Convenient Synthesis of 5-Arylidene-2-imino-4-thiazolidinone Derivatives Using Microwave Irradiation

Abstract

A concise approach for the preparation of 5-arylidene-2-imino-4-thiazolidinone derivatives is described. Structurally diverse amines, isothiocyanates, aldehydes, and chloroacetyl chloride were combined under microwave irradiation to afford new 5-arylidene-2-imino-4-thiazolidinone derivatives. The one-pot synthesis involves the in situ formation of a thiourea followed by reaction with chloroacetyl chloride and an aldehyde to generate the target compounds.

The thiazolidin-4-one scaffold is found in a large number of heterocyclic compounds with a wide variety of biological properties.[1] [2] In particular, 5-arylidene-2-imino-4-thiazolidinone derivatives I have been identified as antimicrobial,[3–5] anti-inflammatory,[5] [6] [7] antibacterial,[8] [9] [10] antihypertensive,[11] antithrombotic,[12] [13] and anticancer agents[14] [15] (Figure [1]). Finally, ponesimod, which is a selective agonist of the S1P₁ receptor, has completed phase II trials for multiple sclerosis treatment.[16] [17] [18] Only a few compounds of type II bearing identical substituents on the imino group and at position 3 of the thiazolidin-4-one ring have been described in the literature. For example, thiazolidinone IIa has been reported to exhibit bacterial antibiofilm activity,[19] and derivative IIb was identified as an inhibitor of PTPMT1 phosphatase activity[20] (Figure [1]).

Synthesis of 5-arylidene-2-iminothiazolidin-4-one derivatives has been widely explored and two routes are generally followed (Scheme [1]).[21] [22] Both synthetic pathways involve initial formation of the 2-iminothiazolidinone core followed by a Knoevenagel condensation. In the first procedure (A), the 2-iminothiazolidinone ring is obtained by cyclization of a thiourea in the presence of an α-haloacetic acid derivative. In this step, the nature of R¹ and R², the α-haloacetic acid derivative and the reaction conditions are crucial for the regioselectivity of the cyclization.

In case B, the condensation between a primary amine and chloroacetyl chloride leads to the formation of the corresponding amide derivative which can react with an isothiocyanate to afford the 2-iminothiazolidinone ring. In 2006, Kasmi-Mir et al. reported an attractive microwave synthesis of 5-arylidene-2-imino-4-thiazolidinones using a three-component reaction between N,N′-diarylthioureas, chloroacetic acid, and aldehydes under solvent-free conditions.[23] This strategy was also used by Abdel-Aziz et al.[24] However, in both cases, this approach was applied only to a very limited number of arylthioureas that were either prepared by the authors or were commercially available.

Herein, we report a convenient method for the synthesis of 5-arylidene-2-imino-4-thiazolidinones of type II bearing diversely substituted alkyl chains R¹ and R², using microwave irradiation. This sequential reaction, which utilizes readily available starting materials, is achieved in one-pot, reduces significantly the reaction time as well as solvent and reagent use.

Table 2 Synthesis of 2-Iminothiazolidin-4-ones 2–13 Using Different Aldehydes

Product	Aldehyde	Yield (%)a
2	4-MeSC6H4	55
3	4-MeC6H4	46
4	Ph	37
5	4-O2NC6H4	39
6	4-HO2CC6H4	29
7	4-MeO2SC6H4	28
8	3,4-Cl2C6H3	48
9	3-MeOC6H4	47
10	3-O2NC6H4	28
11	2-MeOC6H4	30
12	1-naphthyl	42
13	5-phenyl-2-furyl	51

^a Isolated yield.

To this end, the reaction conditions of a model reaction were tested using 4-methoxybenzylamine and its corresponding isothiocyanate, chloroacetyl chloride, and 4-methoxybenzaldehyde as the starting materials (Scheme [2]).

