.88 (2C_ar), 132.75 (2C_ar), 132.06 (4C_ar),130.45 ( 2C_ar), 129.70 (4C_ar), 129.43 (4C_ar), 128.78 (2C_ar), 128.51 ( 4C_ar), 127.00 (2C_ar), 125.87 (2C_ar), 121.06 (2C_ar), 115.37 ( 4C_ar), 67.39 (2C-C=O), 65.37 (2O-C), 40.93 (-C-), 29.72 (2C-S).

3,3′-(methylenebis(4,1-phenylene))bis(2-(4-((3-chlorobenzyl)oxy)phenyl) thiazolidin-4-one) (9e)

Yellow solid, (86%), R_f = 0.2, (58-61) °C; ¹H-NMR :δ(ppm)= 7.86 (m, 4H, CH_aromatic), 7.53 (d, J = 9.2 Hz, 4H, CH_aromatic), 7.43 (s, 2H, CH_aromatic), 7.36 (s, 6H, CH_aromatic), 7.30-7.28 (m, 4H, CH_aromatic), 7.06 (d, J = 8.8 Hz, 4H, CH_aromatic), 6.39 (s, 2H, 2(CH-S)), 5.03 (s, 4H, (O-CH₂)), 3.96 (s, 4H, 2(CH₂-S)), 3.84 (s, 2H, -CH₂-).

¹³C-NMR : δ (ppm)= 171.28 (2C=O), 158.51 (2C_ar), 147.14 (2Car), 140.10 (2C_ar), 136.13 (2C_ar), 130.82 (4C_ar), 129.33 (2C_ar), 128.79 (4C_ar), 128.26 (2C_ar), 127.83 (4C_ar), 126.81 ( 2C_ar), 126.66 (2C_ar), 126.14 (2C_ar), 121.53 (2C_ar), 115.23 ( 4C_ar), 68.71 (2C-C=O), 63.65 (2O-C), 52.62 (-C-), 33.17 (2C-S).

3,3′-(methylenebis(4,1-phenylene))bis(2-(4-((4-chlorobenzyl)oxy)phenyl) thiazolidin-4-one) (9f)

White solid, (88%), R_f = 0.2, (175-177) °C; ¹H-NMR : δ(ppm)= 7.89-7.84 (m, 2H, CH_aromatic), 7.48-7.46 (m, 3H, CH_aromatic), 7.35-7.27 (m, 6H, CH_aromatic), 7.21-7.12 (m, 8H, CH_aromatic), 7.06 (d, J = 8.4 Hz, 2H, CH_aromatic), 7.87 (d, _J = 8.8 Hz, 2H, CH_aromatic), 6.38 (s, 2H, 2(CH-S)), 5.01 (s, 4H, (O-CH₂)), 3.97 (d, J = 15.2 Hz,  4H, 2(CH₂-S)), 3.84 (s, 2H, (-CH₂-)).

¹³C-NMR : δ (ppm)= 170.82 (2C=O), 158.56 (2C_ar), 139.45 (2C_ar), 136.36 (4C_ar), 136.13 (2C_ar), 132.92 (2C_ar), 132.62 (2C_ar), 130.00 (8C_ar), 129.34 (4C_ar), 129.01 (2C_ar), 128.84 (4C_ar), 115.22 ( 4C_ar), 69.25 (2C-C=O), 68.78 (2O-C), 34.48 (-C-), 33.16 (2C-S).

3,3′-(sulfonylbis(4,1-phenylene))bis(2-(4-((2-chlorobenzyl)oxy)phenyl) thiazolidin-4-one) (9g)

Pale-yellow solid, (93%), R_f = 0.2, (178-179) °C; ¹H-NMR : δ(ppm)= 7.81-7.74 (m, 4H, CH_aromatic), 7.67 (d, J = 8.8 Hz, 2H, CH_aromatic), 7.51 (t, J = 8.8 Hz, 4H, CH_aromatic), 7.45-7.40 (m, 4H, CH_aromatic), 7.34 (d, J = 6 Hz, 3H, CH_aromatic), 7.31 (appearant t, J = 3.2 and 3.6 Hz, 3H, CH_aromatic), 6.99 (d, J = 8.8 Hz, 4H, CH_aromatic), 6.50 (s, 2H, 2(CH-S)), 5.13 (d, J = 4 Hz, 4H, (O-CH₂)), 3.19 (d, J = 8.4 Hz,  2H, (CH₂-S)), 3.07 (d, J = 15.6 Hz,  2H, (CH₂-S)).

¹³C-NMR : δ (ppm)= 171.19 (2C=O), 158.84 (2C_ar), 150.09 (2C_ar), 141.01 (2C_ar), 140.29 (2C_ar), 134.20 (2C_ar), 133.44 (2C_ar), 132.43 (4C_ar), 131.91 (4C_ar), 129.21 (4C_ar), 128.99 ( 4C_ar), 126.89 ( 4C_ar), 126.81 (4C_ar),  67.17 (2C-C=O), 64.61 (2O-C), 33.25 (2C-S).

