Synthesis of (Z)-3-Allyl-5-(4-nitrobenzylidene)-2-sulfanylidene-1,3-thiazolidin-4-one and Determination of Its Crystal Structure

Abstract

To extend the existing library of arylidenerhodanines which display a potential biological activity, 3-N-allylrhodanine 1 was condensed under Knoevenagel conditions with p-nitrobenzaldehyde in acetic acid to afford the π-conjugated heterocyclic compound 3-allyl-5-(4-nitrobenzylidene)-2-sulfanylidene-1,3-thiazolidin-4-one 2. Compound 2 was characterized by IR and NMR spectroscopy, and its UV-vis spectrum was compared with that of compound 3-allyl-5-(4-methoxybenzylidene)-2-sulfanylidene-1,3-thiazolidin-4-one 3. The molecular structure is ascertained by a single-crystal X-ray diffraction study performed at 100 K.

1. Introduction

The five-membered heterocyclic compound rhodanine, also called 2-thioxo-4-thiazolidinone (see Figure 1) and its derivatives [1] not only play a role in organic chemistry as building blocks for further transformations but have also found application in various therapeutic areas [2,3] due to their broad spectrum of biological and pharmacological activities. These include antidiabetic activity [4], protein kinase inhibitors [5,6], topoisomerase II inhibition potency [7,8], anticancer activity against MCF-7 breast cancer [9,10] and potential cholinesterase inhibitors [11,12]. After approval of the N-substituted rhodanine Epalrestat [13] by the Food and Drug Administration (FDA) as an inhibitor drug for the treatment of diabetic neuropathy [14], several arylidene N-substituted rhodanine derivatives have also been identified as potential inhibitors of essential therapeutic targets such as PTP1B [15], α-amylase [16] and α-glucosidase [17] for the clinical management of Type 2 diabetes mellitus (T2DM) (Figure 1). Very recently, we successfully synthesized a series of novel dispirooxindoles-based rhodanine derivatives as potent inhibitors against α-amylase enzyme with in vivo hypoglycemic activity [18].

Arylidene-functionalized rhodanines were also recently screened to evaluate their anticancer activity against several cancer cell lines [19,20] or their propensity as antibacterial, antifungal or antioxidants agents [21,22,23]. In this context, we have reacted a series of 4-arylidene-5-thioxo-thiazolidin-2-ones with the secondary cyclic amine tetrahydroisoquinoline (THIQ) to convert them to (Z)-5-ylidene-2-aminothiazol-4(5H)-ones [18]. Some selected compounds incorporating the rhodanine motive and displaying a pharmacological activity are presented in Figure 1.

Furthermore, rhodanine derivatives attracted the attention of coordination chemists, since the soft C=S thione function (according Pearson’s HSAB principle) [24] readily coordinates to a wide range of transition metal complexes producing complexes with Cu(I), Pd(II), Pt(II) etc. [25,26,27,28]. The research presented here is (i) a continuation of our investigations into the coordination chemistry of thione-type ligand on diverse metal centers [29,30,31,32,33] and (ii) the design of novel rhodanine-based scaffolds for probing their biological activities [18].

2. Results and Discussion

The hitherto unknown arylidene rhodanine derivate 3-allyl-5-(4-nitrobenzylidene)-2-sulfanylidene-1,3-thiazolidin-4-one 2 was obtained by addition of p-nitrobenzaldehyde to a solution of commercially available N-allylrhodanine 1 in acetic acid via a classical Knoevenagel condensation route [34] (Scheme 1). Note that the synthesis of an isomer of 2 bearing the NO₂ group at the meta-position has been described by Ajlaoui et al. by the reaction of N-allylrhodanine 1 with (3-nitrobenzylidene)-4-methyl-5-oxopyrazolidin-2-ium ylide [35] and its NH analogue 5-(3-nitrobenzylidene)-2-sulfanylidene-1,3-thiazolidin-4-one has been isolated by Hesse using an L-proline-based deep eutectic solvent [22].