Ethanol was chosen as the solvent and sodium acetate as the base for the Knoevenagel condensation. To avoid reaction between the amine and chloroacetyl chloride, we decided to achieve initial preparation of the thiourea intermediate. For this model reaction, formation of the thiourea starting from 4-methoxybenzylamine and its corresponding isothiocyanate was complete within 20 minutes at room temperature which allowed the subsequent addition of sodium acetate, chloroacetyl chloride, and 4-methoxybenzaldehyde in the reaction vial.

In a first trial, the suspension was heated at 120 °C for 15 minutes under microwave irradiation, when thiazolidinone 1 was obtained in 39% yield (Table [1], entry 1).

Increasing the reaction time to 20 and 30 minutes resulted in only a slight increase in yield [Table [1], entries 2 (45%) and 3 (43%), respectively]. In these cases, the 3-(4-methoxybenzyl)-2-(4-methoxybenzylimino)-thiazolidin-4-one intermediate and unreacted aldehyde were observed at the end of the reaction. This indicated that the Knoevenagel condensation was the limiting step of the reaction. All the following reactions were then performed for 20 minutes. An excess of 4-methoxybenzaldehyde (2 equiv) was used which afforded product 1 with a comparable yield (48%, Table [1], entry 4). The use of molecular sieves or MgSO₄ to trap water released from Knoevenagel condensation also did not increase the yield (Table [1], entries 5 and 6).The temperature was then screened (Table [1], entries 7–9) with the yield varying from 34–45% (Table [1], entry 2) at elevated temperatures. In addition, the reaction was conducted under classical heating conditions. After refluxing for seven hours, the desired compound 1 was isolated in 23% yield (Table [1], entry 10). Thus, the optimal reaction time and temperature were set at 20 minutes and 120 °C (Table [1], entry 2). The effect of the base was then examined. Increasing amounts of NaOAc decreased the yield (Table [1], entries 11 and 12) as well as the absence of a base. Other solvents such as methanol, THF, or dioxane were used (Table [1], entries 14–16). In the case of methanol, the 27% yield may be due to a higher solubility of the product in this solvent. Finally, solvent-free conditions did not lead to the formation of the expected thi­azolidinone 1 (Table [1], entry 17).

The scope of the multicomponent reaction was then extended to a variety of substituted aldehydes using the optimized conditions.[25] As described in Table [2, a] subseries of new 5-arylidene-2-iminothiazolidin-4-one derivatives (compounds 2–13) was synthesized. The presence of other electron-donating substituents at position 4 of the phenyl moiety was also well tolerated and afforded thiazolidinones 2 and 3 in 55% and 46% yields, respectively.

Yields decreased when substituents with electron-withdrawing properties were introduced (compounds 5–7) while product 8 with two chlorine substituents was isolated in a better yield (48%). In the case of substituents at the meta position of the phenyl ring (compounds 9 and 10), a similar profile was observed. Finally, the multicomponent reaction could also be applied to other aryl aldehydes such as 1-naphthaldehyde and 5-phenyl-2-furaldehyde which afforded compounds 12 and 13 in 42% and 51% yields, respectively.

Different amines and their corresponding isothiocyanates were then tested in the presence of 4-methoxybenzaldehyde, 5-phenyl-2-furaldehyde, or 4-methylthiobenzaldehyde. Ten new compounds were obtained with yields between 22% and 57% (Figure [2]). In the case of the benzylamines/isothiocyanates, the presence of electron-withdrawing groups at position 3 afforded compounds 18 and 19 in lower yields. The multicomponent reaction could also be applied to alkylamines and their corresponding isothiocyanates to afford compounds 20–23 with yields between 29% and 46%. It is to be noted that microwave irradiation was also used to allow a rapid and complete formation of the thiourea for the preparation of compounds 18–20 and 23.

