Table of Contents
International Journal of Spectroscopy
Volume 2015, Article ID 609250, 9 pages
http://dx.doi.org/10.1155/2015/609250
Research Article

Stereochemical Investigations of Diastereomeric N-[2-(Aryl)-5-methyl-4-oxo-1,3-thiazolidine-3-yl]-pyridine-3-carboxamides by Nuclear Magnetic Resonance Spectroscopy (1D and 2D)

1Department of Chemistry, Abant İzzet Baysal University, 14030 Bolu, Turkey
2Department of Pharmaceutical Chemistry, Istanbul University, 34116 Istanbul, Turkey

Received 13 October 2015; Revised 19 November 2015; Accepted 10 December 2015

Academic Editor: Craig J. Eckhardt

Copyright © 2015 Öznur Demir-Ordu et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Some new N-[2-(aryl)-5-methyl-4-oxo-1,3-thiazolidine-3-yl]-pyridine-3-carboxamides were synthesized and their structures were investigated by IR, NMR (1H, 13C, and 2D), and mass spectra. The presence of C-2 and C-5 stereogenic centers on the thiazolidinone ring resulted in diastereoisomeric pairs. The configurations of two stereogenic centers were assigned based upon 1H NMR analysis of coupling constants and 2D nuclear overhauser enhancement spectroscopy (NOESY) experiment. Resolution of the diastereoisomers was performed by high performance liquid chromatography (HPLC) using a chiral stationary phase.

1. Introduction

Pyridine-3-carboxamide (nicotinamide), known as vitamin PP (pellagra protective), is part of the vitamin B group and plays an important role in biological oxidative chemistry. Pyridine-3-carboxamide derivatives have gained attention because of their diverse pharmacological activities, such as cytoprotective [1], antiviral [2], antitumor [3], and anxiolytic [4] activities.

Thiazolidin-4-one derivatives possess versatile biological activities [5], including antifungal [6], antibacterial [7, 8], anticancer [9, 10], anti-inflammatory [1113], analgesic [14], anticonvulsant [15, 16], antiviral [17, 18], and antidiabetic activities [19, 20].

Currently, nearly 50% of the drugs are in use as racemates. But stereochemical factors generally have important influence on biological activity of the drug molecules. The two enantiomers present in a racemic mixture can possess different biological activities; that is, one enantiomer has therapeutic value; the other enantiomer may be less effective, inactive, or highly toxic [2127]. Therefore, the identification and separation of stereoisomers are considered to be important. Chiral compounds bearing thiazolidin-4-one ring have also been studied for their stereochemistry. Several studies have been done on these compounds regarding enantiodifferentiation of stereoisomers in the presence of chiral auxiliary [28], separation of enantiomers by chiral HPLC [29, 30], and determination of absolute conformations [31, 32].

It is well known that combinations of two or more heterocyclic scaffolds in one molecule can provide a series of compounds with a broad spectrum of biological activity. Here, we combine thiazolidin-4-one and pyridine-3-carboxamide scaffolds together as part of an ongoing project directed towards the design and synthesis of biologically active nitrogen and sulfur containing heterocyclic compounds [33]. Our research focused on stereochemical investigations on diastereomeric -[2-(aryl)-5-methyl-4-oxo-1,3-thiazolidine-3-yl]-pyridine-3-carboxamides (2a–f) (Figure 1) by one- and two-dimensional NMR techniques. In addition, the analytical chromatographic separation of some derivatives by chiral HPLC has been examined using a chiral column.

Figure 1: The synthesized compounds, 2a–f.

2. Experimental

2.1. General

1D 1H and 13C NMR spectra of all compounds were recorded on a Varian-Unity Inova 500 spectrometer operating at 499.7 MHz for 1H and 124.9 MHz for 13C, using tetramethylsilane (TMS) as an internal standard. Chemical shifts () were reported in parts per million (ppm). Spectral widths of 14 and 230 ppm were used in 1H and 13C NMR, respectively. The splitting patterns of 1H NMR were designed as follows: s: singlet, d: doublet, q: quartet, qd: quartet of doublets, dd: doublet of doublets, and m: multiplet. NOESY experiment was performed on a Varian-Mercury VX-400-BB (spectrometer frequency: 399.98 MHz, temperature: 24°C, relaxation delay: 2.0 sec, acquisition time: 0.15 sec, number of increments: the number of points in t1: 200, number of points in each FID (t2): 1920, and spectral width: 1H channel; 14 ppm). HMBC experiment was performed on a Varian-Unity Inova 500 spectrometer (spectrometer frequency: 499.7 MHz, temperature: 30°C, relaxation delay: 1.0 sec, acquisition time: 0.128 sec, 400 increments, and spectral width: 1H channel; 14 ppm, 13C channel: 230 ppm). IR analyses were performed on a Shimadzu IR Affinity-I FTIR using KBr discs; peaks are reported in cm−1. UV analyses were performed on Shimadzu UV-1601; wavelengths are reported in nm. Liquid chromatography analyses were performed on Shimadzu SCL-10AVP with a diode array detector and using Chiralpak AD column (particle size: 5 μm, column size: 250 × 4.6 mm). Eluent was n-hexane: 2-propanol (85 : 15) (v : v) with a flow rate of 0.9 mL min−1. Reactions were followed by TLC using silica gel 60-F254. Elemental analyses were performed on Thermo Finnigan Flash EA 1112 CHNS-932 analyzer. Melting points were recorded using Buchi B-540 melting point apparatus. The mass spectra were obtained using Finnigan LCQ Advantage Max Waters 2695 Alliance Micromass ZQ.

