3-(2-Diisopropylaminoethyl)-5-(4-methoxybenzylidene)thiazolidine-2,4-dione

Abstract

Thiazolidine-2,4-dione core is widely used in the medicinal chemistry of different types of potential drug-like small molecules. In the present work, the synthesis of a novel non-condensed thiazolidine-2,4-dione-bearing derivative is reported by the two-step cost-effective approach including alkylation and Knoevenagel condensation. The structure of the synthesized 3-(2-diisopropylaminoethyl)-5-(4-methoxybenzylidene)thiazolidine-2,4-dione was determined and characterized using ¹H, ¹³C NMR, LC-MS spectra and the X-ray diffraction method.

1. Introduction

The current cancer chemotherapy includes the use of synthetic/semi-synthetic agents with an impact on a wide range of molecular targets; however, searching for novel chemotherapeutics is an important and topical issue—first of all, due to drug resistance [1]. Modern directions in anticancer medicinal chemistry are aiming to use small molecules that tend to be prepared following cost-effective approaches, which are at a lesser risk of degradation in vivo and are more permeable to tumor penetration [2,3,4,5,6,7].

The 3-(2-aminoethyl)-5-ene-thiazolidine-2,4-diones were reported as potential multitarget anticancer agents effective in vitro via the inhibition of the Raf/MEK/extracellular signal regulated kinase (ERK) and phosphatidylinositol 3-kinase (PI3K)/Akt signaling cascades (Figure 1) [8,9,10].

Reported in [8,9,10], hit/lead compounds were found to be promising for developing novel anticancer agents and encourage further structure optimization. It should be noted that the preparative organic chemistry of 5-ene-thiazolidine-2,4-diones is often complicated with the selection of optimal reaction conditions that affect the yield, reaction time, etc., and it is especially important for medicinal chemistry needs [11,12].

Herein, we report a synthesis of a structure-related derivative described in [8,9,10]—namely, 3-(2-diisopropylaminoethyl)-5-(4-methoxybenzylidene)thiazolidine-2,4-dione (3)—using a simplified two-stage protocol. The proposed approach follows the requirements of cost-effective methodology and could be applied for the synthesis of 3-(2-aminoethyl)-5-ene-thiazolidine-2,4-diones using commercially available (alkylamino)alkyl halides.

2. Results and Discussion

2.1. Synthesis of the Title Compound 3

The thiazolidine-2,4-dione (1) was used as a starting “building block” with the following modification of the core at the N3 (by alkylation) and C5 (by Knoevenagel condensation) positions (Scheme 1). The alkylation was performed using classic conditions [13] by a reflux of 1 with 2-diisopropylaminoethyl chloride hydrochloride during 4 h in acetone with the presence of anhydrous potassium carbonate. After completing the reaction (monitored by TLC), the synthesized 3-(2-diisopropylaminoethyl)thiazolidine-2,4-dione (2) was isolated from the reaction mixture and used without any additional purification. The Knoevenagel condensation of 2 with p-methoxybenzaldehyde was performed by reflux during 5 h in the ethanol without the addition of the catalyst, and title compound 3 was obtained with a yield of 71%. Probably, the diisopropylaminoethyl residue of molecule 2 performs the role of the basic catalyst of the mentioned reaction.

The structure of synthesized compound 3 was confirmed using ¹H, ¹³C NMR, LC-MS spectra and X-ray analysis (copies of the spectra are presented in the Supplementary Materials). In the ¹H NMR spectrum of compound 3, the characteristic signals of all the protons are presented. The protons of the methyl groups resonated as a singlet at 0.90 ppm. Two protons of the methine groups gave a septet at 2.95 ppm. The two methylene groups are characterized with two triplets at 2.58 and 3.62 ppm. The chemical shift of the methoxy group was observed as a singlet at 3.83 ppm. The aromatic protons resonated as two doublets at 7.10 and 7.59 ppm, with J = 8.3 Hz. The 5-CH = group gave a characteristic signal at 7.81 ppm, which confirmed the Z-isomerism of the arylidene moiety [14]. It is important to note that the formation of 5-Z-arylidene derivatives is typical for the Knoevenagel reaction of 4-thiazolidinones and aromatic aldehydes [5,13].