Finally, all 5-arylidene-thiazolidinones 1–23 were obtained as a single isomer. The formation of the thermodynamically stable Z isomer was confirmed by the chemical shift of the methine proton, which was comparable to reported data for analogous derivatives.[26] [27] [28] [29]

In summary, we have described the synthesis of new 5-arylidene-2-iminothiazolidin-4-one derivatives using a one-pot sequential reaction. Microwave irradiation has been used, leading to shorter reaction times and higher yields. This strategy gives an easy access to a series of structurally diverse thiazolidinone compounds. Moreover, it affords, under simple conditions, access to quantities sufficient (50–130 mg) for preliminary evaluation on a panel of biological tests. Finally, this approach could be extended to the preparation of other 5-arylidene-2-iminothiazolidin-4-ones.

Acknowledgment

The authors would like to thank the research group of Dr Christine Gravier-Pelletier for allowing us to use their CEM microwave apparatus and especially Dr Laurent Le Corre for helpful discussions. This work has benefited from the facilities and expertise of the Small Molecule Mass Spectrometry platform of IMAGIF (Centre de Recherche de Gif - http://www.imagif.cnrs.fr/).

• References and Notes

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• 8 Felise HB, Nguyen HV, Pfuetzner RA, Barry KC, Jackson SR, Blanc MP, Bronstein PA, Kline T, Miller SI. Cell Host Microbe 2008; 4: 325
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• 9 Kline T, Felise HB, Barry KC, Jackson SR, Nguyen HV, Miller SI. J. Med. Chem. 2008; 51: 7065
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• 11 Bhandari SV, Bothara KG, Patil AA, Chitre TS, Sarkate AP, Gore ST, Dangre SC, Khachane CV. Bioorg. Med. Chem. 2009; 17: 390
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• 12 Kato Y, Kita Y, Hirasawa-Taniyama Y, Nishio M, Mihara K, Ito K, Yamanaka T, Seki J, Miyata S, Mutoh S. Eur. J. Pharmacol. 2003; 473: 163
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• 13 Kato Y, Kita Y, Nishio M, Hirasawa Y, Ito K, Yamanaka T, Motoyama Y, Seki J. Eur. J. Pharmacol. 1999; 384: 197
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• 14 Havrylyuk D, Mosula L, Zimenkovsky B, Vasylenko O, Gzella A, Lesyk R. Eur. J. Med. Chem. 2010; 45: 5012
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• 15 Zhou H, Wu S, Zhai S, Liu A, Sun Y, Li R, Zhang Y, Ekins S, Swaan PW, Fang B, Zhang B, Yan B. J. Med. Chem. 2008; 51: 1242