2.1.1. General Procedure for the Preparation of N-[2-(Aryl)-5-methyl-4-oxo-1,3-thiazolidine-3-yl]-pyridine-3-carboxamides

To a suspension of 0.01 mol of aryl -(substituted benzylidene)pyridine-3-carbohydrazide (1a–f) in 30 mL dry benzene was added 2.5 mL (0.028 mol) of 2-sulfanylpropanoic acid. The mixture was refluxed for 6–18 hours using a Dean-Stark trap. Excess benzene was evaporated in vacuo. The resulting residue was triturated with NaHCO3 solution until CO2 evolution ceased and was allowed to stand refrigerated until solidification. The solid thus obtained was washed with water, dried, and recrystallized from ethanol.

Some spectral and X-ray crystallographic data of compounds 2a, 2b, and 2f were reported regardless of stereochemistry in our previously published articles [3436].

2.1.2. N-[2-(4-Chlorophenyl)-5-methyl-4-oxo-1,3-thiazolidin-3-yl]-pyridine-3-carboxamide (2a)

Diastereomer ratio % (major/minor): 54 : 46. 1H-NMR (500 MHz, DMSO-) δ: 7.43–7.47 (2H, m, phenyl-H); 7.48–7.50 (1H, m, pyridine-H); 7.52-7.53 (2H, m, phenyl-H); 8.04–8.09 (1H, m, pyridine-H); 8.73 (1H, dd,  Hz, 1.4 Hz, pyridine-H); 8.84, 8.85 (1H, 2d,  Hz, 1.4 Hz, pyridine-H) [35] (for 1H NMR data of other protons see Table 1). 13C-NMR (125 MHz) (DMSO-) (ppm): 20.6 (C-6, CH3); 39.8, 39.9 (C-5, CH); 60.4, 60.6 (C-2, CH); 124.3, 124.4 (C13, CH); 127.9, 128.0 (C9, C); 129.3, 129.4 (C16, 20, CH); 130.4, 130.7 (C17, 19, CH); 134.2, 134.4 (C18, C); 135.9, 136.0 (C14, CH); 137.2, 138.1 (C15, C); 149.1, 149.2 (C10, CH); 153.5, 153.6 (C12, CH); 164.5, 164.6 (C-8, C=O); 172.5, 172.6 (C-4, C=O) (for designations of carbons see Figure 3).

Table 1: 1H NMR (500 MHz) data of compounds 2a2f in .
2.1.3. N-[2-(4-Bromophenyl)-5-methyl-4-oxo-1,3-thiazolidin-3-yl]-pyridine-3-carboxamide (2b)

Diastereomer ratio % (major/minor): 60 : 40. 1H-NMR (500 MHz, DMSO-) : 7.44–7.46 (2H, m, phenyl-H); 7.49–7.56 (1H, m, pyridine-H); 7.57–7.60 (2H, m, phenyl-H); 8.05–8.09 (1H, m, pyridine-H); 8.72–8.73 (1H, m, pyridine-H); 8.86, 8.87 (1H, 2d,  Hz, pyridine-H) [36] (for 1H NMR data of other protons see Table 1). 13C-NMR (125 MHz) (DMSO-) (ppm): 20.2 (CH3, C-6; 60%), 20.6 (CH3, C-6; 40%); 39.7 (CH, C-5; 40%), 39.8 (CH, C-5; 60%); 60.4 (CH, C-2; 40%), 60.7 (CH, C-2; 60%); 122.8 (C, C18; 40%), 123.1 (C, C18; 60%); 124.3 (CH, C13; 40%), 124.4 (CH, C13; 60%); 127.8 (C, C9; 60%), 127.9 (C, C9; 40%); 130.7 (CH, C16, 20; 40%), 130.9 (CH, C16, 20; 60%); 132.2 (CH, C17, 19; 40%), 132.3 (CH, C17, 19; 60%); 135.9 (CH, C14; 60%), 136.0 (CH, C14; 40%); 137.7 (C, C15; 60%), 138.6 (C, C15; 40%); 149.1 (CH, C10; 60%), 149.2 (CH, C10; 40%); 153.6 (CH, C12; 40%), 153.7 (CH, C12; 60%); 164.5 (C=O, C-8; 40%), 164.6 (C=O, C-8; 60%); 172.6 (C=O, C-4; 40%), 172.7 (C=O, C-4; 60%) (for designations of carbons see Figure 3).

