One-pot synthesis of 2-thioxothiazolidin-4-one, thiazolidine-2,4-dione, 2-iminothiazolidin-4-one based spiro-thiolane and bicyclic chromene-thiolane hybrids via Knoevenagel, 1,4-sulfa-Michael and aldol Reactions

A simple and efficient method for the synthesis of new class of 2-thioxothiazolidin-4-one (Rhodanine), thiazolidine-2,4-dione, and 2-iminothiazolidin-4-one based spiro-thiolane hybrids is reported. The title compounds were obtained by the reaction of Knoevenagel adducts of 2-thioxothiazolidin-4-one, thiazolidine-2,4-dione, 2-iminothiazolidin-4-ones and α -mercaptoacetaldehyde in the presence of DABCO (20 mol %) at room temperature. The reaction proceeds via 1,4-sulfa-Michael followed by intramolecular aldol reaction to form spiro-thiolane in good to moderate yields. This method was extended for the one-pot synthesis of bicyclic chromene-thiolane hybrids to generate functionalized chromene-tetrahydrothiophene derivatives in good yield


Results and Discussion
From the above discussion, the thiazolidine-2,4-dione, 2-thioxothiazolidin-4-one, 2-iminothiazolidin-4-ones, tetrahydrothiophenes are important in medicinal chemistry and biology.Also, the above discussion indicates that the spiro-derivatives of the above compounds are also equally important in biology.Considering the medicinal importance of thiazolidine-2,4-dione, 2-thioxothiazolidin-4-one, 2-iminothiazolidin-4-ones, tetrahydrothiophenes and with our experience in the thiolane chemistry, we envisaged the synthesis of thiolane-hybrids (spiro compounds) of these compounds via C-S bond formations (sulfa 1,4-Michael addition and aldol reaction as key steps).
To achieve our goal and based on our previous results in catalyst-free reactions, we started the investigation using 4-methoxy benzaldehyde (1a) (1.0 mmol) and 2,4-thioxothiazolidinone (rhodanine) (2) (1.0 mmol) without catalyst in EtOH, water, and CH3CN at 80 o C for 5 h, but the formation of intermediate (6a) was not observed.Later, the same reaction was performed in the presence of TEA (10 mol %) to give an intermediate (6a), which was subsequently treated with 1,4-dithiane-2-5-diol (5) (1.0 mmol) at RT for 6 h to give the desired product (7a) with yields of 65%, 58%, and 50%, respectively (Scheme 1 ; Table 1, Entry 1 to 3).Encouraged by these results and to improve the yield, many experiments were conducted by varying the base, solvent, and reaction time.All the results are summarized in Table 1.Among the screened conditions, DABCO in EtOH was found to be the best suitable condition for obtaining the desired product with a good yield (up to 85%) (Table 1, Entry 18).Having optimized reaction condition, different aldehydes (1b-1h) were treated with 2,4-thioxothiazolidinone (rhodanine) (2) (1.0 mmol) in EtOH at 80 o C (first step) to generate the intermediates (in situ), and 1,4-dithiane-2-5-diol (5) (1.0 mmol) were added at RT to give the spiro thioxothiazolidinonethiolane hybrids (7b-7h) in moderate to good yields (75-90%).All the newly synthesized compounds are characterized by using 1 H NMR, 13 C NMR, and mass spectral techniques.For instance, spectral data of compound 7a, the -CH3 protons of OMe group found at 3.8 δ ppm the CH2-protons of thiolane ring appeared at 2.59, and 2.89 δ ppm along with N-H peak in amide group, and alcohol proton observed at 12.68 and 5.13 δ ppm in 1 H NMR. Also, in 13 C NMR spectrum, the S-C=S bond in thiolane ring, C=O (carbonyl group) of amide are found 199 and 178 δ ppm respectively.In the FT-IR spectrum, the C=S stretching frequency of thiolane ring attributed at 1510 cm -1 , and the stretching frequency of -OH, and C=O groups in amide was identified at 3410, and 1603 cm -1 , respectively.

Proposed reaction mechanism:
Based on the experimental observations and literature reports, 48,49,56 a mechanism is proposed as shown in Figure 4.The cleavage of 1,4-dithiane-2,5-diol into mercaptaldehyde, Michael addition followed by intramolecular aldol reaction of the mercaptaldehyde with  −unsaturated system has been studied well in organic synthesis. 57The unsaturated system (I) (Knoevenagel condensation product) is formed from the reaction of aldehyde (1) and 2,4-thiazolidinedione (2) in the presence of DABCO which is further reacted with α-mercaptoacetaldehyde via sulfa 1,4-Michael addition (II) and intramolecular aldol reaction (III) to give the expected cyclic spiro-thiophene compound 7a.In conclusion, we successfully synthesized novel spiro-based 2,4-thioxothiazolidinone, 2,4-thiazolidinedione, substituted 2-imino-4-thiazolidinedione thiolane derivatives using 20 mol % of DABCO as a catalyst with moderate to good yields in one-pot MCR approach.The key steps for the reaction include Knoevenagel condensation followed by 1,4-sulfa-Michael reactions and intramolecular aldol reaction which led to cyclization and formation of a new C-S bond for the construction of thiolane hybrids.Same method was extended for the bicyclic chromene-thiolane hybrids.

Experimental Section
General.All the commercial compounds were bought from Spectrochem, SRL, SD-Fine, and Sigma-Aldrich. 1 H and 13 C NMR spectra were recorded on Bruker 400 MHz spectrometer using CDCl3 or DMSO-d6 solvents (reported in δ ppm).The mass spectra were recorded on Shimadzu LCMS-2020 or Agilent 6530 QTOF with a 1290 quaternary UHPLC system.IR spectra were recorded using the Perkin Elmer FT-IR instrument and melting points are recorded using the Stuart melting point apparatus.

Table 1 .
Optimization of Conditions[a]