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• 16 Bolli MH, Abele S, Binkert C, Bravo R, Buchmann S, Bur D, Gatfield J, Hess P, Kohl C, Mangold C, Mathys B, Menyhart K, Müller C, Nayler O, Scherz M, Schmidt G, Sippel V, Steiner B, Strasser D, Treiber A, Weller T. J. Med. Chem. 2010; 53: 4198
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• 17 Bolli M, Sherz M. WO 054215, 2005
• 18 Piali L, Froidevaux S, Hess P, Nayler O, Bolli MH, Schlosser E, Kohl C, Steiner B, Clozel M. J. Pharmacol. Exp. Ther. 2011; 337: 547
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• 19 Pan B, Huang RZ, Han SQ, Qu D, Zhu ML, Wei P, Ying HJ. Bioorg. Med. Chem. Lett. 2010; 20: 2461
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• 20 Park H, Kim SY, Kyung A, Yoon TS, Ryu SE, Jeong DG. Bioorg. Med. Chem. Lett. 2012; 22: 1271
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• 21 Brown FC. Chem. Rev. 1961; 61: 463
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• 23 Kasmi-Mir S, Djafri A, Paquin L, Hamelin J, Rahmouni M. Molecules 2006; 11: 597
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• 24 Abdel Aziz HA, El-Zahabi HS. A, Dawood KM. Eur. J. Med. Chem. 2010; 45: 2427
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• 25 Optimized Procedure for the Synthesis of 5-Arylidene-2-aryliminothiazolidin-4-ones In a 10 mL reaction vial, the amine (0.5 mmol) was added to a solution of isothiocyanate (0.5 mmol) in absolute EtOH (1 mL). The formation of the thiourea was achieved either at r.t. or by irradiating the reaction mixture for the duration indicated for each compound at a maximum power of 90 W and 120 °C. Anhydrous NaOAc (61.5 mg, 1.5 equiv), chloroacetyl chloride (59.7 μL, 1.5 equiv), and aldehyde (1 equiv) were added successively. The reaction mixture was then irradiated for 20 min at a maximum power of 30 W and 120 °C. The precipitate was filtered and dissolved in CH₂Cl_2. The organic phase was washed with H₂O and brine, dried over Na₂SO₄, and concentrated in vacuo. Either crystallization from EtOH or purification by flash chromatography afforded the corresponding 5-arylidene-2-aryliminothiazolidin-4-ones.
• 26 Sarkis M, Tran DN, Kolb S, Miteva MA, Villoutreix BO, Garbay C, Braud E. Bioorg. Med. Chem. Lett. 2012; 22: 7345
  CrossrefSearch in Google Scholar
• 27 Bourahla K, Dercour A, Rahmouni M, Carreaux F, Bazureau JP. Tetrahedron Lett. 2007; 48: 5785