The ¹³C NMR spectra of 3 showed 13 carbon signals. The carbons of the four methyl groups gave a signal at 20.9 ppm. Two methylene carbons resonated at 41.6 at 42.2 ppm. Two aliphatic methine carbons gave a signal at 47.9. The carbon of the methoxy group resonated at 56.0 ppm. The carbons of the benzene ring and double bound appeared in the range from 115.5 to 161.6 ppm. The thiazolidine C=O carbon atoms resonated at 166.3 and 167.8 ppm.

2.2. X-ray Crystallographic Study of the Title Compound 3

The structure of the synthesized compound 3 has been additionally confirmed by X-ray analysis (Figure 2). In the crystal structure, the asymmetric part of the unit cell was found to contain two symmetry-independent molecules, denoted as A and B, which differ to a rather moderate extent in conformation (unit weigh r.m.s.d. = 0.985 Å [15]; Figure 3). The largest conformational differences between molecules A and B correspond to the angular arrangement of the 2-diisopropylaminoethyl residue or, more precisely, its diisopropylamino fragment, although the differences were also found in the positioning of the 4-methoxyphenylmethylidene moiety, but to a much lesser extent. The spatial arrangement of diisopropylamino fragments is described with torsion angles C2–N3–C7–C8 and N3–C7–C8–N9 (molecule A: 71.04(13) and 179.92(9)°, molecule B: 87.72(13) and 173.67(9)°). The angular orientation of two isopropyl moieties in molecules A and B reveal two pairs of torsional angles—C8–N9–C10–C11/C8–N9–C10–C12 and C8–N9–C13–C14/C8–N9–C13–C15 (molecule A: −64.43(13)/62.91(12)° and −60.16(13)/179.16(10)°; molecule B: −177.54(11)/62.61(13) and −56.93(13)/69.10(13)°)—due to their rotation around the N9–C10 and N9–C13 bond, respectively. The torsional angles indicate that pairs of the bonds C8–N9/C10–C11(12) and C8–N9/C13–C14(15) in molecule An adopt a mutual synclinal (+sc, −sc) and synclinal, antiperiplanar (−sc, ap) conformation, while in molecule B, they adopt antiperiplanar, synclinal (ap, +sc) and synclinal (−sc, +sc) conformations.

The observed interatomic C5–C17 distance in molecules A and B (1.3453(16) and 1.3458(15) Å, respectively) confirms the presence of a double bond between these atoms. Simultaneously, the torsion angle S1–C5–C17–C18 (molecule A: 2.01(19)°, molecule B: −0.29(19)°) indicates a Z configuration of the 4-(methoxyphenyl)methylidene group. The dihedral angles between the mean planes of the almost flat p-methoxyphenyl and thiazolidin-2,4-dione systems are 3.63(4)° in molecule A and 19.29(4)° in molecule B due to the rotation around the C17–C18 bond.

In the crystal lattice, molecules A and B are connected by the N7A–H7A∙∙∙O16B and C15B–H15D∙∙∙O6Aⁱ hydrogen bonds and the C2B=O6B∙∙∙Cg1ⁱ intermolecular interactions into the tapes extending along the c axis. The neighboring tapes of molecules are linked through the hydrogen bonds C20B–H20B∙∙∙O16Bⁱⁱ, C23A–H23A∙∙∙O16Aⁱⁱⁱ and C25B–H25E∙∙∙O6B^iv into layers parallel to the bc plane (

Table 1. Hydrogen bonds and Y-X∙∙∙Cg interactions in the crystal structure of 3.