2.1.4. N-[2-(4-Trifluoromethylphenyl)-5-methyl-4-oxo-1,3-thiazolidin-3-yl]-pyridine-3-carboxamide (2c)

Diastereomer ratio % (major/minor): 53 : 47. White powder (2.78 g, 73%); mp 170.0–173.1°C; 1H-NMR (500 MHz, DMSO-) δ: 7.49–7.51 (1H, m, pyridine-H); 7.72–7.78 (4H, m, 2-phenyl-H); 8.05–8.10 (1H, m, pyridine-H); 8.72–8.73 (1H, m, pyridine-H); 8.85, 8.88 (1H, 2d,  Hz, pyridine-H) (for 1H NMR data of other protons see Table 1); 13C-NMR (100 MHz, DMSO-) : 20.2, 20.3 (C-6, CH3); 38.6, 39.2 (C-5, CH); 60.1, 60.4 (C-2, CH); 124.2, 124.3 (C13, CH); 124.6 (CF3, q,  Hz); 126.1, 126.2 (C17, 19, CH); 127.6, 127.7 (C9, C); 129.0, 129.4 (C16, 20, CH); 129.8 and 130.0 (C18, C, q,  Hz); 135.8, 135.9 (C14, CH); 143.1, 144.0 (C15, C); 148.9, 149.0 (C10, CH); 153.5, 153.6 (C12, CH); 164.4, 164.5 (C-8, C=O); 172.5, 172.7 (C-4, C=O) (for designations of carbons see Figure 3); IR (KBr): , 3037, 1732, 1676, 1620, 1595, 1544; UV (EtOH): (28135), 219.6 (23655), 262.8 (63.68); ESI MS: ([M − H], 100); Anal. Calcd. for C17H14F3N3O2S: C, 53.54; H, 3.70; N, 11.02%. Found: C, 53.75; H, 3.92; N, 10.96%.

2.1.5. N-[2-(4-Benzyloxyphenyl)-5-methyl-4-oxo-1,3-thiazolidin-3-yl]-pyridine-3-carboxamide (2d)

Diastereomer ratio % (major/minor): 80 : 20. White powder; yield: 3.68 g (88%); mp 140.4–143.5°C; 1H-NMR (500 MHz, DMSO-) δ: 5.08 (2H, s, O-CH2-C6H5); 6.99–7.02 (2H, m, 2-phenyl-H); 7.31–7.35 (1H, m, pyridine-H); 7.37–7.51 (7H, m, 2-phenyl and -O-CH2-C6H5); 8.06–8.09 (1H, m, pyridine-H); 8.73 (1H, dd,  Hz, 2.0 Hz, pyridine-H); 8.84, 8.86 (1H, 2d,  Hz, pyridine-H) (for 1H NMR data of other protons see Table 1); 13C-NMR (125 MHz, DMSO-) : 20.0 (CH3, C-6; 20%), 20.8 (CH3, C-6; 80%); 39.8 (CH, C-5; 20%), 39.9 (CH, C-5; 80%); 60.8 (CH, C-2); 70.0 (CH2, C21); 115.5 (C17, 19, CH); 124.3 (CH, C13; 80%), 124.4 (CH, C13; 20%); 128.0 (C9, C); 128.3 (CH, C24, 26; 80%), 128.4 (CH, C24, 26; 20%); 128.6 (CH, C25); 129.1 (CH, C23, 27); 130.0 (CH, C16, 20; 80%), 130.3 (CH, C16, 20; 20%); 130.6 (C15, C); 135.9 (CH, C14; 20%), 136.0 (CH, C14; 80%); 137.5 (C, C22; 20%), 137.6 (C, C22; 80%); 149.1 (CH, C10; 20%), 149.2 (CH, C10; 80%); 153.6 (C12, CH); 159.6 (C18, C); 164.5 (C-8, C=O); 172.6 (C-4, C=O) (for designations of carbons see Figure 5); IR (KBr): , 3163, 3066, 1710, 1672, 1606, 1591; 1244. UV (EtOH): (59593), 233.2 (280.89), 266.8 (13560). ESI MS: ([M − H], 100); Anal. Calcd. for C23H21N3O3S: C, 64.47; H, 5.17; N, 9.81%. Found: C, 64.63; H, 5.06; N, 9.76%.

2.1.6. N-[2-(3-Methoxyphenyl)-5-methyl-4-oxo-1,3-thiazolidin-3-yl]-piridine-3-carboxamide (2e)

Diastereomer ratio % (major/minor): 73 : 27. White powder; yield: 2.24 g (65%); mp 101.0–105.0°C; 1H-NMR (500 MHz, DMSO-) : 3.74 (3 h, s, OCH3); 6.90–6.93 (1H, m, 2-phenyl-H); 7.02–7.04 (2H, m, 2-phenyl-H); 7.27–7.30 (1H, m, 2-phenyl-H); 7.50 (1H, dd, , 4.8 Hz, pyridine-H); 8.05–8.08 (1H, m, pyridine-H); 8.72 (1H, dd, , 2.0 Hz, pyridine-H); 8.85 (major diastereomer), 8.87 (minor diastereomer) (1H, 2d,  Hz,  Hz, pyridine-H) (for 1H NMR data of other protons see Table 1). 13C-NMR (125 MHz, DMSO-) : 20.2 (CH3, C-6; 73%), 20.6 (CH3, C-6; 27%); 39.8 (CH, C-5; 27%), 39.9 (CH, C-5; 73%); 55.8 (OCH3); 60.9 (CH, C-2; 27%), 61.2 (CH, C-2; 73%); 113.5 (CH, C18; 27%), 113.8 (CH, C18; 73%); 115.3 (CH, C16; 27%), 115.4 (CH, C16; 73%); 120.4 (CH, C20; 27%), 120.8 (CH, C20; 73%); 124.3 (CH, C13; 27%), 124.4 (CH, C13; 73%); 127.9 (C, C9; 73%), 128.0 (C, C9; 27%); 130.4 (CH, C19; 27%), 130.5 (CH, C19; 73%); 136.0 (CH, C14; 73%), 136.1 (CH, C14; 27%); 139.8 (C, C15; 73%), 140.5 (C, C15; 27%); 149.1 (CH, C10; 73%), 149.2 (CH, C10; 27%); 153.6 (CH, C12); 160.1 (C, C17; 73%), 160.2 (C, C17; 27%); 164.6 (C-8, C=O); 172.8 (C=O, C-4; 27%), 172.9 (C=O, C-4; 73%) (for designations of carbons see Figure 3); IR (KBr): , 3176, 3076, 1707, 1670, 1610, 1591, 1546; 1260; UV (EtOH): (42863), 225.0 (17859), 263.8 (6101); ESI MS: ([M − H], 100); Anal. Calcd. for C17H17N3O3S: C, 56.50, H, 5.30, N, 11.63%. Found: C, 56.47; H, 4.77; N, 11.50%.