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• 29 Selected Analytical Data Compound 1: pale yellow solid (106 mg, 45%); mp 143–145 °C. ¹H NMR (250 MHz, CDCl₃): δ = 3.81 (s, 3 H, CH₃), 3.84 (s, 3 H, CH₃), 3.88 (s, 3 H, CH₃), 4.60 (s, 2 H, CH₂), 5.04 (s, 2 H, CH₂), 6.84 (d, 2 H, J = 6.2 Hz, ArH), 6.91 (d, 2 H, J = 6.5 Hz, ArH), 7.00 (d, 2 H, J = 6.5 Hz, ArH), 7.26 (d, 2 H, J = 6.2 Hz, ArH), 7.47 (d, 2 H, J = 6.5 Hz, ArH), 7.51 (d, 2 H, J = 6.5 Hz, ArH), 7.73 (s, 1 H, C=CH). ¹³C NMR (63 MHz, CDCl₃): δ = 45.5, 55.2, 55.3, 55.4, 55.8, 113.7 (2 C), 113.8 (2 C), 114.5 (2 C), 118.8, 126.6, 128.6 (2 C), 128.8, 130.0, 130.5 (2 C), 131.3, 131.8 (2 C), 149.0, 158.6, 159.2, 160.7, 166.9. IR: ν = 2951, 2829, 1697, 1644, 1615, 1599, 1509, 1468, 1443, 1426, 1380, 1338, 1297, 1249, 1173, 1163, 1117, 1106, 1032 cm^–1. ESI-HRMS: m/z calcd for C₂₇H₂₇N₂O₄S [M + H]⁺: 475.1692; found: 475.1707. Compound 2: yellow solid (134 mg, 55%); mp 169–170 °C. ¹H NMR (250 MHz, CDCl₃): δ = 2.54 (s, 3 H, CH₃), 3.81 (s, 3 H, CH₃), 3.84 (s, 3 H, CH₃), 4.61 (s, 2 H, CH₂), 5.05 (s, 2 H, CH₂), 6.84 (d, 2 H, J = 6.5 Hz, ArH), 6.91 (d, 2 H, J = 6.5 Hz, ArH), 7.25–7.33 (m, 4 H, ArH), 7.47 (d, 2 H, J = 8.0 Hz, ArH), 7.71 (s, 1 H, C=CH). ¹³C NMR (63 MHz, DMSO-d ₆): δ = 16.5, 47.1, 56.7, 56.8, 57.2, 115.1 (2 C), 115.3 (2 C), 121.8, 127.4 (2 C), 130.0 (2 C), 130.1, 131.0, 131.7 (2 C), 131.8, 131.9 (2 C), 132.5, 143.0, 150.2, 160.1, 160.6, 168.1. IR: ν = 2840, 1698, 1646, 1610, 1585, 1513, 1497, 1467, 1423, 1403, 1380, 1331, 1295, 1248, 1171, 1162, 1092, 1072, 1041, 1030 cm^–1. ESI-HRMS: m/z calcd for C₂₇H₂₇N₂O₃S₂ [M + H]⁺: 491.1463; found: 491.1440. Compound 13: yellow solid (130 mg, 51%); mp 141–143 °C. ¹H NMR (250 MHz, CDCl₃): δ = 3.81 (s, 3 H, OCH₃), 3.84 (s, 3 H, OCH₃), 4.66 (s, 2 H, C=NCH₂), 5.05 (s, 2 H, NCH₂), 6.84–6.94 (m, 6 H, ArH), 7.29–7.55 (m, 8 H, ArH and C=CH), 7.78 (d, 2 H, J = 6.8 Hz, ArH). ¹³C NMR (63 MHz, CDCl₃): δ = 45.5, 55.2, 55.3, 55.5, 108.3, 113.7 (2 C), 113.8 (2 C), 116.2, 118.3, 119.0, 124.3 (2 C), 128.5, 128.7 (2 C), 128.9 (2 C), 129.0, 129.6, 130.3, 130.4 (2 C), 131.4, 149.7, 156.9, 158.7, 159.1, 166.4. IR: ν = 2924, 2851, 1728, 1697, 1678, 1647, 1608, 1510, 1439, 1415, 1379, 1328, 1289, 1244, 1163, 1110, 1088, 1029 cm^–1. ESI-HRMS: m/z calcd for C₃₀H₂₇N₂O₄S [M + H]⁺: 511.1685; found: 511.1694. Compound 21: yellow solid (52 mg, 29%); mp 68 °C. ¹H NMR (250 MHz, CDCl₃): δ = 0.94–1.01 (m, 6 H, 2 × CH₃), 1.34–1.49 (m, 4 H, 2 × CH₂), 1.63–1.74 (m, 4 H, 2 × CH₂), 2.54 (s, 3 H, SCH₃), 3.42 (t, 2 H, J = 6.8 Hz, C=NCH₂), 3.87 (t, 2 H, J = 7.2 Hz, NCH₂), 7.30 (d, 2 H, J = 8.5 Hz, H_ar), 7.47 (d, 2 H, J = 8.5 Hz, H_ar), 7.66 (s, 1 H, C=CH). ¹³C NMR (63 MHz, CDCl₃): δ = 13.7, 13.9, 15.1, 20.0, 20.5, 29.5, 32.8, 42.8, 52.9, 120.9, 126.0 (2 C), 128.6, 130.2 (2 C), 130.6, 141.1, 147.3, 166.9. IR: ν = 2952, 2851, 2817, 1706, 1641, 1602, 1586, 1490, 1429, 1381, 1295, 1261, 1198, 1116, 1090, 1009 cm^–1. ESI-HRMS: m/z calcd for C₁₉H₂₇N₂OS₂ [M + H]⁺: 363.1559; found: 363.1559

