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Catalyst-, solvent- and desiccant-free three-component synthesis of novel C-2,N-3 disubstituted thiazolidin-4-ones
⁎Corresponding author. rodrigo.abonia@correounivalle.edu.co (Rodrigo Abonia)
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Received: ,
Accepted: ,
This article was originally published by Elsevier and was migrated to Scientific Scholar after the change of Publisher.
Peer review under responsibility of King Saud University.
Abstract
Herein it is provided an efficient, environmentally friendly and one-pot procedure for the synthesis of a library of new and diversely substituted 1,3-thiazolidin-4-ones in short reaction times and good yields through a solvent-, catalyst- and desiccant-free three-component process. Reactions proceeded by treatment of primary benzyl(aryl)amines with aromatic aldehydes (and ketones) and 2-mercaptoacetic acid acting as both reagent and self-catalyst. All reactions were performed in sand bath instead of the commonly used oil bath avoiding the generation of undesired volatile materials proceeding of the thermal decomposition of the oils. IR, Mass and NMR experiments as well as X-ray diffraction confirmed structures of the obtained products.
Keywords
2-Mercaptoacetic acid
Primary benzylamines
Multicomponent reactions
Solvent-free conditions
Green synthesis
Thiazolidin-4-ones
1 Introduction
The structural and therapeutic diversity of small heterocyclic molecules coupled with their commercial availability has fascinated organic and medicinal chemists. For this reason, the design of new substances based on privileged scaffolds is one of the successful directions in drug discovery. According to this approach, thiazolidin-4-one scaffold has been gaining prominence in recent years, due to the fact that many of them have proved interesting activity profiles namely anti-inflammatory (Look et al., 1996), anti-histaminic (Diurno et al., 1992), antibacterial (Anders et al., 2000; Kucukguzel et al., 2002), antifungal (Karali et al., 1998; Fahmy, 2001), anticonvulsant (Ergenc and Capan, 1994; Capan et al., 1966), antituberculosis (Bukowski et al., 1998; Ulusoy, 2002; Babaoglu et al., 2003), anticancer (Lesyk et al., 2011; Kaminsky et al., 2011; Kaminsky and Lesyk, 2010; Gududuru et al., 2004a, 2004b; Ottanà et al., 2005), antiviral (Rawal et al., 2007, 2008; Barreca et al., 2001; Rao et al., 2002, 2003, 2004) and anti-Candida and antioxidant (Secci et al., 2016; De Monte et al., 2016). Fig. 1 shows some representative examples of this family of compounds.
Some 1,3-thiazolidin-4-one derivatives of biological interest.
Compound 1 showed a potent activity as a non-nucleoside inhibitor of the hepatitis C virus NS5B RNA-dependant RNA polymerase (Rawal et al., 2008). Compound 2 displayed a superior in vitro anticancer activity than other related compounds, showing its highest susceptibility against the Leukemia panel (Kaminsky et al., 2011), compounds 3 exhibited high COX-2 inhibitory selectivity and potency (Unsal-Tan et al., 2012), while compound 4 and some of its analogues have been reported as promising and selective HIV-1 reverse transcriptase inhibitors. From a structure-activity relationship (SAR) point of view, the anti-HIV activity displayed by this family of compounds is strongly dependent on the nature of the substituents at C-2 and N-3 of the thiazolidin-4-one ring (Rao et al., 2003, 2004; Barreca et al., 2001).
Because of the high reaction rates, selectivity and efficiency, as well as the low cost and small environmental impact, multicomponent reactions (MCRs) have become a powerful tool to access a vast number of synthetic and pharmaceutically relevant compounds (Dömling, 2005a; Dömling et al., 2012; Jarusiewicz et al., 2009). MCRs are convergent reactions in which three or more starting materials react in a single chemical step to form a product that incorporates substantial portions of all components. Thus, there is a network of reaction equilibria, which all finally flow into an irreversible step that leads to the formed products (Tietze, 1996; Dömling, 2005b; Coquerel et al., 2010).
Usually the synthesis of the thiazolidin-4-ones has been carried out via two- and three-component reactions involving primary amines, an oxo-compound and thiolic acids, commonly under harsh and environmentally unfriendly reaction conditions. In this sense, several synthetic approaches, with minor or major success, have been reported, as shown in Scheme 1, entry (a).![Synthetic approaches for preparing 1,3-thiazolidin-4-ones. [a]Kaminsky et al. (2011), [b]Rawal et al. (2007), [c]Rawal et al. (2008), [d]Srivastava et al. (2002), [e]Rao et al. (2004), [f]Barreca et al. (2001), [g]Rao et al. (2003), [h]Rao et al. (2002), [i]Dandia et al. (2006), Gududuru et al. (2004a, 2004b), Bolognese et al. (2004), Pawełczyk and Zaprutko (2009), [j]Yadav et al. (2009).](/content/184/2019/12/1/img/10.1016_j.arabjc.2016.11.016-fig2.png)
Synthetic approaches for preparing 1,3-thiazolidin-4-ones. [a]Kaminsky et al. (2011), [b]Rawal et al. (2007), [c]Rawal et al. (2008), [d]Srivastava et al. (2002), [e]Rao et al. (2004), [f]Barreca et al. (2001), [g]Rao et al. (2003), [h]Rao et al. (2002), [i]Dandia et al. (2006), Gududuru et al. (2004a, 2004b), Bolognese et al. (2004), Pawełczyk and Zaprutko (2009), [j]Yadav et al. (2009).
In contrast, we are proposing here an environmentally friendly synthesis of new C-2 and N-3 disubstituted thiazolidin-4-ones through a catalyst-, solvent- and desiccant-free three-component approach, as shown in Scheme 1, entry (b).
2 Results and discussion
Continuing with our current studies on the synthetic utility of benzylamines (Castillo et al., 2009; Abonia et al., 2010a, 2013) and 2-mercaptoacetic acid (Abonia, 2014), herein, we report an efficient synthetic procedure to prepare 1,3-thiazolidin-4-ones in good to excellent yield starting from primary benzylamines and anilines through a three-component approach without using solvent, catalyst or desiccant agents, constituting the main advantage with respect to the previous reported methods.
Recently, we found that the heating of a solvent- and catalyst-free three-component mixture of 5-aminopyrazoles 5, benzaldehydes 6 and 2-mercaptoacetic acid 7a at 120 °C, afforded the respective pyrazolothiazepinones 8 in good to excellent yields (Scheme 2) (Abonia, 2014). In order to evaluate the effect of replacing the 5-aminopyrazole motifs 5 by primary benzylamines 9, a mixture of benzylamine 9a (R1 = H) (1 equiv), 3,4,5-trimethoxybenzaldehyde 6a (R = 3,4,5-(OCH3)3) (1 equiv) and 2-mercaptoacetic acid 7a (1.1 equiv) was subjected to the above reaction conditions as a model approach (Scheme 2). Upon consumption of the starting materials after 30 min of heating (monitored by thin-layer chromatography, TLC), the obtained residue was purified from aqueous ethanol, affording a yellow solid. After analysis by spectroscopic techniques, interestingly we noticed the formation of the thiazolidin-4-one derivative 10a in 78% yield instead of its corresponding eightmembered thiazocinone 11 structurally related to the structure 8.
Amine-dependent three-component synthesis of pyrazolothiazepinones 8 or thiazolidin-4-one derivative 10a (R = 3,4,5-(OCH3)3; R1 = H; n = 1).
The most relevant spectroscopic features to confirm the structure proposed for compound 10a corresponded to the presence of NC⚌O and C—O absorption bands at 1675 and (1237, 1007) cm−1, respectively, in the IR spectrum. Two doublets at 3.71 and 5.08 ppm (J = 14.8 Hz and J = 14.8 Hz, respectively) corresponding to the PhCH2 protons, a double-doublet integrating for 1H at 3.78 ppm (J = 1.0, 15.6 Hz) assigned to Ha-5, a multiplet integrating for 10H in the range of 3.82–3.88 ppm assigned to (OCH3)3 and Hb-5, and a doublet integrating for 1H at 5.36 ppm (J = 1.5 Hz) assigned to H-2, along with the remaining 7H aromatic protons are the most relevant signals in the 1H NMR spectrum of 10a. The absence of a NH signal in both IR and 1H NMR spectra also agrees with the proposed structure 10a. The presence of two methylene carbon atoms at 33.1 and 46.5 ppm assigned to C-5 and PhCH2 respectively, two types of (OCH3) carbon atoms at 56.2 and 63.5 ppm, the C-2 signal at 60.8 ppm and the NC⚌O signal at 171.2 ppm are the most relevant features in the 13C NMR spectrum of 10a. Finally, a molecular ion with m/z 359 (88%), and a base peak with m/z 284 [M-75] (100%), also confirmed the proposed structure for compound 10a.