2.1.7. N-[2-(2-Nitrophenyl)-5-methyl-4-oxo-1,3-thiazolidin-3-yl]-piridine-3-carboxamide (2f)

Diastereomer ratio % (major/minor): 52 : 48. 1H-NMR (500 MHz, DMSO-) : 7.51 (1H, dd,  Hz, 4.4 Hz, pyridine-H); 7.61–7.65 (1H, m, 2-phenyl-H); 7.85–7.90 (2H, m, 2-phenyl-H); 8.04–8.11 (2H, m, 2-phenyl-H and pyridine-H); 8.73 (1H, dd,  Hz, 2.0 Hz, pyridine-H); 8.71, 8.79 (1H, 2d,  Hz,  Hz, pyridine-H) [34] (for 1H NMR data of other protons see Table 1). 13C-NMR (125 MHz) (DMSO-) (ppm): 19.0, 21.9 (C-6, CH3); 37.2, 39.2 (C-5, CH); 56.6, 56.7 (C-2, CH); 124.2, 124.3 (C13, CH); 125.6, 125.7 (C9, C); 127.9, 128.0 (C17, CH); 128.3, 128.5 (C20, CH); 130,3, 130.5 (C19, CH); 135.3, 135,4 (C18, CH); 135.5, 135.8 (C15, C); 136.1, 136.2 (C14, CH); 148.1, 148.6 (C16, C); 149.2, 149.3 (C10, CH); 153.5, 153.6 (C12, CH); 164.7, 164.8 (C-8, C=O); 172.8, 173.2 (C-4, C=O) (for designations of carbons see Figure 3).

3. Results and Discussion

3.1. Chemistry

Novel compounds 2a–f have been synthesized by the reaction of compounds 1a–f with racemic (±)-2-sulfanylpropanoic acid in dry benzene (Figure 2).

Figure 2: The preparation of compounds 2a–f.
Figure 3: Selected HMBC correlations for 2b.

The structures of the compounds were determined by microanalysis, IR, 1H-NMR, 13C-NMR, HMBC, and ESI mass spectrometry. IR spectra of 2a–f showed common characteristic absorption bands at 3142–3176 cm−1 (NH), 1707–1732 cm−1 (thiazolidinone C=O), and 1670–1681 cm−1 (NH-C=O) which provided evidence for the ring closure reaction between 1a–f and 2-sulfanylpropanoic acid. Disappearance of the peak at 8 ppm corresponding to N=CH proton of 1a–f [37] and the observation of C-2 proton of 2a–f at 5.88–6.30 ppm in the 1H-NMR spectra were also taken as the proof of the formation of thiazolidin-4-one ring.

The structure of 2b was confirmed by the HMBC spectrum in which the correlations of C-8 ( 164.5, 164.6 ppm) with H-10 ( 8.86 ppm), H-14 ( 8.07 ppm), and N-H (H-7) ( 10.94, 10.95 ppm); C-4 ( 172.6, 172.7 ppm) with H-5 ( 4.12, 4.22 ppm) and H-6 ( 1.54, 1.55 ppm); and C-6 ( 20.6, 20.2 ppm) with H-2 ( 5.90 ppm), H-5 ( 4.12, 4.22 ppm), and H-6 ( 1.54, 1.55 ppm) enabled definite assignment of CONH (C-8) and thiazolidinone C=O (C-4) carbons (Figure 3).

3.2. Stereochemical Investigations

Due to the formation of a new stereocenter at C-2, in principle four stereoisomers were expected to form the following: two enantiomeric (2S-5R/2R-5S, 2S-5S/2R-5R) and two diastereomeric pairs (2S-5R/2S-5S, 2R-5S/2R-5R) (Figure 4). In fact, compounds 2a–f were obtained as mixtures of unequal composition of two diastereomers which were differentiated by their 1H NMR spectra (Figure 5). It has been observed that the ratios of the major and minor diastereomers calculated from the integration values of the C-5 methine proton signals were 54% : 46%, 40% : 60%, 47% : 53%, 80% : 20%, 27% : 73%, and 48% : 52% for compounds 2a–f, respectively. 13C signals at C-2, C-4, C-5, and C-6 positions for compounds 2b and 2e also appeared as double peaks in the HMBC spectra due to the formation diastereoisomers (see Section 2). Chiral HPLC of compounds 2b and 2c on the Chiralpak AD-H column resulted in four peaks (Figure 6) which further proved the presence of four stereoisomers.

Figure 4: The stereoisomers of compounds 2a–f.
Figure 5: 500 MHz 1H NMR spectrum of compound 2d in DMSO-. S: solvent.
Figure 6: (a) HPLC chromatogram of compound 2b; (b) HPLC chromatogram of compound 2c. Peaks marked with the same sign belong to enantiomers according to their % areas. Column: Chiralpak AD-H; eluent: n-hexane: 2-propanol (85 : 15) (v : v); diode array detector.

