Synthesis of Some New Functionalized Bis-thiazolidin-5-one and Bis-thiazolidin-4-one Derivatives

A series of bis-thiazo lidin-5-one and bis-thiazo lid in-4-one derivatives 3and5 was prepared by the treatment of highly functional thiocarbamoyl intermediates 2 and 4 with chloroacetyl chloride and chloroacetic acid, respectively. Treatment of the bis-thiocarbamoyl derivative 4a with diazotized sulphanilic acid affected acetyl cleavage to afford the corresponding arylhydrazono-thiocarbamoyl derivative 6.The tit le compounds bis-thiazolid in-5-one and bis-thiazolidin -4-one derivatives showed high reactiv ity towards azo coupling react ion with diazotized sulphanilic acid and Knoevenagel reaction with 4-isopropylbenzaldehyde.


Introduction
The chemistry of thiazo le derivatives, including new methodologies for their preparation, and recent applicat ions, such as their growing use in organic synthesis in the biological field and asymmetric catalysis as ligands has been recently reviewed [1]. Th iazo lidinones are known main ly as biologically active co mpounds with a broad range of activity and as intermediates in the synthesis of antibiotics and dyes [2][3][4]. Several papers have been published on the use of these compounds as antimicrobial [5,6], antifungal [7,8], anti-inflammatory activity [9], anticonvulsant [10], anesthetic [11] and antiviral drugs [12]. 2-A minothiazo les and its derivatives are also used in the syntheses of various types of dyes [13][14][15][16]. In this work, a series of bis-thiazolidin-5-one and bis-thiazolidin-4-one derivatives was prepared by treatment of their corresponding thiocarbamoyl intermediates with chloroacetyl ch loride and ch loroacetic acid, respectively. Also, the reactions of title compounds bis-thiazolidin -one derivatives with diazotized sulphanilic acid and with 4-isopropylbezaldehyde were studied.

Materials and Methods
All melting points were measured on an electrothermal Gallen kamp melt ing apparatus. Elemental analyses were carried out at the Microanalytical Unit, Faculty of Science, University of Mansoura, Egypt; the results were in satisfactory agreement with the calculated values. IR spectra (KBr) were determined on a Mattson 5000 FTIR spectrometer (not all frequencies are reported). Mass spectra were obtained at a Finnigan MAT 212 instrument (electron impact: 70 eV).
The title compound 1 was prepared by boiling a hot solution of ethyl acetoacetate (7.6 ml, 0.06 mo l) in 30 ml dry xy lene with a hot solution of benzidine (5.5 g, 0.03 mo l) in dry xylene (30 ml). The precipitate that formed on cooling was filtered off, dried and recrystallized fro m ethanol to give compound 1 as buff crystals, m.p. = 230 -232℃, y ield = 85%. IR (ν/cm -1 ): 3356 (NH), 1668 (C=O), 1633 (C=O). To a cold suspension of finely d ivided KOH (0.78 g, 14 mmo l) in DMF (20 ml) was added the title co mpound1 (2.46 g, 7 mmo l) fo llo wed by phenyl isothiocyanate (1.68 ml, 14 mmo l). The mixture was stirred at roo m temperature overnight, and then treated with chloroacetyl chloride (1.12 ml, 14 mmol). The stirring was continued at room temperature for 8 hours. The reaction mixture was poured into ice-cold water. The resultant solid product was collected by filtration, washed with water, dried, and recrystallized fro m ethanol. m.p.

'-biphenyl]-4,4'-diy l)-bis-(2-(aryl-thiocarbamoy l)-3-o xo-butanamide) derivatives (4)
To a cold suspension of finely d ivided KOH (0.78 g, 14 mmo l) in DM F (20 ml) were added the title compound1 (2.46 g, 7 mmol) fo llo wed by phenyl isothiocyanate (1.68 ml, 14 mmo l). The reaction mixture was stirred at room temperature overnight, poured into ice-cold water, and then neutralized with d ilute HCl. The resultant solid product was collected by filtration, washed with water, dried, and recrystallized fro m ethanol to afford co mpounds 4a and 4b.  (5) A mixture of bis-thiocarbamoyl4 (3 mmo l) and choloroacetic acid (0.57 g, 6 mmol) was reflu xed for 4-6 hours in glacial acetic acid (30 ml) containing fused sodium acetate (0.5 g, 6 mmo l). The reaction mixtu re was cooled and poured into cooled water. The solid precipitate that formed was filtered off, dried and recrystallized fro m ethanol to afford the bis-thiazo lidin-4-one derivatives 5. The diazotized solution of sulphanilic acid (0.69 g, 2 mmo l) was added with continuous stirring to a cold solution of compound 3 or compound 5a (4 mmo l) in 20 ml ethanol containing sodium acetate (0.75 g). The reaction mixture was stirred at 0-5℃ fo r 2 hours, left to stand at room temperature. The solid product that obtained was filtered off, dried and recrystallized fro m ethanol to afford co mpound 7 or compound 8, respectively. Formation of co mpounds 9 and 10 A mixture o f b is-thiazo lid in-5-one derivative 3 or bis-thiazolidin -4-one derivative 5a(3 mmo l) and 4-isopropylbenzaldehyde (0.9 ml, 6 mmo l) was reflu xed for 4 hours in ethanol (30 ml) containing catalytic amount of piperidine. The solid products that formed on cooling were filtered off, dried and recrystallized fro m ethanol to afford the corresponding arylidene derivatives 9 or 10, respectively.
Insitu treatment of the non-isolable intermed iates 2 with dilute HCl gave the corresponding bis-thiocarbamoyl derivatives 4a and 4b. Reflu xing of 4 with ch loroacetic acid in acetic acid containing anhydrous sodium acetate afforded the corresponding bis-thiazolidin -4-one derivatives 5. The mo lecular structure of 5 was confirmed by analytical and spectral data.
Treat ment of bis-thiocarbamoyl derivative 4a with diazotized sulphanilic acid in the presence of sodium acetate affected acetyl cleavage (Japp-Kling mann reaction type) with the formation of ary lhydrazono-thiocarbamoyl derivative 6 (Scheme 2). The structure of the highly functionalizedarylhydrazono-thiocarbamoyl derivative 6 was elucidated on the basis of its elemental analysis and spectral data.
The reactivity of the methylene group in bis-thiazolidin -5-one derivative 3 and bis-thiazolidin-4-one derivative 5a was tested toward the azo coupling reactionwith diazoniu m salts. Thus, when two moles of diazotized sulphanilic acid at 0-5 ℃ reacted with the thiazolidinonederivatives 3 and 5a yielded the corresponding bis-hydrazono derivatives 7 and 8 respectively. The structures of compounds 7 and 8 were assigned on the basis of their elemental analyses and spectral data.

Conclusions
We have synthesized new bis-thiazolidin -5-one and bis-thiazolidin -4-one derivatives by the reaction of availab le thiocarbamoyl derivatives with chloroacetyl chloride and chloroacetic acid, respectively.The title co mpounds bis-thiazolidin -5-one and bis-thiazolidin -4-one derivatives showed high reactivity towards azo coupling react ion with diazotized sulphanilic acid and Knoevenagel reaction with 4-isopropylbenzaldehyde.