Given the success of the model reaction, we decided to evaluate the scope of this multicomponent approach by extending our synthetic methodology to the benzaldehydes chemset 6a–d and the benzylamines and anilines chemset 9a–f, Fig. 2.
Diverse aldehydes 6 and amines 9 employed for the synthesis of product 10.
Similar to our first test, the reactions proceeded smoothly and a set of diversely substituted thiazolidin-4-ones 10 was obtained in moderate to excellent yields, Table 1. [a]Yields are based on isolated products after crystallization. [b–e]These compounds have previously been reported. Please see: [b]Raval and Trivedi (1960), [c]Yadav et al. (2009), [d]Kumar et al. (2012), [e]Tu et al. (2009).
A further exploration of the scope and limitations of this methodology consisted in trying the reaction with heterocyclic aldehydes 6e–g and ketones 6h,i chemsets as carbonylic precursors, Fig. 3.
Additional aldehydes 6e-g and ketones 6h,i employed for the synthesis of a further family of product 10.
In all cases, reaction proceeded in similar manner and the expected products 10p–w were obtained in good yields, Table 2. Interestingly, the six-membered 1,3-thiazin-4-one 12 was obtained when 3-mercaptopropionic acid 7b was used instead of the 2-mercaptoacetic one 7a. [a]Yields are based on isolated products after crystallization. [b,c]These compounds have previously been reported. Please see: [b]El-Zohry et al. (1993)), [c]Joshi et al. (1981).
The presence of the NC⚌O functionality (evidenced in the range of 1652–1736 cm−1 in IR and 170.6–172.8 ppm in 13C NMR spectra), two double-doublets for C-5(Ha)/C-5(Hb) proton [carbon] (in the range of 3.62–3.88/3.75–5.16 ppm and [31.3–33.4] ppm) in the 1H and 13C NMR spectra respectively, and a narrow doublet (singlet for structures 10e, 10g, 10i, 10j, 10m, 10p and 10r–10t) assigned to C-2(H) proton [carbon] (in the range of 5.34–6.57, and [54.3–65.2] ppm), were the determinant structural features of the thiazolidin-4-one skeleton in compounds 10. Particularly, in the case of the spiro-derivatives 10u–w, the quaternary C-2 carbon atoms appeared in the range of 70.5–74.4 ppm in their 13C NMR spectra. In the case of the 1,3-thiazin-4-one 12, its NC⚌O functionality appeared at 1645 cm−1 in the IR and 169.5 ppm in 13C NMR spectra, while the C-2(H) proton [carbon] appeared as singlet at 5.38 ppm in the 1H NMR and 61.2 ppm in the 13C NMR spectra, respectively.
In addition to the above spectroscopic experiments and in order to unequivocally demonstrate the formation of the thiazolidin-4-one derivatives 10, single crystals suitable for X-ray diffraction of compounds 10a (Fig. 4) and 10l (Moreno-Fuquen et al., 2014), were grown by slow evaporation in ethanol at room temperature, as shown in Fig. 4 and Tables 3 and 4. According to the results there is no doubt that, the obtained compounds effectively corresponded to 1,3-thiazolidin-4-ones 10 as proposed in Scheme 1 and Tables 1 and 2.
ORTEP drawing of the asymmetric unit for compound 10a; ellipsoids are displayed at the 50% probability level.
Empirical formula
C19H21NO4S
Formula weight
359.4
Temperature
120 (2) K
Wavelength
0.71073 Å
Crystal system
Triclinic
Space group
P − 1
Unit cell dimensions
a = 8.316(5) Å α = 100.72(4)°
b = 10.297(3) Å β = 110.25(6)°
c = 11.781(8) Å γ = 96.74(4)°
Volume
911.6(9) Å3
Z
2
Density (calculated)
1.309 Mg/m3
Absorption coefficient
0.200 mm−1
F(000)
380
Crystal size
0.12 × 0.31 × 0.36 mm3
Theta range for data collection
2.62–27.5°
Index ranges
−10 ⩽ h ⩽ 10, −13 ⩽ k ⩽ 13, −15 ⩽ l ⩽ 15
Reflections collected
22,225
Independent reflections
4189 [R(int) = 0.0742]
Completeness to theta = 27.5°
99.9%
Refinement method
Full-matrix least-squares on F2
Data/restraints/parameters
4189/0/229
Goodness-of-fit on F2
1.028
Final R indices [I > 2sigma(I)]
R1 = 0.0696, wR2 = 0.1830
R indices (all data)
R1 = 0.0944, wR2 = 0.2056
Largest diff. peak and hole
1.833 and −0.374 e.Å−3
Bond lengths
S(1)-C(5); 1.792(4)
N(3)-C(2); 1.449(4)
S(1)-C(2); 1.860(3)
O(4)-C(4); 1.220(4)
N(3)-C(4); 1.361(4)
Angles
C(5)-S(1)-C(2); 92.60(15)
N(3)-C(4)-C(5); 111.4(3)
C(4)-N(3)-C(2); 119.6(2)
C(4)-C(5)-S(1); 107.6(2)
N(3)-C(2)-S(1); 104.90(18)
Torsion angles
C(4)-N(3)-C(31)-C(311); 99.8(3)
C(4)-N(3)-C(2)-S(1); −8.5(3)
C(4)-N(3)-C(2)-C(21); 114.4(3)
C(31)-N(3)-C(2)-S(1); 165.05(19)
N(3)-C(2)-C(21)-C(22); 160.3(2)
The more likely mechanism for the formation of the thiazolidin-4-one 10 and thiazin-4-one 12 skeletons is described in Scheme 3.
Proposed mechanistic sequence for the formation of products 10 and 12 via the iminium intermediate 13.
According to this mechanistic approach, formation in situ of the iminium species 13 is suggested as the first step, followed by a nucleophilic attack of the —SH moiety of 7 on the activated azomethinic carbon atom in 13 affording the γ-amino-acid 14. This latter, suffers an intramolecular amidation process releasing a molecule of water to afford the isolated compounds 10, 12. Interestingly, the source of protons during the process is supplied by the mercapto-acids 7a,b themselves. Therefore, this process certainly corresponds to a self-catalyzed three-component approach with a double role of the mercapto-acids 7a,b acting as both the reagents and the catalysts. The last step in Scheme 3 is associated with the rate limiting for obtaining low or high yields of thiazolidin-4-ones 10 (Srivastava et al., 2002) and for instance thiazin-4-ones 12. Consequently, to enhance the efficiency of this reaction, a variety of desiccants has been employed for removing the water during the cyclization process. Currently, either azeotropic distillation or molecular sieves have been used with this purpose (Kaminsky et al., 2011; Rawal et al., 2008; Holmes et al., 1995). Additionally, anhydrous ZnCl2 (Srinivas et al., 2008), trimethylorthoformate (Holmes et al., 1995) or sodium sulfate (Sharma and Kumar, 2000) have also worked as desiccants. Particularly, in our case the use of a desiccant was unnecessary because our methodology proceeded without using solvent and the mixture was heated at 120 °C in open vessel glassware. This fact guaranteed the removal of the water as soon as it was forming during the reaction progress.
The general character of this approach was confirmed by using not only primary benzylamines (products 10a–10l, 10p–10v and 12) but also primary anilines (products 10m–10o and 10w) which worked well although with relative lower yields. The reaction worked well not only with the ordinary aldehydes (products 10a–10o and 12) but also with heterocyclic aldehydes (products 10p–10t) and ketones (products 10u–10w) as the carbonyl reagents. Interestingly, no limitation was found when 2-mercaptoacetic acid 7a was replaced by 3-mercaptopropionic acid 7b. As expected, the larger six-membered thiazin-4-one ring 12 was effectively obtained, extending moreover the scope of this simple methodology and opening a future research line on thiazin-4-one derivatives under the established reaction conditions.
It is worth mentioning that all reactions were performed in a sand bath instead of the commonly recommended oil baths. This fact avoided the generation of undesired volatile materials associated with the thermal decomposition of the utilized oils. Consequently, no final disposition of the bath was required. It is also remarkable, that in this three-component procedure, three new bonds were formed during the process. This finding is in agreement with the atomic economy and bond-forming efficiency (BFE) concepts characteristic of the multicomponent reactions (Dömling, 2005a, 2005b; Dömling et al., 2012; Jarusiewicz et al., 2009; Tietze, 1996; Coquerel et al., 2010). Moreover, production of water as the unique by-product during the overall process, brings this approach effectively near to an environmentally friendly three-component synthesis.
