An Atom-economic and Facile Synthesis of Novel 4-Imino-3-phenyl-2-substitutedphenyl-5-tolyl-2H,3H,5H[1,2,5]thiadiazolidine-1-oxide through 1,3-Dipolar Cycloaddition Reactions

Organic synthesis has been one of the most successful scientific disciplines, and has also been of enormous practical utility. In the course of few last years, the progress of organic synthesis has been manifold and has gained importance in the field of heterocyclic compounds. This synthetic organic chemistry provides cornucopia of heterocyclic systems. Among various synthetic methods, cycloaddition reactions involving two simple components appear to be an attractive choice for the stereoselective synthesis of heterocyclic compounds due to its atom-economic and facile nature. Compounds incorporating heterocyclic ring systems continue to attract considerable interest due to the wide range of biological activities they possess. Amongst them, five-membered heterocyclic compounds occupy a unique place in the realm of natural and synthetic organic chemistry. Five-membered heterocycles like thiadiazolidine have found wide applications in the fields of pharmaceutical chemistry and have stimulated much interest in the field of medicinal and biological chemistry. The value of thiadiazolidine derivatives is significant among various heterocycles, as they are found to possess antibacterial [1-4], anti-inflammatory [5,6], antiviral [7], antiparasitic [8], antifungal [9-11] and other diverse biological activities [12]. Many thiadiazolidines are used for the production of anticonvulsant drugs [13,14] and in the treatment of depression also [15]. In addition to this, thiadiazolidine derivatives have played a crucial role in the theoretical development of heterocyclic chemistry and are also used extensively in organic synthesis.


Introduction
Organic synthesis has been one of the most successful scientific disciplines, and has also been of enormous practical utility. In the course of few last years, the progress of organic synthesis has been manifold and has gained importance in the field of heterocyclic compounds. This synthetic organic chemistry provides cornucopia of heterocyclic systems. Among various synthetic methods, cycloaddition reactions involving two simple components appear to be an attractive choice for the stereoselective synthesis of heterocyclic compounds due to its atom-economic and facile nature. Compounds incorporating heterocyclic ring systems continue to attract considerable interest due to the wide range of biological activities they possess. Amongst them, five-membered heterocyclic compounds occupy a unique place in the realm of natural and synthetic organic chemistry. Five-membered heterocycles like thiadiazolidine have found wide applications in the fields of pharmaceutical chemistry and have stimulated much interest in the field of medicinal and biological chemistry. The value of thiadiazolidine derivatives is significant among various heterocycles, as they are found to possess antibacterial [1][2][3][4], anti-inflammatory [5,6], antiviral [7], antiparasitic [8], antifungal [9][10][11] and other diverse biological activities [12]. Many thiadiazolidines are used for the production of anticonvulsant drugs [13,14] and in the treatment of depression also [15]. In addition to this, thiadiazolidine derivatives have played a crucial role in the theoretical development of heterocyclic chemistry and are also used extensively in organic synthesis.
Encouraged by the diverse biological activities of thiadiazolidine substituted compounds, in our investigation we found an interesting approach to synthesize these substituted ring systems.

Experimental General
Unless otherwise indicated, all common reagents were used as obtained from commercial suppliers (Sigma Aldrich) without further purification and the solvents were dried before use. All melting points were recorded on Gallen-Kamp apparatus and are uncorrected. IR spectra were recorded on a Perkin Elmer RXIFT General procedure for the synthesis of substituted benzalaniline (3a-i) The solution of benzaldehyde (0.01 mol) in ethanol (15 mL) taken in 100 mL beaker was added to the solution of substituted aniline (0.01 mol) in ethanol (15 mL) at room temperature. The reaction mixture was stirred for half an hour and then cooled in an ice bath for fifteen minutes (Scheme 1). The crude compound separated out was filtered at the suction pump and recrystallised from ethanol.