The structure of 2 was established using spectroscopic characterization and elemental analysis. On the infrared spectrum, an intense band at 1700 cm⁻¹ is associated with the carbonyl group and the thiocarbonyl vibration is observed at 1217 cm⁻¹. The NO stretching bands of the nitro group are located at 1509 and 1327 cm⁻¹ and the ν(C=C) appear near 1590 cm⁻¹ (see Figure S1). The ¹H-NMR recorded in d₆-DMSO (Figure 2) reveals the aryl signals as doublets at δ 7.91 and 8.36 ppm. The chemical shift in the vinyl proton at δ 7.93 indicates that the exocyclic double bond has a Z-configuration, as already observed for other 5-arylidene rhodanines described in the literature [6]. Its signal appears at a lower field than that of the E-isomer due to the stronger deshielding effect of the carbonyl group compared to the sulfur atom [36]. Four multiplets between 4.90–5.90 ppm are assigned to the allyl group. A pseudo doublet of triplet is present at δ 4.67 for the NCH₂, resulting from ³J and ⁴J allylic couplings of 5.2 and 1.4 Hz, respectively. The terminal vinyl gives rise to two broad doublets of doublets at δ 5.17 and 5.21 ppm with trans and cis coupling across the double bond of 17.7 (H1H2) and 10.9 (H’1H2) Hz. The two doublets at δ 5.15 and 5.22 are broad with a small coupling of 1.2 Hz. These apparent quartets result from a ⁴J allylic coupling with H3 and a geminal ²J coupling between H1H’1s with similar values. (Figure 1). The proton-decoupled ¹³C NMR spectrum (Figure 3) reveals the presence of two signals at δ 193.2 and 166.9 ppm attributed to the thiocarbonyl and carbonyl groups of the rhodanine moiety. A resonance at δ 46.7 corresponds to NCH₂, and olefinic carbon appears at 118.4 (C1) and 130.6 (C2, C7).

The UV-vis spectrum of highly π-conjugated 2 bearing a strongly electron-withdrawing NO₂-group exerting a -M effect is shown in Figure 4. For comparison, we have also recorded the benzylidene derivative 3 bearing a MeO-group (+M effect) at the para-position of the aryl cycle [34]. This literature-known compound has been synthesized using the same experimental procedure described for 2 in 84% yield. The superposition of their UV-vis spectra reveals a bathochromic shift in the absorption bands for 2 compared to 3, indicating that the NO₂-group causes a diminution in the energetic gap between the frontier orbitals HOMO-LUMO with respect to the methoxy group. The UV-vis spectra recorded in solvents of different polarity are shown in the Supplementary Materials as Figure S2. We tentatively attribute the adsorption bands presented in

Table 1. Absorption data of compounds 2 and 3 in CH₂Cl₂ at 298 K.

Comp.	Absorption: λabs nm (ε × 10−3M−1cm−1)
2	239 (5.5), 281 (6.7), 303 sh (4.8), 381 (17.9), 399 sh (16.0)
3	242 (2.8), 262 (3.2), 294 (6.1), 313 sh (3.6), 399 (18.1)

as n-π* and π-π* transitions but exclude a push–pull effect despite the strong acceptor propensity of the p-nitro group.

To complete the characterization of this compound, we examined 2 crystallizing in the monoclinic space group P2₁/c by an X-ray diffraction study performed at 100 K. As shown in Figure 5, the two cycles linked through the C6=C7 double bond are almost coplanar including the nitro group (torsion angle: 5.81(5)°); the allyl substituent points out of this plane in a perpendicular manner (torsion angle C4N1C1C2 93.6°). The C8 atom of the six-membered benzylidene cycle and the S1 atom are cis-arranged with respect to the C6=C7 double bond. Overall, the structure resembles those of other benzylidenerhodanines found in the Cambridge Structural Database (CSD) such as 3-allyl-5-(3-methoxybenzylidene)-2-sulfanylidene-1,3-thiazolidin-4-one (refcod GACVOY) [37], 3-allyl-5-(4-fluorobenzylidene)-2-sulfanylidene-1,3-thiazolidin-4-one (refcod ISAMIA) [38], 3-allyl-5-(4-chlorobenzylidene)-2-sulfanylidene-1,3-thiazolidin-4-one (refcod JADVUI) [39] and 5-benzylidene-3-(prop-2-en-1-yl)-2-sulfanylidene-1,3-thiazolidin-4-one (refcod QIBKOE) [35]. Other crystallographically characterized N-allyl rhodanines containing five-membered heterocycles within their framework are 2-thio-3-allyl-5-(2-(3′methylthiazolidinylidene))-thiazolidine-2,4-dione (refcod SALAZO) [40] and (E)-3-Allyl-5-(2-thienylmethylene)-2-thioxo-1,3-thiazolidin-4-one (refcod MUGFUR) [41]. Particularly noteworthy is the occurrence of an intramolecular C-H··· S contact between the H9 atom attached at C9 of the aromatic cycle and S1 forming a pseudo-six-membered cycle with d(C-H ···S) 2.51 Å, with the angle C-H ···S being 133.4°. This kind of contact is also observed in the structures JADVUI (dC-H ···S 2.55 Å, angle 133°) and GACVOY (dC-H ···S 2.55 Å, angle 133°) [37].

In the packing (Figure 6), several secondary weak intermolecular interactions are present such as C-H contacts with the NO₂ group of neighbored molecules (dC13-H13… O2¹ 2.505(11) Å, angle 153.4°, symmetry code ¹1 + x, y,1 + z) and (dC3-H3B… O3² 2.70(2) Å, angle 162.0°, symmetry code ²1-x,1-y,-z). Furthermore, a shorter C-H ···O contact occurs with the carbonyl C=O (dC10-H10·····O1¹ 2.4260(13) Å, angle 130.7°). An intermolecular C-H ···S contact occurs between a CH group of the allyl substituent and the thione function (dC2-H2·····S2³ 2.9259(5) Å, angle 144.0°, symmetry code ³1 + x,1/2 − y, −1/2 + z). As observed for the p-chloro derivative [39], the cohesion of the crystal structure also is ensured by an π-π stacking interaction between individual molecules forming inversion dimers. The centroid-to-centroid separation between two stacked benzylidene rings amounts to 3.7986(12) Å (see Figure S3).