3 Conclusions
In summary, we have implemented a simple, efficient and environmentally friendly solvent-, catalyst- and desiccant-free three-component approach for the synthesis of a library of new and diversely disubstituted 1,3-thiazolidin-4-ones in short reaction times and good yields. Reaction proceeded by the heating at 120 °C, in a sand bath, a mixture of benzyl(aryl)amines 9, aromatic aldehydes (and ketones) 6 and 2-mercaptoacetic acid 7a acting as both a reagent and a self-catalyst. When acid 7a was replaced by 3-mercaptopropionic acid 7b, the six-membered thiazin-4-one 12 was obtained as unique product. Although most previous reports have required acid catalysts and/or desiccant agents to remove the releasing water to guarantee good yields, our open vessel methodology proceeded efficiently without using any of these additives.
4 Material and methods
4.1 Materials
Melting points were determined on a Büchi melting point B-450 apparatus and are uncorrected. IR spectra were recorded on a Shimadzu FTIR 8400 spectrophotometer in KBr disks and films. 1H and 13C NMR spectra were recorded on a Bruker Avance 400 spectrophotometer operating at 400 MHz and 100 MHz respectively, and using CDCl3 as solvent and tetramethylsilane as internal standard. Mass spectra were run on a SHIMADZU-GCMS 2010-DI-2010 spectrometer (equipped with a direct inlet probe) operating at 70 eV. Single-crystal X-ray data for compound 10a were collected at temperature (120 K) on a Kappa-CCD diffractometer, Monochromator graphite, CCD rotation images, using MoKα radiation (0.71073 Å) and deposited at Cambridge Crystallographic Data Center (CCDC reference: 1471083). Microanalyses were performed on an Agilent elemental analyzer and the values are within ±0.4% of the theoretical values. Silica gel aluminum plates (Merck 60 F254) were used for analytical TLC. The starting amines 9 and the remaining reagents and solvents were purchased from Aldrich, Fluka and Acros (analytical reagent grades) and were used without further purification. Due to the heterocyclic aldehyde 6e is commercially unavailable, and it was synthesized following a similar procedure described earlier (Abonia et al., 2010b).
4.2 General procedure for the synthesis of thiazolidin-4-ones 10 and thiazin-4-one 12
A 5 mL pyrex test tube was charged with a mixture of aldehyde 6 (0.74 mmol), 2-mercaptoacetic acid 7a (0.82 mmol) and amine 9 (0.74 mmol) in the absence of solvent. The mixture was heated in a sand bath at 120 °C for 20–30 min until the starting materials were no longer detected by TLC. The obtained residues were purified from aqueous ethanol. In the case of thiazin-4-one 12, 2-mercaptoacetic acid 7a was replaced by 3-mercaptopropionic acid 7b.
4.2.1 (±)-3-Benzyl-2-(3,4,5-trimethoxyphenyl)thiazolidin-4-one 10a
This compound was obtained from benzylamine 9a (109 mg, 1.02 mmol), 3,4,5-trimethoxybenzaldehyde 6a (201 mg, 1.02 mmol) and 2-mercaptoacetic acid 7a (105 mg, 1.14 mmol) as a yellow solid. Yield: 78% (285 mg). Mp 100–102 °C. Data: FTIR (KBr): ν = 2937, 2839, 1675 (C⚌O), 1237 and 1007 (C—O) cm−1. 1H NMR (400 MHz, CDCl3): δ = 3.71 (d, J = 14.8 Hz, 1H, Bn-H), 3.78 (dd, J = 0.6, 15.6 Hz, 1H, H-5a), 3.82 (s, 6H, OCH3 x 2), 3.86–3.90 (m, 4H, OCH3, H-5b), 5.08 (d, J = 14.8 Hz, 1H, Bn-H), 5.36 (d, J = 1.5 Hz, 1H, H-2), 6.42 (s, 2H, Ar-H), 7.09–7.13 (m, 2H, Ph-H), 7.28–7.31 (m, 3H, Ph-H) ppm. 13C NMR (100 MHz, CDCl3): δ = 33.1 (CH2), 46.5 (PhCH2), 56.2 (OCH3 x 2), 60.8 (C-2), 63.5 (OCH3), 104.3, 127.9, 128.4, 128.6, 134.1 (Cq), 135.5 (Cq), 138.7 (Cq), 153.7 (Cq), 171.2 (C⚌O) ppm. MS (70 eV, EI): m/z (%) = 359 [M]+ (88), 284 (100), 268 (25), 212 (23), 146 (6), 147 (11), 104 (5), 91 (79) [PhCH2]. C19H21NO4S (359,12): calcd. C 63.49, H 5.89, N 3.90; found: C 63.32, H 5.67, N 4.08.
4.2.2 (±)-3-Benzyl-2-(4-chlorophenyl)thiazolidin-4-one 10b
This compound was obtained from benzylamine 9a (104 mg, 0.97 mmol), p-chlorobenzaldehyde 6b (137 mg, 0.98 mmol) and 2-mercaptoacetic acid 7a (98 mg, 1.06 mmol) as a yellow solid. Yield: 84% (247 mg). Mp 100–101 °C (73 °C by Raval and Trivedi, 1960). FTIR (KBr): ν = 2925, 2832, 1679 (C⚌O) cm−1. 1H NMR (400 MHz, DMSO-d6): δ = 3.66 (d, J = 15.3 Hz, 1H, Bn-H), 3.78 (d, J = 15.7 Hz, 1H, H-5a), 3.97 (dd, J = 1.4, 15.6 Hz, 1H, H-5b), 4.83 (d, J = 15.1 Hz, 1H, Bn-H), 5.59 (d, J = 1.6 Hz, 1H, H-2), 7.09 (d, J = 7.2 Hz, 2H, Ph-H), 7.25–7.34 (m, 3H, Ph-H), 7.34 (d, J = 8.4 Hz, 2H, Ar-H), 7.43 (d, J = 8.4 Hz, 2H, Ar-H) ppm. 13C NMR (100 MHz, DMSO-d6): δ = 31.6 (CH2), 45.6 (PhCH2), 61.0 (C-2), 127.5, 127.6, 128.5, 128.8 (2 x C), 133.2 (Cq), 135.7 (Cq), 139.1 (Cq), 170.8 (C⚌O) ppm. MS (70 eV, EI): m/z (%) = 305/303 [M]+ (1/3), 230/228 (6/17), 214/212 (6/17), 178 (11), 146 (25), 147 (31), 104 (16), 91 (100) [PhCH2]. C16H14ClNOS (303, 05): calcd. C 63.25, H 4.64, N 4.61; found: C 63.39, H 4.45, N 4.36.
4.2.3 (±)-2-(Benzo[d][1,3]dioxol-5-yl)-3-benzylthiazolidin-4-one 10c
This compound was obtained from benzylamine 9a (97 mg, 0.91 mmol), benzo[d][1,3]dioxole-5-carbaldehyde 6c (137 mg, 0.91 mmol) and 2-mercaptoacetic acid 7a (93 mg, 1.01 mmol) as a yellow solid. Yield: 71% (201 mg). Mp 77 °C. Data: FTIR (KBr): ν = 2915, 2849, 1678 (C⚌O), 1246 and 1037 (C—O) cm−1. 1H NMR (400 MHz, DMSO-d6): δ = 3.66 (d, J = 15.3 Hz, 1H, Bn-H), 3.74 (d, J = 15.5 Hz, 1H, H-5a), 3.97 (dd, J = 1.6, 15.5 Hz, 1H, H-5b), 4.80 (d, J = 15.3 Hz, 1H, Bn-H), 5.50 (d, J = 1.6 Hz, 1H, H-2), 6.03 (d, J = 5.0 Hz, 2H, OCH2O), 6.77 (dd, J = 1.6, 7.9 Hz, 1H, Ar-H), 6.87 (d, J = 7.8 Hz, 1H, Ar-H), 6.91 (d, J = 1.8 Hz, 1H, Ar-H), 7.12 (d, J = 7.4 Hz, 2H, Ph-H), 7.25–7.35 (m, 3H, Ph-H) ppm. 13C NMR (100 MHz, DMSO-d6): δ = 31.7 (CH2), 45.5 (PhCH2), 61.8 (C-2), 101.3 (OCH2O), 107.0, 107.9, 120.9, 127.4, 127.6, 128.5, 133.5 (Cq), 135.8 (Cq), 147.7 (Cq), 147.9 (Cq), 170.6 (C⚌O) ppm. MS (70 eV, EI): m/z (%) = 313 [M]+ (39), 238 (100), 222 (31), 146 (16), 147 (19), 104 (9), 91 (90) [PhCH2]. C17H15NO3S (313,08): calcd. C 65.16, H 4.82, N 4.47; found: C 65.09, H 5.03, N 4.33.