D—H∙∙∙A	D—H (Å)	H∙∙∙A (Å)	D∙∙∙A (Å)	D—H∙∙∙A (°)
N7A-H7A∙∙∙O16B	0.99	2.55	3.4291(14)	149
C15B-H15D∙∙∙O6A i	0.98	2.60	3.5659(17)	169
C19A-H19A∙∙∙S1A	0.95	2.59	3.2963(17)	132
C19B-H19B∙∙∙S1B	0.95	2.63	3.3017(17)	128
C20B-H20B∙∙∙O16B ii	0.95	2.50	3.4307(14)	166
C23A-H23A∙∙∙O16A iii	0.95	2.43	3.3489(14)	164
C25B-H25E∙∙∙O6B iv	0.98	2.56	3.4543(16)	151
Y—X∙∙∙Cg	Y—X (Å)	X∙∙∙Cg (Å)	Y∙∙∙Cg (Å)	Y—X∙∙∙Cg (°)
C2B=O6B∙∙∙Cg1 i	1.2087(15)	3.4383(10)	3.7847(12)	97.20(7)

Symmetry codes: (i) x,1−y,−1/2+z; (ii) 1/2−x,−1/2+y,1/2−z; (iii) 1/2−x,3/2−y,1−z; (iv) −1/2+x,1/2+y, 1/2−z; Cg1 = thiazolidin-2,4-dione system.

, Figure 4). The layer thickness is about half of the a parameter length. Within a layer, the contacts Cg1∙∙∙Cg2^v and Cg2∙∙∙Cg1^v (symmetry code: (v) 1/2−x,1/2−y,1−z) between the molecules are also observed. Perpendicular distances amount to 3.3909(4) and 3.4452(5) Å, respectively (Figure 5).

3. Materials and Methods

The melting points were measured in open capillary tubes on a BÜCHI B-545 melting point apparatus (BÜCHI Labortechnik AG, Flawil, Switzerland) and were uncorrected. The elemental analyses (C, H, N) were performed using the Perkin-Elmer 2400 CHN analyzer (PerkinElmer, Waltham, MA, USA) and were within ±0.4% of the theoretical values. The 400 MHz ¹H and 126 MHz ¹³C NMR spectra were recorded on a Varian Unity Plus 400 (400 MHz) spectrometer (Varian Inc., Paulo Alto, CA, USA). All spectra were recorded at room temperature, except where indicated otherwise, and were referenced internally to solvent reference frequencies. Chemical shifts (δ) are quoted in ppm, and coupling constants (J) are reported in Hz. The LC-MS spectra were obtained on a Finnigan MAT INCOS-50 (Thermo Finnigan LLC, San Jose, CA, USA). The reaction mixture was monitored by thin layer chromatography (TLC) using commercial glass-backed TLC plates (Merck Kieselgel 60 F254). The solvents and reagents that are commercially available were used without further purification. The starting compound 1 was prepared according to the protocol described in [16].

3.1. 3-(2-Diisopropylaminoethyl)thiazolidine-2,4-dione (2)

To a heated solution of thiazolidine-2,4-dione (1.17 g, 10 mmol) (1) and potassium hydroxide (2.76 g, 20 mmol) in acetone (20 mL), 2-diisopropylaminoethyl chloride hydrochloride (2.20 g, 11 mmol) was added slowly. The mixture was then heated to reflux for 4 h. After completion, the reaction mixture was cooled to room temperature. The organic solvent was separated from the white inorganic solid by filtration. The filtrate was evaporated to obtain the spectroscopically pure colorless liquid of 2, used in the further step without additional purification.

3.2. 3-(2-Diisopropylaminoethyl)-5-(4-methoxybenzylidene)thiazolidine-2,4-dione (3)

A mixture of compound 2 (2.7 g, 10 mmol) and 4-methoxybenzaldehyde (1.5 g, 10 mmol) in ethanol (15 mL) was heated to reflux for 5 h (monitored by TLC). After the completion of the reaction, the mixture was cooled to room temperature and the solvent was evaporated to the pure yellow liquid of 3 that was poured with distilled water. The resulting yellow solid of 3 was filtrated and recrystallized from ethanol.