3,3′-(sulfonylbis(4,1-phenylene))bis(2-(4-((3-chlorobenzyl)oxy)phenyl) thiazolidin-4-one) (9h)

Orang solid, (79%), R_f = 0.3, (105-108) °C; ¹H-NMR : δ(ppm)= 7.92 (d, J = 6 Hz, 4H, CH_aromatic), 7.33-7.15 (m, 16H, CH_aromatic), 6.94 (d, J = 6 Hz, 4H, CH_aromatic), 6.60 (s, 2H, 2(CH-S)), 5.18 (s, 4H, (O-CH₂)), 3.71 (dd, J = 15.6 and 15.6 Hz, 4H, 2(CH₂-S)).

¹³C-NMR : δ (ppm)= 170.99 (2C=O), 160.74 (2C_ar), 139.78 (2C_ar), 136.48 (2C_ar), 133.64 (2C_ar), 133.54 (4C_ar), 130.78 (6C_ar), 128.99 (2C_ar), 128.84 (2C_ar), 128.15 (2C_ar). 127.88 (2C_ar), 127.70 (2C_ar), 126.50 (2C_ar), 115.03 ( 4C_ar), 68.66 (2C-C=O), 60.98 (2O-C), 31.16 (2C-S).

3,3′-(sulfonylbis(4,1-phenylene))bis(2-(4-((4-chlorobenzyl)oxy)phenyl) thiazolidin-4-one) (9i)

White solid, (89%), R_f = 0.3, ( 257-259) °C; ¹H-NMR : δ(ppm)= 7.81 (d, J = 6 Hz, 4H, CH_aromatic), 7.39-7.22 (m, 13H, CH_aromatic), 7.11-7.04 (m, 6H, CH_aromatic), 6.94 (d, J = 6 Hz, 2H, CH_aromatic), 6.32 (s, 2H, 2(CH-S)), 5.18 (s, 4H, (O-CH₂)), 3.75 (dd, J = 15.6 and 15.6 Hz, 4H, 2(CH₂-S)).

¹³C-NMR : δ (ppm)= 173.3 (2C=O), 160.4 (2C_ar), 145.9 (2C_ar), 137.1 (2C_ar), 135.2 (2C_ar), 135.1 (4C_ar), 134.2 (2C_ar), 134.1 (4C_ar), 129.3 (4C_ar), 128.7 (2C_ar). 128.3 (4C_ar), 128.1 (4C_ar), 127.3 (2C_ar), 126.7 (2C_ar), 123.8 (2C_ar), 116.1(2C_ar),70.9 (2C-C=O), 66.9 (2O-C), 35.6 (2C-S).

Conclusion

In conclusion, we have reported a practical method towered the synthesis of 1,3-Thiazolidin-4-ones derivatives. This process started with the etherification step between p-hydroxy benzaldehyde substrate and o-, m-, and p-chloro substitution of benzyl chloride at room temperature, followed by appropriate synthesis of various new Bis-Schiff bases derivatives through the reaction of 4-((chlorobenzyl)oxy)benzaldehyde with some aromatic di-amine substrates under the condensation reaction conditions. Lastly the cyclization process between Bis-Schiff bases and thioglycolic acid afforded the desired 1,3-Thiazolidin-4-one’s products over three functional and efficient steps.

Acknowledgment

The authors are grateful to the Zakho University, Science Faculty, Chemistry Department for providing necessary facilities.

Conflict of Interest

There are no conflict of interest.