4.2.4 (±)-3-Benzyl-2-(2-chlorophenyl)thiazolidin-4-one 10d
This compound was obtained from benzylamine 9a (93 mg, 0.87 mmol), o-chlorobenzaldehyde 6d (123 mg, 0.88 mmol) and 2-mercaptoacetic acid 7a (88 mg, 0.96 mmol) as a yellow solid. Yield: 61% (160 mg). Mp 105–106 °C (75 °C by Raval and Trivedi, 1960). Data: FTIR (KBr): ν = 2946, 2837, 1690 (C⚌O) cm−1. 1H NMR (400 MHz, CDCl3): δ = 3.67 (d, J = 14.8 Hz, 1H, Bn-H), 3.72 (d, J = 15.6 Hz, 1H, H-5a), 3.84 (dd, J = 1.0, 15.6 Hz, 1H, H-5b), 5.22 (d, J = 14.8 Hz, 1H, Bn-H), 5.88 (d, J = 1.0 Hz, 1H, H-2), 7.14–7.17 (m, 2H, Ar-H), 7.23 (dd, J = 2.0, 7.0 Hz, 1H, Ar-H), 7.29–7.35 (m, 5H, Ph-H), 7.41 (dd, J = 2.0, 7.2 Hz, 1H, Ar-H) ppm. 13C NMR (100 MHz, CDCl3): δ = 32.3 (CH2), 46.7 (PhCH2), 62.7 (C-2), 127.6, 128.0, 128.3 (2 x C), 128.8, 129.7, 130.3, 132.8 (Cq), 134.9 (Cq), 136.6 (Cq), 171.7 (C⚌O) ppm. MS (70 eV, EI): m/z (%) = 305/303 [M]+ (0.5/1), 230/228 (1/3), 214/212 (2/6), 147 (7), 146 (8), 104 (12), 91 (100) [PhCH2]. C16H14ClNOS (303,05): calcd. C 63.25, H 4.64, N 4.61; found: C 63.59, H 4.79, N 4.45.
4.2.5 (±)-3-(3,4-Dimethoxybenzyl)-2-(4-chlorophenyl)thiazolidin-4-one 10e
This compound was obtained from 3,4-dimethoxybenzylamine 9b (94 mg, 0.56 mmol), p-chlorobenzaldehyde 6b (80 mg, 0.57 mmol) and 2-mercaptoacetic acid 7a (58 mg, 0.63 mmol) as a yellow solid. Yield: 86% (176 mg). Mp 102 °C. Data: FTIR (KBr): ν = 2933, 2834, 1679 (C⚌O), 1239, 1157, 1140 and 1027 (C—O) cm−1. 1H NMR (400 MHz, DMSO-d6): δ = 3.59 (d, J = 14.8 Hz, 1H, Bn-H), 3.68 (s, 3H, OCH3), 3.73 (s, 3H, OCH3), 3.76 (d, J = 15.7 Hz, 1H, H-5a), 3.95 (d, J = 15.7 Hz, 1H, H-5b), 4.69 (d, J = 14.8 Hz, 1H, Bn-H), 5.57 (s, 1H, H-2), 6.61–6.62 (d, 2H, Ar-H), 6.87 (d, J = 8.6 Hz, 1H, Ar-H), 7.34 (d, J = 8.2 Hz, 2H, Ar-H), 7.43 (d, J = 8.2 Hz, 2H, Ar-H) ppm. 13C NMR (100 MHz, DMSO-d6): δ = 31.7 (CH2), 45.5 (PhCH2), 55.3 (OCH3), 55.5 (OCH3), 61.0 (C-2), 111.7, 111.8, 120.2, 127.9 (Cq), 128.8, 128.9, 133.1 (Cq), 139.2 (Cq), 148.3 (Cq), 148.7 (Cq), 170.7 (C⚌O) ppm. MS (70 eV, EI): m/z (%) = [M]+ 365/363 (7/18), 207 (38), 176 (100), 164 (16), 151 (73). C18H18ClNO3S (363, 07): calcd. C 59.42, H 4.99, N 3.85; found: C 59.36, H 5.05, N 3.91.
4.2.6 (±)-3-(3,4-Dimethoxybenzyl)-2-(benzo[d][1,3]dioxol-5-yl)thiazolidin-4-one 10f
This compound was obtained from 3,4-dimethoxybenzylamine 9b (106 mg, 0.63 mmol), benzo[d][1,3]dioxole-5-carbaldehyde 6c (96 mg, 0.64 mmol) and 2-mercaptoacetic acid 7a (65 mg, 0.71 mmol) as a yellow solid. Yield: 91% (216 mg). Mp 112 °C. Data: FTIR (KBr): ν = 2933, 2835, 1677 (C⚌O), 1244, 1156, 1140 and 1033 (C—O) cm−1. 1H NMR (400 MHz, CDCl3): δ = 3.54 (d, J = 14.3 Hz, 1H, Bn-H), 3.73 (d, J = 15.6 Hz, 1H, H-5a), 3.83 (s, 3H, OCH3), 3.87 (dd, J = 1.6, 15.4 Hz, 1H, H-5b), 3.87 (s, 3H, OCH3), 5.06 (d, J = 14.6 Hz, 1H, Bn-H), 5.34 (d, J = 1.5 Hz, 1H, H-2), 6.00 (s, 2H, OCH2O), 6.62–6.68 (m, 3H, Ar-H), 6.76–6.80 (m, 3H, Ar-H) ppm. 13C NMR (100 MHz, CDCl3): δ = 33.1 (CH2), 46.0 (PhCH2), 55.9 (OCH3 x 2), 62.8 (C-2), 101.5 (OCH2O), 107.1, 108.1, 111.1, 111.7, 121.0, 121.2, 127.8 (Cq), 132.9 (Cq), 148.4 (Cq), 148.6 (Cq), 148.8 (Cq), 149.1 (Cq), 171.0 (C⚌O) ppm. MS (70 eV, EI): m/z (%) = 373 [M]+ (17), 207 (60), 192 (13), 176 (100), 164 (13), 151 (70), 135 (11), 121 (13), 107 (21). C19H19NO5S (373, 10): calcd. C 61.11, H 5.13, N 3.75; found: C 61.05, H 5.02, N 3.61.
4.2.7 (±)-3-(3,4-Dimethoxybenzyl)-2-(2-chlorophenyl)thiazolidin-4-one 10g
This compound was obtained from 3,4-dimethoxybenzylamine 9b (116 mg, 0.69 mmol), o-chlorobenzaldehyde 6d (98 mg, 0.70 mmol) and 2-mercaptoacetic acid 7a (71 mg, 0.77 mmol) as a yellow solid. Yield: 87% (219 mg). Mp 108–109 °C. Data: FTIR (KBr): ν = 2923, 2840, 1668 (C⚌O), 1235, 1142 and 1030 (C—O) cm−1. 1H NMR (400 MHz, CDCl3): δ = 3.60 (d, J = 14.5 Hz, 1H, Bn-H), 3.71 (d, J = 15.5 Hz, 1H, H-5a), 3.83 (s, 3H, OCH3), 3.84 (d, J = 15.5 Hz, 1H, H-5b), 3.88 (s, 3H, OCH3), 5.15 (d, J = 14.5 Hz, 1H, Bn-H), 5.87 (s, 1H, H-2), 6.65–6.68 (m, 2H, Ar-H), 6.79 (d, J = 8.5 Hz, 1H, Ar-H), 7.23 (dd, J = 1.7, 7.1 Hz, 1H, Ar-H), 7.30–7.37 (m, 2H, Ar-H), 7.42 (dd, J = 1.7, 7.5 Hz, 1H, Ar-H) ppm. 13C NMR (100 MHz, CDCl3): δ = 32.5 (CH2), 46.6 (PhCH2), 55.8 (OCH3), 55.9 (OCH3), 59.0 (C-2), 111.2, 111.6, 121.1, 127.2, 127.4 (Cq), 127.6, 129.8, 130.3, 132.8 (Cq), 136.8 (Cq), 148.8 (Cq), 149.2 (Cq), 171.7 (C⚌O) ppm. MS (70 eV, EI): m/z (%) = 365/363 [M]+ (0.5/3), 176 (42), 151 (46), 107 (25), 91 (10) [PhCH2], 28 (100). C18H18ClNO3S (363, 07): calcd. C 59.42, H 4.99, N 3.85; found: C 59.59, H 4.85, N 3.91.