For all diastereomeric compounds (Figure 4), it was observed that C-5 methine proton on the thiazolidinone moiety was coupled with C-6 methyl protons and appeared as two quartets (Table 1, Figure 5). Similarly the signal of C-6 methyl protons was coupled with C-5 methine and observed as two doublets for compounds 2b–2f. In all of the 1H NMR spectra of compounds 2a–2f (except 2b) the higher frequency signals of C-5 methine appeared as a quartet of doublets due to the long-range coupling with the C-2 proton. The two diastereotopic C-2 hydrogens could be observed separately only for compounds 2c–2f. Aromatic protons of pyridyl and C-2 aryl rings gave signals between 6.9 and 9.0 ppm. In this region some of the aromatic peaks corresponding to two diastereomers could also be observed separately for all compounds (Figure 5). The N-H proton was observed at around 11 ppm as two singlets with unequal integral ratios for compounds 2b, 2c, and 2f and only one singlet for 2a, 2d, and 2e.

We have previously elucidated the stereostructures of some oxazolidine derivatives by NOESY experiment [3840]. The configurations of the major and minor stereoisomers of thiazolidin-4-one derivatives (2a–2f) were determined by means of 1H NMR and NOESY spectra of compound 2f. The 1H NMR spectrum of 2f showed that the major diastereomer had its C-5 methine signal (quartet) at a lower frequency (4.10 ppm,  Hz) than the signal of the minor component (4.21 ppm, qd,  Hz : 1.96 Hz). The signal of C-2 proton of compound 2f was observed as two separate signals (: 0.04 ppm) corresponding to two diastereomers: a singlet at 6.26 ppm for the major diastereomer and a doublet at 6.22 ppm ( Hz) for the minor diastereomer. The observed long-range coupling constant () of the doublet, which is characteristic of trans protons [41], was consistent with that of the higher frequency quartet of minor diastereomer. Based on these results, the stereochemistry of the minor diastereomer was assigned as 2S, 5S or 2R, 5R, in which C-2 and C-5 methine protons are trans to each other (Figure 4).

NOESY spectrum for compound 2f was taken in order to further prove that the stereochemistry of the minor and the major diastereomers was 2S, 5S/2R, 5R and 2S, 5R/2R, 5S, respectively (Figure 7). Observation of the cross peaks at 6.26 ppm and 4.10 ppm in 2D NOESY spectrum indicated the spatial proximity of C-2 and C-5 methine hydrogens of the major diastereomer (Figure 7(a)). Cross peaks at 1.52 ppm and 7.86 ppm also revealed that C-6 methyl and the hydrogens of the aryl ring [42, 43] of the major diastereomer are in close proximity (Figure 7(b)). These observations were consistent with the 2R, 5S or 2S, 5R configurations. Similarly, for the minor diastereomer cross peaks between the signals of C-6 methyl and C-2 methine hydrogens were observed (Figure 7(c)). A NOESY correlation between C-5 methine and aromatic protons (Figure 7(d)) further confirmed that the configurations of C-2 and C-5 positions of the minor diastereomer were 2S, 5S or 2R, 5R. Since the spectra of 2a–2f have the feature in common, by analogy, it could be concluded that all the deshielded signals of C-5 methine belong to 2S, 5S or 2R, 5R stereoisomer (Table 1). Based on these results, the configurations of C-2 and C-5 centers of the major and minor diastereomers are given in Table 2.

Table 2: The configurations of C-2 and C-5 centers of major and minor diastereomers.
Figure 7: Selected 2D NOESY correlations for compound 2f (solvent: DMSO-, 400 MHz).

The diastereomeric isomer ratios of compounds 2b and 2c obtained by the integration of the 1H NMR signals have been found identical with those obtained by HPLC analysis. Therefore, with the knowledge of the configurations of the C-2 and C-5 centers of the major and minor diastereomers of 2b and 2c, the HPLC peaks (Figures 6(a) and 6(b)) marked by “” could be assigned to 2S, 5R or 2R, 5S (major) and the others to 2S, 5S or 2R, 5R (minor).

In order to determine the reason of the diastereoselectivity of the synthesis, samples of 2d and 2e were recrystallized once again from ethanol and the composition of crystals precipitated first was analyzed by NMR. We have found a different composition for 2d and 2e. Therefore, the different isomer ratios showed that the obvious diastereoselectivity upon recrystallization from ethanol was due to different solubilities of the diastereomeric isomers in ethanol which was observed previously [29, 30, 39, 40] and not related to any remarkable favorable attack during ring closure. Nevertheless fractional crystallization of the product from ethanol allowed for an easy access to diastereomerically enriched 2b, 2d, and 2e (Table 2).

4. Conclusions

The reaction of aryl -(substituted benzylidene)pyridine-3-carbohydrazide with 2-mercaptopropanoic acid produced mixtures of unequal composition of two diastereomeric -[2-(aryl)-5-methyl-4-oxo-1,3-thiazolidine-3-yl]-pyridine-3-carboxamide derivatives which were differentiated by 1H NMR spectra. The configurations of C-2 and C-5 stereogenic centers of thiazolidin-4-one ring for the major and the minor diastereomers have been found via one- and two-dimensional NMR spectroscopy. Four stereoisomers of compounds 2b and 2c were resolved by chiral HPLC.

