Regioselective Synthesis of New 2-(E)-Cyano(thiazolidin-2-ylidene)thiazoles

Cyclocondensation of 2-[bis(methylthio)methylene]malononitrile (1) and cysteamine (2) afforded 2-(thiazolidin-2-ylidene)malononitrile (3). This compound on treatment with NaSH gave the corresponding thioamide derivative 4a in a regioselective manner on the basis of its single crystal X-ray diffraction analysis. Reaction of this compound with several α-bromocarbonyl compounds gave new 2-(E)-cyano(thiazolidin-2-ylidene)thiazoles 5a-g.

Our interest in the synthesis of heterocyclic compounds of biologically importance has encouraged us to study the synthesis of some new functionalized thiazoles. In this context we wish to report on the reactions and single crystal X-ray diffraction analysis of a newly synthesized thioamide which on treatment with various α-bromocarbonyl compounds afforded some new 2-(E)-cyano(thiazolidin-2ylidene)thiazoles.

Results and Discussion
2-(E)-Cyano(thiazolidin-2-ylidene)thiazoles 5a-g were prepared in a three-step procedure starting from the dinitrile 3 (Scheme 1). Cyclocondensation of 2-[bis(methylthio)methylene]malononitrile (1) and cysteamine (2) in ethanol afforded thiazolidine 3, which was filtered off and thionated by sodium hydrosulfide hydrate in water to give 2-cyano-2-(thiazolidin-2-ylidene)ethanethioamide (4) that can form either E and/or Z geometric isomers 4a,b. Scheme 1. Synthesis of 2-(E)-cyano(thiazolidin-2-ylidene)thiazoles 5a-g. For substituents R 1 and R 2 see Table 1 For exact determination of these geometric isomers 4a,b, single crystal X-ray analysis would seem to be preferable to other available techniques but all our efforts to prepare a suitable single crystal from compound 4 were unsuccessful, but instead we obtained a single crystal from the derivative ethyl 2-(E)-cyano(thiazolidin-2-ylidene)methyl)thiazole-4-carboxylate (5a). X-ray quality crystals were grown from ethanol with slow evaporation. A crystal structure was determined for product 5a and is shown in Figure 1. The molecule exists in the E geometric form with respect to C1-C4 bond. This observation clearly indicates that compound 4 must have the E isomeric structure 4a. The packing diagram of 5a shows that there is intermolecular hydrogen bonding between the hydrogen atom on the N1 and the N2 atom. Another intramolecular interaction is Van der Waals interaction between molecules. The high contact interaction between S1…S1 (3.777 Å) and O1…H9A (2.709 Å) gives rise to crystal growth expansion along b axis (see Figure 2).  The bond lengths of five-membered ring C5S2C7C6N2 are shorter than that ring C1S1C3C2N1, confirming the aromacity of the former ring. In this compound the C4C11N3 bond and the aromatic ring are in the same plane.
The thioamide 4a was treated with α-bromocarbonyl compounds in DMF to afford the new 2-(E)cyano(thiazolidin-2-ylidene)thiazoles 5a-g ( Table 1). The structures of compounds 3, 4a and 5a-g were deduced from their elemental analyses and 1 H-NMR spectral data. The 1 H-NMR spectra of compounds 3, 4a and 5a-g showed triplet signals at 3.47-3.63 ppm and 3.99-4.32 ppm (J ~ 7.6 Hz) due to the two methylene groups of the thiazolidine rings, and broad signals due to the NH group at 6.84-12.17 ppm. The 13 C-NMR spectrum of 4a showed signals due to nitile and thiocarbonyl groups at 119.42 ppm and 189.56 ppm. IR spectroscopy also confirmed the structure of products.

General
All of the melting points are uncorrected and were recorded on an Electrothermal type 9100 melting point apparatus. The mass spectra observed on a Varian Mat CH-7 at 70 ev. The infrared spectra were determined on 4300 Shimadzu spectrometer and only noteworthy absorptions are listed. The 1 H-NMR spectra were recorded on a Bruker AC 100 spectrometer. The 13 C-NMR spectrum was recorded on a Bruker Avance DRX-500 Fourier transform spectrometer. Chemical shifts are reported in ppm downfield from TMS as internal standard. All solvents and chemicals were of research grade and were used as obtain from Merck. Elemental analyses were performed on a Thermo Finnigan Flash EA microanalyzer. Compound 1 was prepared according to the procedure reported in the literature [20].

Crystal data for 5a
Crystallographic data and details of 5a are presented in Tables 2 and 3. The X-ray diffraction data for crystals of 5a were collected on Bruker AXS Smart Apex II CCD diffractometer at 100 K. The raw intensity data frames were integrated with the SAINT program, which also applied corrections [21]. Data were corrected for absorption effects by the SADABS procedure [22]. The software package SHELXTL v6.12 was used for the space group determination, structure solution and refinement. The structures were solved by direct methods (SHELXS-97) [