4.2.8 (±)-3-(3,4-Dimethoxybenzyl)-2-(3,4,5-trimethoxyphenyl)thiazolidin-4-one 10h
This compound was obtained from 3,4-dimethoxybenzylamine 9b (89 mg, 0.53 mmol), 3,4,5-trimethoxybenzaldehyde 6a (106 mg, 0.54 mmol) and 2-mercaptoacetic acid 7a (55 mg, 0.60 mmol) as a yellow solid. Yield: 82% (183 mg). Mp 104–105 °C. Data: FTIR (KBr): ν = 2937, 2836, 1688 (C⚌O), 1237, 1124, 1027 and 1005 (C—O) cm−1. 1H NMR (400 MHz, CDCl3): δ = 3.62 (d, J = 14.3 Hz, 1H, Bn-H), 3.76 (d, J = 15.1 Hz, 1H, H-5a), 3.82 (s, 3H, OCH3), 3.83 (s, 6H, OCH3 x 2), 3.84–3.89 (m, 7H, H-5b, OCH3 x 2), 5.05 (d, J = 14.3 Hz, 1H, Bn-H), 5.35 (d, J = 1.5 Hz, 1H, H-2), 6.42 (s, 2H, Ar-H), 6.61 (dd, J = 1.9, 8.0 Hz, 1H, Ar-H), 6.64 (d, J = 1.8 Hz, 1H, Ar-H), 6.77 (d, J = 8.0 Hz, 1H, Ar-H) ppm. 13C NMR (100 MHz, CDCl3): δ = 33.2 (CH2), 46.3 (PhCH2), 55.9 (OCH3 x 2), 56.2 (OCH3 x 2), 60.8 (OCH3), 63.3 (C-2), 104.2, 111.1, 111.8, 121.0, 127.9 (Cq), 134.3 (Cq), 138.6 (Cq), 148.8 (Cq), 149.2 (Cq), 153.7 (Cq), 171.2 (C⚌O) ppm. MS (70 eV, EI): m/z (%) = 419 [M]+ (34), 344 (11), 268 (12), 207 (35), 176 (100), 151 (82), 107 (12). C21H25NO6S (419,14): calcd. C 60.13, H 6.01, N 3.34; found: C 60.21, H 5.85, N 3.19.
4.2.9 (±)-3-((Benzo[d][1,3]dioxol-6-yl)methyl)-2-(4-chlorophenyl)thiazolidin-4-one 10i
This compound was obtained from 3,4-methylenedioxybenzylamine 9c (107 mg, 0.71 mmol), p-chlorobenzaldehyde 6b (100 mg, 0.71 mmol) and 2-mercaptoacetic acid 7a (73 mg, 0.79 mmol) as a white solid. Yield: 61% (167 mg). Mp 115–116 °C. Data: FTIR (KBr): ν = 2924, 2895, 1672 (C⚌O), 1244, 1092 and 1038 (C—O) cm−1. 1H NMR (400 MHz, CDCl3): δ = 3.45 (d, J = 14.6 Hz, 1H, Bn-H), 3.73 (d, J = 15.6 Hz, 1H, H-5a), 3.86 (d, J = 15.8 Hz, 1H, H-5b), 5.02 (d, J = 14.6 Hz, 1H, Bn-H), 5.37 (s, 1H, H-2), 5.95 (s, 2H, OCH2O), 6.48 (d, J = 7.8 Hz, 1H, Ar-H), 6.61 (s, 1H, Ar-H), 6.70 (d, J = 7.8 Hz, 1H, Ar-H), 7.17 (d, J = 8.3 Hz, 2H, Ar-H), 7.35 (d, J = 8.3 Hz, 2H, Ar-H) ppm. 13C NMR (100 MHz, CDCl3): δ = 32.9 (CH2), 46.1 (PhCH2), 62.0 (C-2), 101.1 (OCH2O), 108.2, 108.7, 121.9, 128.5, 128.8 (Cq), 129.3, 135.0 (Cq), 137.7 (Cq), 147.4 (Cq), 148.1 (Cq), 171.0 (C⚌O) ppm. MS (70 eV, EI): m/z (%) = 349/347 [M]+ (3/9), 191 (58), 161 (45), 148 (42), 135 (100), 105 (17), 77 (52). C17H14ClNO3S (347, 04): calcd. C 58.70, H 4.06, N 4.03; found: C 58.95, H 4.24, N 4.18.
4.2.10 (±)-3-((Benzo[d][1,3]dioxol-6-yl)methyl)-2-(2-chlorophenyl)thiazolidin-4-one 10j
This compound was obtained from 3,4-methylenedioxybenzylamine 9c (107 mg, 0.71 mmol), o-chlorobenzaldehyde 6d (102 mg, 0.73 mmol) and 2-mercaptoacetic acid 7a (73 mg, 0.79 mmol) as a white solid. Yield: 97% (238 mg). Mp 119 °C. Data: FTIR (KBr): ν = 2927, 2839, 1677 (C⚌O), 1247 and 1038 (C-O) cm−1. 1H NMR (400 MHz, CDCl3): δ = 3.50 (d, J = 14.8 Hz, 1H, Bn-H), 3.62 (d, J = 15.6 Hz, 1H, H-5a), 3.75 (d, J = 0.9, 15.5 Hz, 1H, H-5b), 5.03 (d, J = 14.6 Hz, 1H, Bn-H), 5.82 (s, 1H, H-2), 5.86 (s, 2H, OCH2O), 6.48 (dd, J = 1.2, 7.6 Hz, 1H, Ar-H), 6.62 (d, J = 1.5 Hz, 1H, Ar-H), 6.64 (d, J = 8.0 Hz, 1H, Ar-H), 7.16 (dd, J = 2.1, 7.2 Hz, 1H, Ar-H), 7.19–7.26 (m, 2H, Ar-H), 7.33 (dd, J = 1.6, 7.6 Hz, 1H, Ar-H) ppm. 13C NMR (100 MHz, CDCl3): δ = 32.1 (CH2), 46.2 (PhCH2), 58.8 (C-2), 100.8 (OCH2O), 107.9, 108.4, 121.6, 126.9, 127.3, 128.4 (Cq), 129.5, 130.0, 132.5 (Cq), 136.4 (Cq), 147.1 (Cq), 147.7 (Cq), 171.3 (C⚌O) ppm. MS (70 eV, EI): m/z (%) = 349/347 [M]+ (6/12), 214/212 (14/27), 191 (70), 161 (52), 148 (42), 135 (100), 105 (21), 77 (50), 46 (88). C17H14ClNO3S (347, 04): calcd. C 58.70, H 4.06, N 4.03; found: C 58.93, H 4.21, N 4.16.
4.2.11 (±)-2-(Benzo[d][1,3]dioxol-5-yl)-3-((benzo[d][1,3]dioxol-6-yl)methyl)thiazolidin-4-one 10k
This compound was obtained from 3,4-methylenedioxybenzylamine 9c (99 mg, 0.66 mmol), 3,4-methylenedioxybenzaldehyde 6c (100 mg, 0.67 mmol) and 2-mercaptoacetic acid 7a (66 mg, 0.72 mmol) as a brown solid. Yield: 91% (213 mg). Mp 129–130 °C. Data: FTIR (KBr): ν = 2931, 2897, 1670 (C⚌O), 1609, 1244, 1097 and 1037 (C—O) cm−1. 1H NMR (400 MHz, CDCl3): δ = 3.50 (d, J = 14.6 Hz, 1H, Bn-H), 3.73 (d, J = 15.6 Hz, 1H, H-5a), 3.86 (dd, J = 1.2, 15.4 Hz, 1H, H-5b), 5.02 (d, J = 14.6 Hz, 1H, Bn-H), 5.35 (d, J = 1.8 Hz, 1H, H-2), 5.96 (s, 2H, OCH2O), 6.00 (s, 2H, OCH2O), 6.54 (dd, J = 1.4, 7.7 Hz, 1H, Ar-H), 6.65 (d, J = 1.5 Hz, 1H, Ar-H), 6.67 (dd, J = 1.9, 7.8 Hz, 1H, Ar-H), 6.72 (d, J = 8.0 Hz, 1H, Ar-H), 6.75–6.79 (m, 2H, Ar-H) ppm. 13C NMR (100 MHz, CDCl3): δ = 33.0 (CH2), 45.9 (PhCH2), 62.7 (C-2), 101.1 (OCH2O), 101.5 (OCH2O), 107.1, 108.1, 108.2, 108.8, 121.2, 122.0, 129.1 (Cq), 132.8 (Cq), 147.3 (Cq), 148.0 (Cq), 148.4 (Cq), 148.6 (Cq), 170.9 (C⚌O) ppm. MS (70 eV, EI): m/z (%) = 357 [M]+ (37), 165 (21), 148 (16), 135 (100), 121 (26), 105 (17), 77 (39), 46 (51). C18H15NO5S (357, 07): calcd. C 60.49, H 4.23, N 3.92; found: C 60.38, H 4.40, N 3.98.