These interactions have also been assessed by means of a Hirshfeld surface analysis using the CrystalExplorer17 software (Figure 7) [43,44]. The Hirshfeld surface was mapped over d_norm in the range from –0.2156 to −1.1392 (arbitrary units). The corresponding fingerprints plots are presented in the Supplementary Materials (Figure S4).

3. Materials and Methods

All reagents were purchased from commercial suppliers and used as received. ¹H and ¹³C NMR spectra were recorded on a Brucker AC 400 (Bruker, Wissembourg, France) spectrometer at 400 and 100 MHz, respectively. The infrared spectrum was recorded on a Vertex 70 spectrometer (Bruker, Wissembourg, France) in ATR mode. UV–Visible spectra were obtained on a VARIAN–Cary 300 array spectrophotometer (Varian, Melbourne, Australia). Elemental analyses were performed on a Thermo Fisher Flashsmart CHNS elemental analyzer.

A mixture of 3-allylrhodanine (1.73 g, 10 mmol), anhydrous sodium acetate (0.82 g, 10 mmol) and 4-nitrobenzaldehyde (1.90 g, 12.5 mmol) was refluxed in 10 mL of glacial acetic acid for 5 h. After cooling, yellow crystals were collected by filtration and washed with H₂O (2 × 5 mL), EtOH (2 × 5 mL) and Et₂O (5 mL). Yield: 95%. Anal. Calc. for C₁₃H₁₀N₂O₃S₂ (M.W = 306.37 g.mol⁻¹): C, 50.97; H, 3.29; N, 9.14; S, 20.93%. Found: C, 50.99; H, 3.38; N, 9.28; S, 20.87%. IR-ATR: 1700 ν(C=O), 1217 ν(C=S) cm⁻¹. ¹H NMR (DMSO-d₆) at 298 K: δ 4.66 (td, ³J = 5.2, ⁴J = 1.4, 2H₃, NCH₂), 5.17 (dd, ³J = 17.7, J = 1.2, H1, =CH₂), 5.21 (dd, ³J = 10.9, J = 1.2, H1′, =CH₂), 5.85 (tdd, ³J = 17.7, ³J = 10.9, ⁴J = 5.2, H2, =CH), 7.91 (d, ³J = 8.82, 2H9, Ar-H), 7.93 (s, H7, =CH), 8.35 (d, ³J = 8.82, 2H10, Ar-H) ppm. ¹³C NMR (DMSO-d₆) at 298 K: δ 46.7 (C3), 118.4 (C1), 124.9 (C9), 127.2 (C6), 130.5 and 130.6 (C7, C2), 132.0 (C10), 139.6 (C8), 148.2 (C11), 166.9 (C5), 193.2 (C4) ppm.

Since the grown single crystals of 2 used for the determination of the crystal structure were quite small, CuK_α radiation was employed instead of MoK_α radiation. A suitable crystal was mounted on an Bruker APEX-II CCD diffractometer Crystal data for C₁₃H₁₀N₂O₃S₂: M = 306.35 g.mol⁻¹, plate-shaped dark yellow crystals, crystal size 0.90 × 0.55 × 0.14 mm³, monoclinic, space group P2₁/c a = 7.8215(4) Å, b = 26.4778(17) Å, c = 7.1851(4) Å, α = 90°, β = 116.5790(10)°, γ = 90°, V = 1130.75(13) ų, Z = 4, D_calc = 1.529 g/cm³, T = 100 K, R₁ = 0.0360, Rw₂ = 0.0966 (all data) for 2726 reflections with I > = 2σ (I) and 2832 independent reflections, GOF = 1.060 Largest diff. peak/hole/e Å⁻³ 0.406/−0.313. The structure was solved using intrinsic phasing and refined using full-matrix least-squares against F² (SHELXT, SHELXL 2015) [45,46]. The data were collected using graphite-monochromated CuK_α radiation l = 1.54178 Å and have been deposited at the Cambridge Crystallographic Data Centre as CCDC 2327984. (Supplementary Materials). The data can be obtained free of charge from the Cambridge Crystallographic Data Centre via http://www.ccdc.cam.ac.uk/getstructures.

4. Conclusions

We have shown that arylidenerhodanine 2 is easily accessible in high yields and crystallographically evidenced that this π-conjugated heterocycle features both intra- and intermolecular secondary interactions. We are currently exploring the propensity of this compound to act as an S-donor ligand in coordination chemistry.