References

1. Ashraf, M. ; Ayaz, M. D.; Shafia, M; Shamsuzzaman, Med. Chem.(Los Angeles). 2016, 6, 280–291.
2. Shireen, R. M. ; Maher, K. A. Orient. J. Chem. 2015, 31(4), 2137–2146.
3. Ojha, M.; Yadav, D.; Kumar,  A.; Dasgupta, S.; Yadav,  R. Mini Rev. Med. Chem. 2021, 21(5), 586–601.
   CrossRef
4. Shireen, R. M. Orient. J. Chem. 2019, 35(2), 611.
   CrossRef
5. Haitham, H.; Shireen, M.; Frédéric R.; Yannick, L. Org. Lett. 2015, 17(18), 4518–4521.
   CrossRef
6. Shireen, R. M.;  Maher K. A. Indian J. Hetero. Chem. 2017, 27(3), 1–6.
7. Shireen, R.  M.; Maher, K. A. Indian J. Heterocy. Chem, 2019, 29, 199–203,.
8. Alya, A. D.; Shireen, R. M.;  Mohammed,  M. Sci. J. Univ. Zakho. 2020, 8(1), 12–18.
9. Shireen, M.; Maher,  K. Indian J. Hetero. Chem. 2017, 27(3), 83–87.
10. Shireen,  R. M. J. Educ. Sci. 2009 , 22(2),  29–37.
11. Maher, K.; Shireen,  M.; Amen, K. Orient. J. Chem. 2020, 36(2), 206.
    CrossRef
12. Layla,  A. O.; Shireen, R. M.; Maher, K. A. Orient. J. Chem. 2023, 39(2), 356–363.
    CrossRef
13. Layla, A. O.; Shireen,  R. M.; and Maher, K. A. Indian J. Heterocycl. Chem. 2022, 32(4), 487–492.
14. Desai, S.Β.; Desai, P. B. and Desai,  K. R. Heterocycl. Commun. 2001, 7(1), 83–90.
    CrossRef
15. Khosrow, Z.;  Khalil, F.;  Taraneh, T.;  Mohammad, R. S. Turkish J. Chem. 2004, 28(1), 95–100.
16. Lesyk, R. B.; Zimenkovsky, B. S. Curr. Org. Chem. 2004,  8(16), 1547–1577.
    CrossRef
17. Caroline, C.; Catherine, M. Eur. J. Med. Chem. 2003, 38(7–8), 645–659.
18. Tomasic, T. ; Masic,  L. P. Curr. Med. Chem. 2009, 16(13), 1596–1629.
    CrossRef
19. Mauricio, J. R. ; Shannon, T. B. ; Samuel, L. K.; Chieko, M.; Shinichi, I.; Hideho, T.; Mitchell, A. L. J. Biol. Chem. 1998, 273(49), 32679–32684.
    CrossRef
20. Rosaria, O;  Rosanna, M.;  Maria, L. B.; Giuseppe, B.; Archimede, R.; Antonietta, R.;  Giuseppa, C.;  Rosanna, D. P.; Lidia, S.; Salvatore, C.;  Maria, G. V. Bioorg. Med. Chem. 2005, 13(13), 4243–4252.
21. Zuping, X.; Christian, K.; Jian, M.; Zanna, M. B.; Campbell, M.; Wenxue, W.; Andrew, S. K.; Charles, D. S. J. Med. Chem. 2009, 52(1), 74–86,.
22. Neil, S. C. ; Christine, O. D.; Marina, P. Med. Chem. Lett. 2005, 15(14), 3374–3379.
    CrossRef
23. Matthew, E. V.; Percy, H. C.; Andrew, J. T.; Peggy, A. S.; Gregory, D. B.; Lorin, A. T.; Meizhong, X.; Yvonne, C. L.; Gengjie, Y.; Rui-Qin, L.; Paul, S.; J. Gerry, E.; James, M. T.; Carl, P. D. Bioorg. Med. Chem. Lett. 2003, 13(3), 533–538.
24. Alexei, D.; Alexey, L.; Michael, C.; Bradley, M.; Gerhard, W.; Timothy, M. ; Junying, Y. Nat. Cell Biol. 2001, 3(2), 173–18.
25. Avinash, C. T.; Shiv, J. G.; Gul, N. F.; Pankaj, K. S.; Amit, V.; Shailendra, K. S. Eur. J. Med. Chem. 2014, 72, 52–77.
26. Wilson, C.; Claudia, R. B.; Walcimar, T. V. Mini. Rev. Org. Chem. 2008, 5(4), 336–344.
27. Milan, C.; Maja, M.; Tomislav, B.; Nela, D. ; Valentina, R. Molecules. 2009, vol. 14(7), 2501–2513.
    CrossRef
28. Sanjeeva, R. C.; Chandrashekar, R. D. ; Yakub, V. ; Nagaraj, A. Org. Commun. 2010, 3(3), 57-69.
29. Vittoria, D.; Orazio, M.; Eugenio, P.; Antonio, C.; Federico, G.; Adele, B. J. Med. Chem. 1992, 35(15), pp. 2910–2912.
    CrossRef
30. Umesh, R. P.; Dhanaji, V. J.; Manisha, R. B.; Ramrao, A. M. Tetrahedron Lett. 2011, 52(14), 1689–1691.
    CrossRef
31. Bokolombe, P. N. ; Nthabeleng, M. ; Jessica, H. ; Gertrude, F. ; John, M. J. Porphyr. Phthalocyanines. 2017, 21(4–6), 431–438.
    CrossRef
32. Rojin, B. H.; Maher, K. A.; Shireen, R. M. Indian J. Heterocycl. Chem. 2022, 32(3), 357–362,.
33. Rabiha, H. S. ;Wissam, M. R. ; Adil, H. D. ; Khalid, A. A. ; Omar, A. M. Ann. Trop. Med. Public Heal. 2020, 23(7), 1012-1031.
34. Adele, B.; Gaetano, C.; Michele, M.;  Antonio, L. ; Ettore, N.; Vincenzo, B. Synth. React. Inorg. Met. Chem. 2000, 30(9), 1805–1816.
35. Abhishek, K. J. ; Ankur, V. ; Veerasamy, R. , Sushil, K. K. ; Ram, K. A. Bioorganic Med. Chem. 2012, 20(11) , 3378–3395.
    CrossRef
36. Adele, B.; Gaetano, C.;  Michele, M.;  Antonio, L. ;  Ettore, N.; Vincenzo, B. Org. Biomol. Chem. 2004, 2(19), 2809–2813.

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