4.2.12 (±)-3-((Benzo[d][1,3]dioxol-6-yl)methyl)-2-(3,4,5-trimethoxyphenyl)thiazolidin-4-one 10l
This compound was obtained from 3,4-methylenedioxybenzylamine 9c (111 mg, 0.74 mmol), 3,4,5-trimethoxybenzaldehyde 6a (145 mg, 0.74 mmol) and 2-mercaptoacetic acid 7a (75 mg, 0.82 mmol) as a white solid. Yield: 66% (196 mg). Mp 122–123 °C. Data: FTIR (KBr): ν = 2934, 2841, 1672 (C⚌O), 1240, 1121 and 1037 (C—O) cm−1. 1H NMR (400 MHz, CDCl3): δ = 3.60 (d, J = 14.6 Hz, 1H, Bn-H), 3.75 (d, J = 15.8 Hz, 1H, H-5a), 3.83–3.89 (m, 10H, H-5b, OCH3 x 3), 4.98 (d, J = 14.6 Hz, 1H, Bn-H), 5.36 (d, J = 1.5 Hz, 1H, H-2), 5.95 (s, 2H, OCH2O), 6.44 (s, 2H, Ar-H), 6.52 (dd, J = 1.4, 7.8 Hz, 1H, Ar-H), 6.64 (d, J = 1.2 Hz, 1H, Ar-H), 6.71 (d, J = 8.0 Hz, 1H, Ar-H) ppm. 13C NMR (100 MHz, CDCl3): δ = 33.1 (CH2), 46.3 (PhCH2), 56.2 (OCH3 x 2), 60.8 (C-2), 63.4 (OCH3), 101.1 (OCH2O), 104.3, 108.1, 108.9, 122.0, 129.2 (Cq), 134.2 (Cq), 138.7 (Cq), 147.3 (Cq), 148.0 (Cq), 153.7 (Cq), 171.2 (C⚌O) ppm. MS (70 eV, EI): m/z (%) = 403 [M]+ (7), 212 (17), 191 (28), 161 (32), 148 (29), 135 (100), 105 (17), 77 (52). C20H21NO6S (403, 11): calcd. C 59.54, H 5.25, N 3.47, found: C 59.87, H 5.34, N 3.23.
4.2.13 (±)-2-(2-Chlorophenyl)-3-phenylthiazolidin-4-one 10m
This compound was obtained from aniline 9d (104 mg, 1.12 mmol), 2-chlorobenzaldehyde 6d (158 mg, 1.13 mmol) and 2-mercaptoacetic acid 7a (114 mg, 1.24 mmol) as a yellow solid. Yield: 46% (149 mg). Mp 115 °C (117–118 °C by Yadav et al., 2009). Data: FTIR (KBr): ν = 2922, 2841, 1693 (C⚌O) cm−1. 1H NMR (400 MHz, CDCl3): δ = 3.82 (d, J = 15.8 Hz, 1H, H-5a), 3.94 (d, J = 15.8 Hz, 1H, H-5b), 6.57 (s, 1H, H-2), 7.16–7.37 (m, 9H, Ph-H, Ar-H) ppm. 13C NMR (100 MHz, CDCl3): δ = 33.0 (CH2), 61.8 (C-2), 124.1, 126.7, 127.4, 129.1 (2 x C), 129.6, 130.2, 132.4 (Cq), 137.1 (Cq), 137.5 (Cq), 171.3 (C⚌O) ppm. MS (70 eV, EI): m/z (%) = 291/289 [M]+ (0.5/1.4), 214 (9), 135 (9), 104 (17), 77 (63), 46 (100). C15H12ClNOS (289,03): calcd. C 62.17, H 4.17, N 4.83; found: C 62.18, H 4.36, N 4.73.
4.2.14 (±)-2-(3,4,5-Trimethoxyphenyl)-3-p-tolylthiazolidin-4-one 10n
This compound was obtained from p-methylaniline 9e (106 mg, 0.99 mmol), 3,4,5-trimethoxybenzaldehyde 6a (198 mg, 1.01 mmol) and 2-mercaptoacetic acid 7a (101 mg, 1.10 mmol) as a yellow solid. Yield: 68% (242 mg). Mp 116 °C (160–162 °C by Kumar et al., 2012). Data: FTIR (KBr): ν = 2937, 2837, 1681 (C⚌O), 1235 and 1004 (C—O) cm−1. 1H NMR (400 MHz, CDCl3): δ = 2.29 (s, 3H, CH3), 3.80 (s, 6H, OCH3 x 2), 3.81 (s, 3H, OCH3), 3.87 (dd, J = 0.5, 16.0 Hz, 1H, H-5a), 3.98 (dd, J = 1.5, 15.8 Hz, 1H, H-5b), 6.00 (d, J = 1.0 Hz, 1H, H-2), 6.50 (s, 2H, Ar-H), 7.06 (d, J = 8.5 Hz, 2H, Ar-H), 7.11 (d, J = 8.5 Hz, 2H, Ar-H) ppm. 13C NMR (100 MHz, CDCl3): δ = 21.0 (CH3), 33.4 (CH2), 56.2 (OCH3 x 2), 60.8 (C-2), 65.9 (OCH3), 104.0, 125.6, 129.8, 134.9 (Cq), 137.2 (Cq), 138.3 (Cq), 143.8 (Cq), 153.5 (Cq), 171.1 (C⚌O) ppm. MS (70 eV, EI): m/z (%) = 359 [M]+ (54), 285 (5), 284 (5), 222 (100), 211 (16), 195 (46), 168 (5), 91 (3) [PhCH2]. C19H21NO4S (359,12): calcd. C 63.49, H 5.89, N 3.90; found: C 63.39, H 5.71, N 3.73.
4.2.15 (±)-2-(4-Chlorophenyl)-3-(4-methoxyphenyl)thiazolidin-4-one 10o
This compound was obtained from p-methoxylaniline 9f (103 mg, 0.84 mmol), p-chlorobenzaldehyde 6b (119 mg, 0.85 mmol) and 2-mercaptoacetic acid 7a (85 mg, 0.92 mmol) as a yellow solid. Yield: 43% (115 mg). Mp 165–166 °C (169–170 °C by Tu et al., 2009). Data: FTIR (KBr): ν = 2932, 2836, 1671 (C⚌O), 1247 and 1029 (C—O) cm−1. 1H NMR (400 MHz, CDCl3): δ = 3.74 (s, 3H, OCH3), 3.88 (d, J = 15.8 Hz, 1H, H-5a), 3.98 (dd, J = 1.8, 15.8 Hz, 1H, H-5b), 5.98 (d, J = 1.5 Hz, 1H, H-2), 6.81 (d, J = 9.0 Hz, 2H, Ar-H), 7.02 (d, J = 9.0 Hz, 2H, Ar-H), 7.24 (d, J = 8.8 Hz, 2H, Ar-H), 7.28 (d, J = 8.8 Hz, 2H, Ar-H) ppm. 13C NMR (100 MHz, CDCl3): δ = 33.3 (CH2), 55.3 (OCH3), 65.2 (C-2), 114.5, 127.4, 128.6, 129.0, 129.8 (Cq), 134.7 (Cq), 138.1 (Cq), 158.5 (Cq), 170.9 (C⚌O) ppm. MS (70 eV, EI): m/z (%) = 321/319 [M]+ (15/38), 247/245 (4/10), 232/230 (7/25), 153 (67), 135 (100), 127/125 (5/18), 77 (16). C16H14ClNO2S (319,04): calcd. C 60.09, H 4.41, N 4.38; found: C 59.95, H 4.58, N 4.31.