Conflict of Interests

The authors declare that there is no conflict of interests regarding the publication of this paper.

Acknowledgment

This work was supported by the Istanbul University Scientific Research Projects (Project no. T-3691).

References

  1. E. M. Slominska, A. Yuen, L. Osman, J. Gebicki, M. H. Yacoub, and R. T. Smolenski, “Cytoprotective effects of nicotinamide derivatives in endothelial cells,” Nucleosides, Nucleotides and Nucleic Acids, vol. 27, no. 6-7, pp. 863–866, 2008. View at Publisher · View at Google Scholar · View at Scopus
  2. A. Moëll, O. Skog, E. Åhlin, O. Korsgren, and G. Frisk, “Antiviral effect of nicotinamide on enterovirus-infected human islets in vitro: effect on virus replication and chemokine secretion,” Journal of Medical Virology, vol. 81, no. 6, pp. 1082–1087, 2009. View at Publisher · View at Google Scholar · View at Scopus
  3. A. S. Girgis, H. M. Hosni, and F. F. Barsoum, “Novel synthesis of nicotinamide derivatives of cytotoxic properties,” Bioorganic and Medicinal Chemistry, vol. 14, no. 13, pp. 4466–4476, 2006. View at Publisher · View at Google Scholar · View at Scopus
  4. C. Spanka, R. Glatthar, S. Desrayaud et al., “Piperidyl amides as novel, potent and orally active mGlu5 receptor antagonists with anxiolytic-like activity,” Bioorganic and Medicinal Chemistry Letters, vol. 20, no. 1, pp. 184–188, 2010. View at Publisher · View at Google Scholar · View at Scopus
  5. A. K. Jain, A. Vaidya, V. Ravichandran, S. K. Kashaw, and R. K. Agrawal, “Recent developments and biological activities of thiazolidinone derivatives: a review,” Bioorganic and Medicinal Chemistry, vol. 20, no. 11, pp. 3378–3395, 2012. View at Publisher · View at Google Scholar · View at Scopus
  6. A. P. Liesen, T. M. de Aquino, C. S. Carvalho et al., “Synthesis and evaluation of anti-Toxoplasma gondii and antimicrobial activities of thiosemicarbazides, 4-thiazolidinones and 1,3,4-thiadiazoles,” European Journal of Medicinal Chemistry, vol. 45, no. 9, pp. 3685–3691, 2010. View at Publisher · View at Google Scholar · View at Scopus
  7. K. Omar, A. Geronikaki, P. Zoumpoulakis et al., “Novel 4-thiazolidinone derivatives as potential antifungal and antibacterial drugs,” Bioorganic &Medicinal Chemistry, vol. 18, no. 1, pp. 426–432, 2010. View at Publisher · View at Google Scholar · View at Scopus
  8. A. Kocabalkanli, Ö. Ates, and G. Ötük, “Synthesis of Mannich bases of some 2,5-disubstituted 4-thiazolidinones and evaluation of their antimicrobial activities,” Archiv der Pharmazie, vol. 334, no. 2, pp. 35–39, 2001. View at Google Scholar · View at Scopus
  9. M. M. Kamel, H. I. Ali, M. M. Anwar, N. A. Mohamed, and A. M. Soliman, “Synthesis, antitumor activity and molecular docking study of novel Sulfonamide-Schiff's bases, thiazolidinones, benzothiazinones and their C-nucleoside derivatives,” European Journal of Medicinal Chemistry, vol. 45, no. 2, pp. 572–580, 2010. View at Publisher · View at Google Scholar · View at Scopus
  10. D. Havrylyuk, L. Mosula, B. Zimenkovsky, O. Vasylenko, A. Gzella, and R. Lesyk, “Synthesis and anticancer activity evaluation of 4-thiazolidinones containing benzothiazole moiety,” European Journal of Medicinal Chemistry, vol. 45, no. 11, pp. 5012–5021, 2010. View at Publisher · View at Google Scholar · View at Scopus
  11. A. A. Bekhit, H. T. Y. Fahmy, S. A. F. Rostom, and A. E.-D. A. Bekhit, “Synthesis and biological evaluation of some thiazolylpyrazole derivatives as dual anti-inflammatory antimicrobial agents,” European Journal of Medicinal Chemistry, vol. 45, no. 12, pp. 6027–6038, 2010. View at Publisher · View at Google Scholar · View at Scopus
  12. A. Kumar, C. S. Rajput, and S. K. Bhati, “Synthesis of 3-[4′-(p-chlorophenyl)-thiazol-2′-yl]-2-[(substituted azetidinone/thiazolidinone)-aminomethyl]-6-bromoquinazolin-4-ones as anti-inflammatory agent,” Bioorganic and Medicinal Chemistry, vol. 15, no. 8, pp. 3089–3096, 2007. View at Publisher · View at Google Scholar · View at Scopus
  13. S. K. Bhati and A. Kumar, “Synthesis of new substituted azetidinoyl and thiazolidinoyl-1,3,4-thiadiazino (6,5-b) indoles as promising anti-inflammatory agents,” European Journal of Medicinal Chemistry, vol. 43, no. 11, pp. 2323–2330, 2008. View at Publisher · View at Google Scholar · View at Scopus