Yield: 71%, yellow crystal powder, mp 83–85 °C (EtOH). ¹H NMR (400 MHz, DMSO-d₆, δ): 0.90 (d, J = 6.4 Hz, 12H, 4*CH₃), 2.59 (t, 2H, J = 6.2 Hz, CH₂), 2.95 (spt, J = 6.4 Hz, 2H, 2*CH), 3.62 (t, 2H, J = 6.2 Hz, CH₂), 3.83 (s, 3H, OCH₃), 7.11 (d, J = 8.3 Hz, 2H, arom.), 7.59 (d, J = 8.3 Hz, 2H, arom.), 7.88 (s, 1H = CH).

¹³C NMR (126 MHz, DMSO-d₆, δ): 21.0, 41.7, 42.2, 48.0, 56.0, 115.5, 118.5, 125.9, 132.7, 133.1, 161.6, 166.3 (C=O), 167.8 (C=O).

LC-MS (Electrospray ionization (ESI+)): m/z 363.4 (100.0%, [M + H]⁺).

Anal. calc. for C₁₉H₂₆N₂O₃S: C, 62.96%; H, 7.23%; N, 7.73%. Found: C 63.10%, H 7.40%, N 8.00%.

3.3. X-ray Crystallographic Study

Crystal data. C₁₉H₂₆N₂O₃S, Mr = 362.48, monoclinic, space group C2/c, a = 44.4536(8), b = 9.1492(2), c = 20.1926(5) Å, β = 113.257(2)°, V = 7545.3(3) ų, Z = 16 (Z’ = 2), T = 130.0(1) K.

Data collection. A pale-yellow lath crystal (EtOH) of 0.32 × 0.25 × 0.06 mm was used to record 38,844 (CuKα radiation, θ_max = 76.78°) intensities on a Rigaku SuperNova Atlas diffractometer [17]. The intensity data collection employed the ω-scans mode. Accurate unit cell parameters were determined by the least-squares techniques from the θ values of 17,063 reflections, with a θ range of 4.02–76.46°. The intensity data were corrected for Lorentz, polarization and absorption effects [17]. The 7882 total unique reflections (R_int = 0.023) were used for structure determination.

Structure solution and refinement. The structure was solved by a dual-space algorithm (SHELXT) [17,18,19] and refined against F² for all data (SHELXL) [17,18,20]. The positions of the H atoms were positioned geometrically and were refined using a riding model, with C-H: 0.98 Å (CH₃), 0.99 Å (CH₂), 1.00 Å (Csp³H), 0.95 Å (Csp²H) and U_iso(H) = 1.2U_eq(C) or 1.5U_eq(C) for methyl H atoms. The methyl groups were refined as rotatable rigid groups. The final refinement converged with R = 0.0319 (for 7456 data with I > 2σ(I)), wR = 0.0886 (on F² for all data) and S = 1.077 (on F² for all data). The largest difference peak and hole was 0.254 and −0.264 eų. The molecular illustrations were drawn using ORTEP-3 for Windows [18]. The software used to prepare the material for publication were WINGX [18], OLEX [17] and PLATON [21]. The deposition number CCDC2175518 contains supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/conts/retrieving.html (or, from the Cambridge Crystallographic Data Centre, 12, Union Road, Cambridge CB2 1EZ, UK; fax: (+44)1223-336033).

4. Conclusions

In this work, a convenient and efficient two-step protocol for the synthesis of a new thiazolidine-2,4-dione-bearing molecule has been described. The compound structure was characterized and confirmed by NMR spectroscopy, LC–MS spectrometry analysis and X-ray analysis. The proposed approach allows for the avoidance of an application of a catalyst in the stage of Knoevenagel condensation and presents interest as a possible synthetic pathway for the obtention of potential biologically active small molecules with the thiazolidine-2,4-dione scaffold.