4.2.16 (±)-3-(3-Benzyl-4-oxothiazolidin-2-yl)quinolin-2(1H)-one 10p
This compound was obtained from benzylamine 9a (102 mg, 0.95 mmol), 1,2-dihydro-2-oxoquinoline-3-carbaldehyde 6e (168 mg, 0.97 mmol) and 2-mercaptoacetic acid 7a (97 mg, 1.05 mmol) as a yellow solid. Yield: 65% (208 mg). Mp 190–192 °C. Data: FTIR (KBr): ν = 3503 (N-H), 2921, 2859, 1688 (C⚌O), 1656 (C⚌O), 1565 cm−1. 1H NMR (400 MHz, CDCl3): δ = 3.72 (d, J = 15.3 Hz, 1H, H-5a), 3.91–3.96 (m, 2H, Bn-H), 5.16 (d, J = 15.1 Hz, 1H, H-5b), 5.68 (s, 1H, H-2), 7.21 (d, J = 7.8 Hz, 2H, Ph-H), 7.24–7.32 (m, 4H, Ph-H, quinolin-H), 7.40 (d, J = 8.3 Hz, 1H, quinolin-H), 7.55–7.61 (m, 3H, quinolin-H), 12.27 (s, 1H, NH) ppm. 13C NMR (100 MHz, CDCl3): δ = 32.6 (CH2), 47.0 (PhCH2), 58.6 (C-2), 116.0, 119.4 (Cq), 123.5, 127.9, 128.0, 128.1, 128.7, 129.5 (Cq), 131.4, 135.0 (Cq), 136.4, 137.4 (Cq), 162.6 (C⚌O, quinolin), 172.9 (C⚌O, thiazolidin) ppm. MS (70 eV, EI): m/z (%) = 336 [M]+ (1), 263 (6), 245 (9), 171 (11), 153 (6), 130 (5), 91 (100) [PhCH2]. C19H16N2O2S (336, 09): calcd. C 67.84, H 4.79, N 8.33; found: C 67.61, H 4.91, N 8.28.
4.2.17 (±)-3-(3-(3,4-Dimethoxybenzyl)-4-oxothiazolidin-2-yl)quinolin-2(1H)-one 10q
This compound was obtained from 3,4-dimethoxybenzylamine 9b (103 mg, 0.62 mmol), 1,2-dihydro-2-oxoquinoline-3-carbaldehyde 6e (109 mg, 0.63 mmol) and 2-mercaptoacetic acid 7a (63 mg, 0.68 mmol) as a green solid. Yield: 72% (176 mg). Mp 208–211 °C. Data: FTIR (KBr): ν = 3508 (N-H), 2936, 2837, 1721 (C⚌O), 1652 (C⚌O), 1568, 1238, 1157, 1140 and 1024 (C—O) cm−1. 1H NMR (400 MHz, CDCl3): δ = 3.72 (d, J = 15.3 Hz, 1H, H-5a), 3.81–3.87 (m, 7H, Bn-H, OCH3 x 2), 3.96 (d, J = 15.3 Hz, 1H, H-5b), 5.14 (d, J = 14.6 Hz, 1H, Bn-H), 5.69 (d, J = 0.7 Hz, 1H, H-2), 6.72–6.79 (m, 3H, Ar-H), 7.27 (t, J = 8.0 Hz, 1H, quinolin-H), 7.42 (d, J = 8.0 Hz, 1H, quinolin-H), 7.53 (s, 1H, quinolin-H), 7.54–7.61 (m, 2H, quinolin-H), 12.46 (s, 1H, NH) ppm. 13C NMR (100 MHz, CDCl3): δ = 33.0 (CH2), 46.8 (PhCH2), 55.9 (OCH3 x 2), 58.7 (C-2), 111.1, 111.4, 116.0, 119.2 (Cq), 120.8, 123.2, 127.8 (Cq), 128.0, 130.0 (Cq), 131.3, 135.8, 138.0 (Cq), 148.8 (Cq), 149.3 (Cq), 162.5 (C⚌O, quinolin), 172.5 (C⚌O, thiazolidin) ppm. MS (70 eV, EI): m/z (%) = 396 [M]+ (19), 245 (100), 208 (32), 176 (32), 171 (19), 151 (52). C21H20N2O4S (396, 11): calcd. C 63.62, H 5.08, N 7.07; found: C 63.60, H 5.22, N 7.31.
4.2.18 (±)-3-(3-((Benzo[d][1,3]dioxol-6-yl)methyl)-4-oxothiazolidin-2-yl)quinolin-2(1H)-one 10r
This compound was obtained from 3,4-methylenedioxybenzylamine 9c (115 mg, 0.76 mmol), 1,2-dihydro-2-oxoquinoline-3-carbaldehyde 6e (132 mg, 0.76 mmol) and 2-mercaptoacetic acid 7a (79 mg, 0.86 mmol) as a yellow solid. Yield: 88% (255 mg). Mp 212–214 °C. Data: FTIR (KBr): ν = 3508 (N-H), 2931, 2860, 1681 (C⚌O), 1655 (C⚌O), 1565, 1249 and 1033 (C—O) cm−1. 1H NMR (400 MHz, DMSO-d6): δ = 3.62 (d, J = 15.3 Hz, 1H, H-5a), 3.82 (d, J = 14.6 Hz, 1H, Bn-H), 3.88 (d, J = 14.8 Hz, 1H, Bn-H), 4.84 (d, J = 15.1 Hz, 1H, H-5b), 5.54 (s, 1H, H-2), 5.96 (d, J = 3.3 Hz, 2H, OCH2O), 6.67 (dd, J = 1.2, 8.0 Hz, 1H, Ar-H), 6.76 (d, J = 1.2 Hz, 1H, Ar-H), 6.82 (d, J = 7.8 Hz, 1H, Ar-H), 7.20 (t, J = 8.0 Hz, 1H, quinolin-H), 7.33 (d, J = 8.0 Hz, 1H, quinolin-H), 7.51 (t, J = 7.6 Hz, 1H, quinolin-H), 7.66–7.71 (m, 2H, quinolin-H), 11.94 (s, 1H, NH) ppm. 13C NMR (100 MHz, DMSO-d6): δ = 31.5 (CH2), 45.7 (PhCH2), 57.4 (C-2), 101.0 (OCH2O), 108.2 (C × 2), 114.9, 118.7 (Cq), 121.2, 122.0, 128.3, 129.8 (Cq), 130.4 (C + Cq), 134.4, 138.2 (Cq), 146.7 (Cq), 147.4 (Cq), 160.4 (C⚌O, quinolin), 171.6 (C⚌O, thiazolidin) ppm. MS (70 eV, EI): m/z (%) = 380 [M]+ (5), 245 (88), 190 (25), 171 (50), 161 (20), 135 (100), 105 (14), 77 (42). C20H16N2O4S (380,08): calcd. C 63.14, H 4.24, N 7.36; found: C 63.01, H 4.37, N 7.30.
4.2.19 (±)-3-Benzyl-2-(3-methyl-1-phenyl-1H-pyrazol-4-yl)thiazolidin-4-one 10s
This compound was obtained from benzylamine 9a (101 mg, 0.94 mmol), 3-methyl-1-phenyl-1H-pyrazole-4-carboxaldehyde 6f (177 mg, 0.95 mmol) and 2-mercaptoacetic acid 7a (99 mg, 1.08 mmol) as a white solid. Yield: 60% (198 mg). Mp 131 °C. Data: FTIR (KBr): ν = 2984, 2830, 1695 (C⚌O), 1599 and 1562 cm−1. 1H NMR (400 MHz, CDCl3): δ = 2.22 (s, 3H, CH3), 3.80–3.90 (m, 3H, Bn-H, H-5a, H-5b), 5.14 (d, J = 14.8 Hz, 1H, Bn-H), 5.59 (s, 1H, H-2), 7.15 (d, J = 7.6 Hz, 2H, Ph-H), 7.29–7.36 (m, 4H, Ph-H), 7.48 (t, J = 7.9 Hz, 2H, Ph-H), 7.64 (d, J = 7.8 Hz, 2H, Ph-H), 7.78 (s, 1H, pyrazol-H) ppm. 13C NMR (100 MHz, CDCl3): δ = 12.1 (CH3), 33.1 (CH2), 46.1 (PhCH2), 54.3 (C-2), 118.7 (C + Cq), 126.5, 126.9, 127.9, 128.2, 128.7, 129.4, 135.3 (Cq), 139.5 (Cq), 148.8 (Cq), 170.7 (C⚌O) ppm. C20H19N3OS (349, 12): calcd. C 68.74, H 5.48, N 12.02; found: C 68.89, H 5.64, N 12.06.