• References and Notes

• 1 Verma A, Saraf SK. Eur. J. Med. Chem. 2008; 43: 897
  CrossrefPubMedSearch in Google Scholar
• 2 Mengden T, Steuer C, Klein CD. J. Med. Chem. 2012; 55: 743
  CrossrefSearch in Google Scholar
• 3 Vicini P, Geronikaki A, Anastasia K, Incerti M, Zani F. Bioorg. Med. Chem. 2006; 14: 3859
  CrossrefSearch in Google Scholar
• 4 Vicini P, Geronikaki A, Incerti M, Zani F, Dearden J, Hewitt M. Bioorg. Med. Chem. 2008; 16: 3714
  CrossrefPubMedSearch in Google Scholar
• 5 Apostolidis I, Liaras K, Geronikaki A, Hadjipavlou-Litina D, Gavalas A, Sokovic M, Glamoclija J, Ciric A. Bioorg. Med. Chem. 2013; 21: 532
  CrossrefSearch in Google Scholar
• 6 Ottanà R, Maccari R, Barreca ML, Bruno G, Rotondo A, Rossi A, Chiricosta G, Di Paola R, Sautebin L, Cuzzocrea S, Vigorita MG. Bioorg. Med. Chem. 2005; 13: 4243
  CrossrefPubMedSearch in Google Scholar
• 7 Ottanà R, Maccari R, Ciurleo R, Vigorita MG, Panico AM, Cardile V, Garufi F, Ronsisvalle S. Bioorg. Med. Chem. 2007; 15: 7618
  CrossrefSearch in Google Scholar
• 8 Felise HB, Nguyen HV, Pfuetzner RA, Barry KC, Jackson SR, Blanc MP, Bronstein PA, Kline T, Miller SI. Cell Host Microbe 2008; 4: 325
  CrossrefSearch in Google Scholar
• 9 Kline T, Felise HB, Barry KC, Jackson SR, Nguyen HV, Miller SI. J. Med. Chem. 2008; 51: 7065
  CrossrefSearch in Google Scholar
• 10 He L, Zhang L, Liu X, Li X, Zheng M, Li H, Yu K, Chen K, Shen X, Jiang H, Liu H. J. Med. Chem. 2009; 52: 2465
  CrossrefSearch in Google Scholar
• 11 Bhandari SV, Bothara KG, Patil AA, Chitre TS, Sarkate AP, Gore ST, Dangre SC, Khachane CV. Bioorg. Med. Chem. 2009; 17: 390
  CrossrefSearch in Google Scholar
• 12 Kato Y, Kita Y, Hirasawa-Taniyama Y, Nishio M, Mihara K, Ito K, Yamanaka T, Seki J, Miyata S, Mutoh S. Eur. J. Pharmacol. 2003; 473: 163
  CrossrefSearch in Google Scholar
• 13 Kato Y, Kita Y, Nishio M, Hirasawa Y, Ito K, Yamanaka T, Motoyama Y, Seki J. Eur. J. Pharmacol. 1999; 384: 197
  CrossrefPubMedSearch in Google Scholar
• 14 Havrylyuk D, Mosula L, Zimenkovsky B, Vasylenko O, Gzella A, Lesyk R. Eur. J. Med. Chem. 2010; 45: 5012
  CrossrefSearch in Google Scholar
• 15 Zhou H, Wu S, Zhai S, Liu A, Sun Y, Li R, Zhang Y, Ekins S, Swaan PW, Fang B, Zhang B, Yan B. J. Med. Chem. 2008; 51: 1242
  CrossrefSearch in Google Scholar
• 16 Bolli MH, Abele S, Binkert C, Bravo R, Buchmann S, Bur D, Gatfield J, Hess P, Kohl C, Mangold C, Mathys B, Menyhart K, Müller C, Nayler O, Scherz M, Schmidt G, Sippel V, Steiner B, Strasser D, Treiber A, Weller T. J. Med. Chem. 2010; 53: 4198
  CrossrefPubMedSearch in Google Scholar