General procedure for the synthesis of N-sulphinyl-4-toluidine (7)
A solution of pure thionyl chloride (0.69 mol) in 100 mL of anhydrous toluene was added slowly to a solution of recrystallised 4-toluidine in 250 mL of anhydrous benzene contained in a 1-litre capacity round bottomed flask with swirling motion and occasional cooling in icebath as the reaction was an exothermic one. Each successive addition of thionyl chloride solution was done only after the previous reaction had subsided. An immediate precipitation of toluidinum sulphinyl chloride occurs. After the addition of the thionyl chloride solution was complete, the mixture was heated to reflux using a calcium chloride guard tube on a heating mantle until a clear solution was obtained. Whole of the solid disappeared in about five hours and the reaction mixture was refluxed for another hour to complete the reaction (Scheme 3). The solvent and the excess of thionyl chloride were distilled off under reduced pressure to yield a yellow N-sulphinyl-4-toluidine.

Results and Discussion
The survey of literature reveals that very few amount of work of N-sulphinylanilines have been taken with N-α-cyanoamines [16]. The present work aims therefore to study the effect of substituent on aniline part and hence to study their behavior on these cycloaddition reactions and to fill the gap in the literature present study has been taken up in this direction. For the present study, dienophile with cumulative double bond N-sulphinyl-4-toluidine has been used for these cycloaddition reactions. N-sulphinyl-4-toluidine has been synthesized from pure (AR) grade p-toluidine which was further purified by recrystallisation and using doubly distilled thionyl chloride as reported in literature [17]. The N-sulphinyl-4-toluidine so obtained was dried over anhydrous sodium sulphate for an overnight period and this was used after distillation in vacuo for these cycloaddition reactions with the N-α-cyanoamines.
Variously substituted N-α-cyanoamines were synthesized by following identical procedure as reported in literature [16]. In the first step, variously substituted azomethines were synthesized by condensing substituted anilines with benzaldehyde in alcohol as solvent (Scheme 1) which were subsequently subjected to hydrocyanation using potassium cyanide in aqueous ethanolic solution containing glacial acetic acid and the usual work up yielded crude crystalline N-α-cyanoamines (Scheme 2; Table 1).
The reaction afforded only one diastereomer exclusively in all cases, as evidenced by thin layer chromatography (TLC) showing the regioselectivity of these 1,3-dipolar cycloadditions ( Table 2).

Scheme 4:
Synthesis of cycloadducts and the probable mechanism. in the region of 3329 cm -1 due to N-H stretch , an another band at 1616 cm -1 was assigned to C=N stretch , a band at 1590 cm -1 was assigned to the skeletal stretching vibrations of the aromatic region and the absorption frequency at 1029 cm -1 has been assigned to S=O stretch .
The mass spectrum of 4-imino-2-(4'-tolyl)-5-tolyl-3-phenyl-2H,3H,5H[1,2,5]thiadiazolidine-1-oxide revealed the presence of the molecular ion peak at m/z 375. With loss of N-sulphinyl-4-toluidine from the parent ion peak a daughter ion peak at m/z 222 appears which subsequently loses a molecule of hydrocyanic acid to provide another daughter ion peak at m/z 195 via 'path a' , is present which corresponds to parent azomethine and this cyclises to give ion peak at m/z 194. This mass ion undergoes fragmentation to give mass ion at m/z 107 attributed to p-toluidine radical ion which may also arise by the fragmentation and rearrangement of molecular ion. Mass ion at m/z 107 may lose a hydrogen radical to give base peak at mass ion at m/z 106 forming base peak which collapses to mass ion peak at m/z 79 which loses a molecule of ethylene to give mass ion m/z 51. The probable mode of fragmentation is as shown in the Figure 1.

Conclusion
In conclusion, we have successfully developed the regioselective version of bioactive substituted thiadiazolidine derivatives through atom-economic and facile cycloaddition reactions. It was observed that the reaction took place in a stereo-and regioselective pathway across the double bond of the dipolarophiles to give novel thiadiazolidine-1oxides.