4.2.20 (±)-3-Benzyl-2-(1,3-diphenyl-1H-pyrazol-4-yl)thiazolidin-4-one 10t
This compound was obtained from benzylamine 9a (96 mg, 0.90 mmol), 3-phenyl-1-phenyl-1H-pyrazole-4-carboxaldehyde 6g (220 mg, 0.89 mmol) and 2-mercaptoacetic acid 7a (93 mg, 1.01 mmol) as a white solid. Yield: 75% (277 mg). Mp 168–169 °C. Data: FTIR (KBr): ν = 2938, 2850, 1686 (C⚌O), 1597 cm−1. 1H NMR (400 MHz, CDCl3): δ = 3.73 (d, J = 15.6 Hz, 1H, H-5a), 3.78 (dd, J = 0.9, 15.8 Hz, 1H, H-5b), 3.92 (d, J = 14.8 Hz, 1H, Bn-H), 4.96 (d, J = 14.8 Hz, 1H, Bn-H), 5.71 (s, 1H, H-2), 6.98–7.01 (m, 2H, Ph-H), 7.14–7.19 (m, 3H, Ph-H), 7.34 (t, J = 7.5 Hz, 1H, Ph-H), 7.38–7.44 (m, 3H, Ph-H), 7.46–7.51 (m, 4H, Ph-H), 7.72 (d, J = 7.8 Hz, 2H, Ph-H), 7.93 (s, 1H, pyrazol-H) ppm. 13C NMR (100 MHz, CDCl3): δ = 33.0 (CH2), 46.5 (PhCH2), 54.5 (C-2), 119.1, 120.0 (Cq), 127.0, 127.3, 127.7, 128.2, 128.4, 128.5, 128.6, 128.7, 129.4, 132.0 (Cq), 135.2 (Cq), 139.5 (Cq), 151.9 (Cq), 170.8 (C⚌O) ppm. C25H21N3OS (411, 14): calcd. C 72.97, H 5.14, N 10.21; found: C 72.91, H 5.28, N 10.09.
4.2.21 4-Benzyl-1-thia-4-azaspiro[4.5]decan-3-one 10u
This compound was obtained from benzylamine 9a (103 mg, 0.96 mmol), cyclohexanone 6h (96 mg, 0.98 mmol) and 2-mercaptoacetic acid 7a (98 mg, 1.06 mmol) as a yellow solid. Yield: 61% (153 mg). Mp 92–93 °C (115–117 °C by El-Zohry et al., 1993). Data: FTIR (KBr): ν = 2929, 2855, 1674 (C⚌O) cm−1. 1H NMR (400 MHz, CDCl3): δ = 1.02–1.10 (m, 1H, cyclohexyl-H), 1.52–1.83 (m, 9H, cyclohexyl-H), 3.63 (s, 2H, H-5), 4.59 (s, 2H, Bn-H), 7.24–7.34 (m, 5H, Ph-H) ppm. 13C NMR (100 MHz, CDCl3): δ = 23.4 (CH2), 24.4 (CH2), 31.3 (CH2), 38.3 (CH2), 45.1 (PhCH2), 74.3 (Cq, C-2), 127.0, 127.1, 128.4, 137.9 (Cq), 171.7 (C⚌O) ppm. C15H19NOS (261,12): calcd. C 68.93, H 7.33, N 5.36; found: C 68.78, H 7.40, N 5.19.
4.2.22 4-(1,3-Benzodioxol-5-ylmethyl)-1-thia-4-azaspiro[4.5]decan-3-one 10v
This compound was obtained from 3,4-methylenedioxybenzylamine 9c (97 mg, 0.64 mmol), cyclohexanone 6h (64 mg, 0.65 mmol) and 2-mercaptoacetic acid 7a (65 mg, 0.71 mmol) as a white solid. Yield: 65% (127 mg). Mp 109–111 °C. Data: FTIR (KBr): ν = 2925, 2855, 1670 (C⚌O), 1241 and 1036 (C—O) cm−1. 1H NMR (400 MHz, CDCl3): δ = 1.00–1.10 (m, 1H, cyclohexyl-H), 1.53–1.83 (m. 9H, cyclohexyl-H), 3.60 (s, 2H, H-5), 4.49 (s, 2H, Bn-H), 5.94 (s, 2H, OCH2O), 6.72–6.74 (d, 2H, Ar-H), 6.81 (s, 1H, Ar-H) ppm. 13C NMR (100 MHz, CDCl3): δ = 23.5 (CH2), 24.6 (CH2), 31.3 (CH2), 38.4 (CH2), 45.0 (PhCH2), 74.4 (Cq, C-2), 101.0 (OCH2O), 107.9, 108.1, 120.4, 132.1 (Cq), 146.8 (Cq), 147.9 (Cq), 171.7 (C⚌O) ppm. MS (70 eV, EI): m/z (%) = 305 [M]+ (8), 191 (9), 161 (11), 148 (9), 135 (100), 105 (8), 77 (27). C16H19NO3S (305, 11): calcd. C 62.93, H 6.27, N 4.59; found: C 63.05, H 6.43, N 4.64.
4.2.23 (±)-3′-(4-methoxyphenyl)spiro[indoline-3–2′-thiazolidine]-2,4′-dione 10w
This compound was obtained from p-methoxyaniline 9f (88 mg, 0.72 mmol), isatin 6i (103 mg, 0.70 mmol) and 2-mercaptoacetic acid 7a (80 mg, 0.87 mmol) as a yellow solid. Yield: 66% (151 mg). Mp 206–207 °C (210 °C by Joshi et al., 1981). Data: FTIR (KBr): ν = 3268 (N-H), 2941, 2837, 1736 (C⚌O), 1682 (C⚌O), 1616, 1193 and 1032 (C—O) cm−1. 1H NMR (400 MHz, CDCl3): δ = 3.66 (s, 3H, OCH3), 3.87 (d, J = 15.3 Hz, 1H, H-5a), 4.32 (d, J = 15.3 Hz, 1H, H-5b), 6.69 (d, J = 9.0 Hz, 2H, Ar-H), 6.74 (d, J = 7.8 Hz, 1H, Ar-H), 6.97 (d, J = 9.0 Hz, 2H, Ar-H), 7.09 (td, J = 1.0, 7.6 Hz, 1H, Ar-H), 7.22 (td, J = 1.1, 7.8 Hz, 1H, Ar-H), 7.48 (d, J = 7.5 Hz, 1H, Ar-H), 8.55 (s, 1H, NH) ppm. 13C NMR (100 MHz, CDCl3): δ = 32.9 (CH2), 55.2 (OCH3), 70.5 (Cq, C-2), 110.9, 114.6, 123.5, 125.2 (Cq), 126.6, 128.2 (Cq), 129.7, 131.1, 140.6 (Cq), 159.4 (Cq), 172.8 (C⚌O, thiazolidin), 177.1 (C⚌O) ppm. C17H14N2O3S (326, 07): calcd. C 62.56, H 4.32, N 8.58; found: C 62.71, H 4.50, N 8.72.
4.2.24 (±)-3-((Benzo[d][1,3]dioxol-6-yl)methyl)-2-(3,4,5-trimethoxyphenyl)-1,3-thiazin-4-one 12
This compound was obtained from 3,4-methylenedioxybenzylamine 9b (101 mg, 0.67 mmol), 3,4,5-trimethoxybenzaldehyde 6a (133 mg, 0.68 mmol) and 3-mercaptopropionic acid 7b (79 mg, 0.74 mmol) as a yellow solid. Yield: 42% (117 mg). Mp 136–138 °C. Data: FTIR (KBr): ν = 2962, 2889, 1645 (C⚌O), 1591, 1234, 1130, 1035 and 1006 (C—O) cm−1. 1H NMR (400 MHz, CDCl3): δ = 2.67–2.76 (m, 1H), 2.89–2.99 (m, 3H), 3.61 (d, J = 14.8 Hz, 1H, Bn-H), 3.84 (s, 6H, OCH3 x 2), 3.87 (s, 3H, OCH3), 5.38 (s, 1H, H-2), 5.54 (d, J = 15.1 Hz, 1H, Bn-H), 5.96 (s, 2H, OCH2O), 6.42 (s, 2H, Ar-H), 6.64 (dd, J = 1.4, 8.0 Hz, 1H, Ar-H), 6.74 (d, J = 8.0 Hz, 1H, Ar-H), 6.76 (d, J = 1.5 Hz, 1H, Ar-H) ppm. 13C NMR (100 MHz, CDCl3): δ = 22.3 (CH2), 34.6 (CH2), 49.4 (PhCH2), 56.3 (OCH3 x 2), 60.8 (OCH3), 61.2 (C-2), 101.1 (OCH2O), 104.0, 108.2, 108.6, 121.5, 130.2 (Cq), 134.5 (Cq), 138.0 (Cq), 147.1 (Cq), 148.0 (Cq), 153.4 (Cq), 169.5 (C⚌O) ppm. C21H23NO6S (417,12): calcd. C 60.42, H 5.55, N 3.36; found: C 60.61, H 5.32, N 3.47.
Acknowledgments
We thank COLCIENCIAS, Universidad del Valle (Project Number CI-7907), the Spanish “Consejería de Innovación, Ciencia y Empresa, Junta de Andalucía” and “Centro de Instrumentación Científico-Técnico de la Universidad de Jaén” for the financial support.
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Appendix A
Supplementary material
Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.arabjc.2016.11.016.
Appendix A
Supplementary material
Supplementary data 1
Supplementary data 1