  14. K. M. Amin, M. M. Kamel, M. M. Anwar, M. Khedr, and Y. N. Syam, “Synthesis, biological evaluation and molecular docking of novel series of spiro [(2H,3H) quinazoline-2,1′-cyclohexan-4(1H)-one derivatives as anti-inflammatory and analgesic agents,” European Journal of Medicinal Chemistry, vol. 45, no. 6, pp. 2117–2131, 2010. View at Publisher · View at Google Scholar
  15. H. Kaur, S. Kumar, P. Vishwakarma, M. Sharma, K. K. Saxena, and A. Kumar, “Synthesis and antipsychotic and anticonvulsant activity of some new substituted oxa/thiadiazolylazetidinonyl/thiazolidinonylcarbazoles,” European Journal of Medicinal Chemistry, vol. 45, no. 7, pp. 2777–2783, 2010. View at Publisher · View at Google Scholar · View at Scopus
  16. G. Akula, B. Srinivas, M. Vidyasagar, and S. Kandikonda, “Synthesis of 3-(1H-benzimidazol-2-yl amino)2-phenyl-1,3-thiazolidin-4-one as potential CNS depressant,” International Journal of PharmTech Research, vol. 3, pp. 360–364, 2011. View at Google Scholar
  17. V. Ravichandran, A. Jain, K. S. Kumar, H. Rajak, and R. K. Agrawal, “Design, synthesis, and evaluation of thiazolidinone derivatives as antimicrobial and anti-viral agents,” Chemical Biology and Drug Design, vol. 78, no. 3, pp. 464–470, 2011. View at Publisher · View at Google Scholar · View at Scopus
  18. F. Göktaş, E. Vanderlinden, L. Naesens, N. Cesur, and Z. Cesur, “Microwave assisted synthesis and anti-influenza virus activity of 1-adamantyl substituted N-(1-thia-4-azaspiro[4.5]decan-4-yl)carboxamide derivatives,” Bioorganic and Medicinal Chemistry, vol. 20, no. 24, pp. 7155–7159, 2012. View at Publisher · View at Google Scholar · View at Scopus
  19. D. Kini and M. Ghate, “Synthesis and oral hypoglycemic activity of3-[5′-Methyl-2′-aryl-3′-(thiazol-2′′-yl amino)thiazolidin-4'-one]coumarin derivatives,” European Journal of Chemistry, vol. 8, no. 1, pp. 386–390, 2011. View at Google Scholar
  20. R. MacCari, A. D. Corso, M. Giglio, R. Moschini, U. Mura, and R. Ottan, “In vitro evaluation of 5-arylidene-2-thioxo-4-thiazolidinones active as aldose reductase inhibitors,” Bioorganic and Medicinal Chemistry Letters, vol. 21, no. 1, pp. 200–203, 2011. View at Publisher · View at Google Scholar · View at Scopus
  21. J. M. Beale and J. H. Block, Wilson and Gisvold's Textbook of Organic Medicinal and Pharmaceutical Chemistry, Lippincott Williams & Wilkins, Philadelphia, Pa, USA, 2011.
  22. D. Taşdemir, A. Karaküçük-Iyidoğan, M. Ulaşli, T. Taşkin-Tok, E. E. Oruç-Emre, and H. Bayram, “Synthesis, molecular modeling, and biological evaluation of novel chiral thiosemicarbazone derivatives as potent anticancer agents,” Chirality, vol. 27, no. 2, pp. 177–188, 2015. View at Publisher · View at Google Scholar · View at Scopus
  23. P. S. Shankar, S. Bigotti, P. Lazzari et al., “Synthesis and cytotoxicity evaluation of diastereoisomers and N-terminal analogues of tubulysin-U,” Tetrahedron Letters, vol. 54, no. 45, pp. 6137–6141, 2013. View at Publisher · View at Google Scholar · View at Scopus
  24. J. Bauer, M. Vine, I. Čorić et al., “Impact of stereochemistry on the biological activity of novel oleandomycin derivatives,” Bioorganic and Medicinal Chemistry, vol. 20, no. 7, pp. 2274–2281, 2012. View at Publisher · View at Google Scholar · View at Scopus
  25. M. Ohashi, I. Nakagome, J.-I. Kasuga et al., “Design, synthesis and in vitro evaluation of a series of α-substituted phenylpropanoic acid PPARγ agonists to further investigate the stereochemistry–activity relationship,” Bioorganic and Medicinal Chemistry, vol. 20, no. 21, pp. 6375–6383, 2012. View at Publisher · View at Google Scholar · View at Scopus
  26. M. G. Vigorita, R. Ottana, F. Monforte et al., “Chiral 3,3′-(1,2-ethanediyl)-bis[2-(3,4-dimethoxyphenyl)-4-thiazolidinones] with anti-inflammatory activity. Part 11: evaluation of COX-2 selectivity and modelling,” Bioorganic & Medicinal Chemistry, vol. 11, no. 6, pp. 999–1006, 2003. View at Google Scholar
  27. T.-D. Tessema, F. Gassler, Y. Shu, S. Jones, and B. S. Selinsky, “Structure—activity relationships in aminosterol antibiotics: the effect of stereochemistry at the 7-OH group,” Bioorganic and Medicinal Chemistry Letters, vol. 23, no. 11, pp. 3377–3381, 2013. View at Publisher · View at Google Scholar · View at Scopus