• 17 Bolli M, Sherz M. WO 054215, 2005
• 18 Piali L, Froidevaux S, Hess P, Nayler O, Bolli MH, Schlosser E, Kohl C, Steiner B, Clozel M. J. Pharmacol. Exp. Ther. 2011; 337: 547
  CrossrefSearch in Google Scholar
• 19 Pan B, Huang RZ, Han SQ, Qu D, Zhu ML, Wei P, Ying HJ. Bioorg. Med. Chem. Lett. 2010; 20: 2461
  CrossrefSearch in Google Scholar
• 20 Park H, Kim SY, Kyung A, Yoon TS, Ryu SE, Jeong DG. Bioorg. Med. Chem. Lett. 2012; 22: 1271
  CrossrefSearch in Google Scholar
• 21 Brown FC. Chem. Rev. 1961; 61: 463
  CrossrefSearch in Google Scholar
• 22 Singh SP, Parmar SS, Raman K, Stenberg VI. Chem. Rev. 1981; 81: 175
  CrossrefSearch in Google Scholar
• 23 Kasmi-Mir S, Djafri A, Paquin L, Hamelin J, Rahmouni M. Molecules 2006; 11: 597
  CrossrefSearch in Google Scholar
• 24 Abdel Aziz HA, El-Zahabi HS. A, Dawood KM. Eur. J. Med. Chem. 2010; 45: 2427
  CrossrefSearch in Google Scholar
• 25 Optimized Procedure for the Synthesis of 5-Arylidene-2-aryliminothiazolidin-4-ones In a 10 mL reaction vial, the amine (0.5 mmol) was added to a solution of isothiocyanate (0.5 mmol) in absolute EtOH (1 mL). The formation of the thiourea was achieved either at r.t. or by irradiating the reaction mixture for the duration indicated for each compound at a maximum power of 90 W and 120 °C. Anhydrous NaOAc (61.5 mg, 1.5 equiv), chloroacetyl chloride (59.7 μL, 1.5 equiv), and aldehyde (1 equiv) were added successively. The reaction mixture was then irradiated for 20 min at a maximum power of 30 W and 120 °C. The precipitate was filtered and dissolved in CH₂Cl_2. The organic phase was washed with H₂O and brine, dried over Na₂SO₄, and concentrated in vacuo. Either crystallization from EtOH or purification by flash chromatography afforded the corresponding 5-arylidene-2-aryliminothiazolidin-4-ones.
• 26 Sarkis M, Tran DN, Kolb S, Miteva MA, Villoutreix BO, Garbay C, Braud E. Bioorg. Med. Chem. Lett. 2012; 22: 7345
  CrossrefSearch in Google Scholar
• 27 Bourahla K, Dercour A, Rahmouni M, Carreaux F, Bazureau JP. Tetrahedron Lett. 2007; 48: 5785
  CrossrefSearch in Google Scholar
• 28 Sing WT, Lee CL, Yeo SL, Lim SP, Sim MM. Bioorg. Med. Chem. Lett. 2001; 11: 91
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• 29 Selected Analytical Data Compound 1: pale yellow solid (106 mg, 45%); mp 143–145 °C. ¹H NMR (250 MHz, CDCl₃): δ = 3.81 (s, 3 H, CH₃), 3.84 (s, 3 H, CH₃), 3.88 (s, 3 H, CH₃), 4.60 (s, 2 H, CH₂), 5.04 (s, 2 H, CH₂), 6.84 (d, 2 H, J = 6.2 Hz, ArH), 6.91 (d, 2 H, J = 6.5 Hz, ArH), 7.00 (d, 2 H, J = 6.5 Hz, ArH), 7.26 (d, 2 H, J = 6.2 Hz, ArH), 7.47 (d, 2 H, J = 6.5 Hz, ArH), 7.51 (d, 2 H, J = 6.5 Hz, ArH), 7.73 (s, 1 H, C=CH). ¹³C NMR (63 MHz, CDCl₃): δ = 45.5, 55.2, 55.3, 55.4, 55.8, 113.7 (2 C), 113.8 (2 C), 114.5 (2 C), 118.8, 126.6, 128.6 (2 C), 128.8, 130.0, 130.5 (2 C), 131.3, 131.8 (2 C), 149.0, 158.6, 159.2, 160.7, 166.9. IR: ν = 2951, 2829, 1697, 1644, 1615, 1599, 1509, 1468, 1443, 1426, 1380, 1338, 1297, 1249, 1173, 1163, 1117, 1106, 1032 cm^–1. ESI-HRMS: m/z calcd for C₂₇H₂₇N₂O₄S [M + H]⁺: 475.1692; found: 475.1707. Compound 2: yellow solid (134 mg, 55%); mp 169–170 °C. ¹H NMR (250 MHz, CDCl₃): δ = 2.54 (s, 3 H, CH₃), 3.81 (s, 3 H, CH₃), 3.84 (s, 3 H, CH₃), 4.61 (s, 2 H, CH₂), 5.05 (s, 2 H, CH₂), 6.84 (d, 2 H, J = 6.5 Hz, ArH), 6.91 (d, 2 H, J = 6.5 Hz, ArH), 7.25–7.33 (m, 4 H, ArH), 7.47 (d, 2 H, J = 8.0 Hz, ArH), 7.71 (s, 1 H, C=CH). ¹³C NMR (63 MHz, DMSO-d ₆): δ = 16.5, 47.1, 56.7, 56.8, 57.2, 115.1 (2 C), 115.3 (2 C), 121.8, 127.4 (2 C), 130.0 (2 C), 130.1, 131.0, 131.7 (2 C), 131.8, 131.9 (2 C), 132.5, 143.0, 150.2, 160.1, 160.6, 168.1. IR: ν = 2840, 1698, 1646, 1610, 1585, 1513, 1497, 1467, 1423, 1403, 1380, 1331, 1295, 1248, 1171, 1162, 1092, 1072, 1041, 1030 cm^–1. ESI-HRMS: m/z calcd for C₂₇H₂₇N₂O₃S₂ [M + H]⁺: 491.1463; found: 491.1440. Compound 13: yellow solid (130 mg, 51%); mp 141–143 °C. ¹H NMR (250 MHz, CDCl₃): δ = 3.81 (s, 3 H, OCH₃), 3.84 (s, 3 H, OCH₃), 4.66 (s, 2 H, C=NCH₂), 5.05 (s, 2 H, NCH₂), 6.84–6.94 (m, 6 H, ArH), 7.29–7.55 (m, 8 H, ArH and C=CH), 7.78 (d, 2 H, J = 6.8 Hz, ArH). ¹³C NMR (63 MHz, CDCl₃): δ = 45.5, 55.2, 55.3, 55.5, 108.3, 113.7 (2 C), 113.8 (2 C), 116.2, 118.3, 119.0, 124.3 (2 C), 128.5, 128.7 (2 C), 128.9 (2 C), 129.0, 129.6, 130.3, 130.4 (2 C), 131.4, 149.7, 156.9, 158.7, 159.1, 166.4. IR: ν = 2924, 2851, 1728, 1697, 1678, 1647, 1608, 1510, 1439, 1415, 1379, 1328, 1289, 1244, 1163, 1110, 1088, 1029 cm^–1. ESI-HRMS: m/z calcd for C₃₀H₂₇N₂O₄S [M + H]⁺: 511.1685; found: 511.1694. Compound 21: yellow solid (52 mg, 29%); mp 68 °C. ¹H NMR (250 MHz, CDCl₃): δ = 0.94–1.01 (m, 6 H, 2 × CH₃), 1.34–1.49 (m, 4 H, 2 × CH₂), 1.63–1.74 (m, 4 H, 2 × CH₂), 2.54 (s, 3 H, SCH₃), 3.42 (t, 2 H, J = 6.8 Hz, C=NCH₂), 3.87 (t, 2 H, J = 7.2 Hz, NCH₂), 7.30 (d, 2 H, J = 8.5 Hz, H_ar), 7.47 (d, 2 H, J = 8.5 Hz, H_ar), 7.66 (s, 1 H, C=CH). ¹³C NMR (63 MHz, CDCl₃): δ = 13.7, 13.9, 15.1, 20.0, 20.5, 29.5, 32.8, 42.8, 52.9, 120.9, 126.0 (2 C), 128.6, 130.2 (2 C), 130.6, 141.1, 147.3, 166.9. IR: ν = 2952, 2851, 2817, 1706, 1641, 1602, 1586, 1490, 1429, 1381, 1295, 1261, 1198, 1116, 1090, 1009 cm^–1. ESI-HRMS: m/z calcd for C₁₉H₂₇N₂OS₂ [M + H]⁺: 363.1559; found: 363.1559

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