  28. E. D. Gómez, I. Doǧan, M. Yilmaz, Ö. Demir-Ordu, D. Albert, and H. Duddeck, “Atropisomeric 3-aryl-2-oxo-4-oxazolidinones and some thione analogues—enantiodifferentiation and ligand competition in applying the dirhodium method,” Chirality, vol. 20, no. 3-4, pp. 344–350, 2008. View at Publisher · View at Google Scholar · View at Scopus
  29. S. Erol and İ. Doğan, “Determination of barriers to rotation of axially chiral 5-methyl-2-(o-aryl)imino-3-(o-aryl)thiazolidine-4-ones,” Chirality, vol. 24, no. 6, pp. 493–498, 2012. View at Publisher · View at Google Scholar · View at Scopus
  30. S. Erol and İ. Doğan, “Axially chiral 2-arylimino-3-aryl-thiazolidine-4-one derivatives: enantiomeric separation and determination of racemization barriers by chiral HPLC,” Journal of Organic Chemistry, vol. 72, no. 7, pp. 2494–2500, 2007. View at Publisher · View at Google Scholar · View at Scopus
  31. S. Erol and İ. Doğan, “Stereochemical assignments of aldol products of 2-arylimino-3-aryl-thiazolidine-4-ones by 1H NMR,” Magnetic Resonance in Chemistry, vol. 50, no. 5, pp. 402–405, 2012. View at Publisher · View at Google Scholar · View at Scopus
  32. Ö. Demir-Ordu, E. M. Yilmaz, and I. Doǧan, “Determination of the absolute stereochemistry and the activation barriers of thermally interconvertible heterocyclic compounds bearing a naphthyl substituent,” Tetrahedron Asymmetry, vol. 16, no. 22, pp. 3752–3761, 2005. View at Publisher · View at Google Scholar · View at Scopus
  33. S. Özkırımlı, F. Kazan, and Y. Tunali, “Synthesis, antibacterial and antifungal activities of 3-(1,2,4-triazol-3- yl)-4-thiazolidinones,” Journal of Enzyme Inhibition and Medicinal Chemistry, vol. 24, no. 2, pp. 447–452, 2009. View at Publisher · View at Google Scholar · View at Scopus
  34. M. Akkurt, Í. Çelik, H. Demir, S. Özkrml, and O. Büyükgüngör, “N-[5-Methyl-2-(2-nitro­phen­yl)-4-oxo-1,3-thia­zolidin-3-yl]pyridine-3-carboxamide monohydrate,” Acta Crystallographica Section E, vol. 67, no. 2, pp. o293–o294, 2011. View at Publisher · View at Google Scholar · View at Scopus
  35. M. Akkurt, İ. Çelik, H. Demir, S. Özkırımlı, and O. Büyükgüngör, “N-[2-(4-chlorophenyl)-5-methyl-4-oxo-1,3-thiazolidin-3-yl]pyridine-3-carboxamide,” Acta Crystallographica Section E, vol. 67, pp. o745–o746, 2011. View at Publisher · View at Google Scholar
  36. M. Akkurt, İ. Çelik, H. Demir, S. Özkırımlı, and O. Büyükgüngör, “N-[2-(4-bromophenyl)-5-methyl-4-oxo-1,3-thiazolidin-3-yl]pyridine-3-carboxamide,” Acta Crystallographica Section E, vol. 67, pp. o914–o915, 2011. View at Publisher · View at Google Scholar
  37. A. Solankee, P. Solankee, and H. Patel, “Synthesis of some novel hydrazones and their thiazolidine-4-ones,” International Journal of Chemical Sciences, vol. 6, pp. 1017–1020, 2008. View at Google Scholar
  38. Ö. Demir-Ordu and I. Doğan, “Axially chiral N-(o-aryl)-4-hydroxy-2-oxazolidinone derivatives from diastereoselective reduction of N-(o-aryl)-2,4-oxazolidinediones: thermally interconvertible atropisomers via ring-chain-ring tautomerization,” Chirality, vol. 22, no. 7, pp. 641–654, 2010. View at Publisher · View at Google Scholar · View at Scopus
  39. Ö. Demir-Ordu and İ. Doğan, “Stereoselective lithiation and alkylation and aldol reactions of chiral 5-methyl-3-(o-aryl)-oxazolidinones,” Tetrahedron Asymmetry, vol. 21, no. 20, pp. 2455–2464, 2010. View at Publisher · View at Google Scholar · View at Scopus
  40. Ö. Demir and İ. Doǧan, “Conformational preferences in diastereomeric (5s)-methyl-3-(o-aryl)-2,4-oxazolidinediones,” Chirality, vol. 15, no. 3, pp. 242–250, 2003. View at Publisher · View at Google Scholar · View at Scopus
  41. V. P. M. Rahman, S. Mukhtar, W. H. Ansari, and G. Lemiere, “Synthesis, stereochemistry and biological activity of some novel long alkyl chain substituted thiazolidin-4-ones and thiazan-4-one from 10-undecenoic acid hydrazide,” European Journal of Medicinal Chemistry, vol. 40, no. 2, pp. 173–184, 2005. View at Publisher · View at Google Scholar · View at Scopus
  42. K. M. Khan, M. Rasheed, Z. Ullah et al., “Synthesis and in vitro leishmanicidal activity of some hydrazides and their analogues,” Bioorganic and Medicinal Chemistry, vol. 11, no. 7, pp. 1381–1387, 2003. View at Publisher · View at Google Scholar · View at Scopus
  43. D. Williams and I. Fleming, Spectroscopic Methods in Organic Chemistry, McGraw-Hill Book Company, London, UK, 1989.