Heteroatom Chemistry

Heteroatom Chemistry / 2020 / Article

Research Article | Open Access

Volume 2020 |Article ID 5945796 | https://doi.org/10.1155/2020/5945796

Hassan Kabirifard, Pardis Hafez Taghva, Hossein Teimouri, Niloofar Koosheshi, Parastoo Javadpour, Hanieh Bagherinejad, Soheila Seyfi, Maryam Hossein Roodbari, Elaheh Golabian, "Synthesis of Organic Ligands via Reactions of 4-Benzoyl-5-phenylamino-2,3-dihydrothiophene-2,3-dione with N-Nucleophiles", Heteroatom Chemistry, vol. 2020, Article ID 5945796, 9 pages, 2020. https://doi.org/10.1155/2020/5945796

Synthesis of Organic Ligands via Reactions of 4-Benzoyl-5-phenylamino-2,3-dihydrothiophene-2,3-dione with N-Nucleophiles

Academic Editor: Mariateresa Giustiniano
Received05 Mar 2020
Accepted10 Jun 2020
Published08 Jul 2020

Abstract

The reaction of 4-benzoyl-5-phenylamino-2,3-dihydrothiophene-2,3-dione (1) with aminoheteroaryls, lamotrigine, 1,3-diaminoheteroaryls, dapsone, NH2R (hydroxylamine, DL-1-phenylethylamine, and metformin), and 4,4′-bipyridine in THF/H2O (1 : 1) at room temperature led to 3-N-phenylthiocarbamoyl-2-butenamides 25, while that with naphthylamines and 1,3-phenylenediamine in ethanol at high temperature led to 5-phenylamino-2,5-dihydrothiophene-2-ones 68 as organic ligands in the medium to good yields. These showed the nucleophilic attacks of N-nucleophiles, except primary aromatic amines, on thioester carboxyl group (C-2) of thiophene-2,3-dione ring 1. However, the nucleophilic attacks of primary aromatic amines on the carbonyl group (C-3) of thiophene-2,3-dione 1 occurred in the form of substituted thiophenes.

1. Introduction

Lamotrigine (3,5-diamino-6-(2,3-dichlorophenyl)-1,2,4-triazine) is a member of the phenyltriazine drug category. This category has its main utility in the adjunctive treatment of partial seizures in epilepsy and generalized seizures of Lennox-Gastaut syndrome [14]. Maintenance treatment of bipolar I disorder and depression is an additional important use of the phenyltriazine category [5, 6]. Metformin (N,N-dimethylimidodicarbonimidic diamide) is a member of the biguanide class of compound. Currently, metformin is a US Food and Drug Administration approved drug for the first-line treatment of type 2 diabetes [79]. The United Kingdom Prospective Diabetic Study (UKPDS) has shown metformin to improve mortality rates in diabetes patients. Moreover, recent studies suggest metformin has additional utility. Positive effects have been noted in treating cancer, obesity, nonalcoholic fatty liver disease (NAFLD), polycystic ovary syndrome (PCOS), and metabolic syndrome [10]. Metformin has also been shown to alleviate weight gain associated with antipsychotic medication [11]. Dapsone (4,4′-diaminodiphenylsulfone) is structurally one of the simplest sulphones, yet, it is also recognized as an active therapeutic agent from this important family of compounds. As an antibiotic, dapsone is active against bacteria and protozoa by inhibiting dihydrofolic acid synthesis. This inhibition is mediated through dapsone competition with para-aminobenzoate for the active site of dihydropteroate synthase [12]. Furthermore, dapsone has been successfully used as an indispensable component for the treatment and prophylaxis of leprosy, actinomycetoma, Pneumocystis pneumonia, and malaria [13].

Recently, effective methods for the synthesis of 4-acylated-5-substituted thiophene-2,3-diones through acylation of 3-oxo-N-phenyl-3-alkyl/aryl-propanethioamides [14] or methyl 3-oxo-3-arylpropanedithioates [15] by oxalyl chloride at the S atom and the active methylene group have been reported. However, we find the synthesis of 4-benzoyl-5-phenylamino-2,3-dihydrothiophene-2,3-dione (1) from the addition of ethyl benzoylpyruvate to phenyl isothiocyanate and KOH in DMF with stirring at room temperature [16]. In addition, 4-acylated-5-substituted thiophene-2,3-diones are feasible and beneficial intermediates for the synthesis of a vast variety of substituted heterocyclic compounds [1719]. In addition, 4-benzoyl-5-phenylamino-2,3-dihydrothiophene-2,3-dione (1) has been recognized as a particularly significant starting material or intermediate for the synthesis of diverse sulfur- and nitrogen-containing heterocyclic compounds [16, 2023]. In the previous study, we found that the reactions of 4-benzoyl-5-phenylamino-2,3-dihydrothiophene-2,3-dione (1) with N-nucleophiles such as primary and secondary aliphatic amines and tertiary aromatic and aliphatic amines in THF/H2O (1 : 1) at room temperature gave amide derivatives that have N-phenylthiocarbamoyl group [20] while those with primary aromatic amines in ethanol at high temperature provided substituted thiophenes [16] (Scheme 1). Regarding the significance and application of the corresponding amide and thiophene derivatives as an organic ligand [2427], in the current study, we have achieved the reactions of 1 with aminoheteroaromatics, N-nucleophiles cum medicinal properties such as lamotrigine, dapsone, and metformin, and primary aromatic amines such as naphthylamines and 1,3-phenylenediamine for the first time (Scheme 2 and Scheme 3).

2. Materials and Methods

2.1. General Information

The reagents were purchased from Merck and used without further purification. Melting points were measured with an Electrothermal 9100 apparatus and are uncorrected. Elemental analyses were performed using a Heraeus CHN-O-Rapid analyzer. These results agree favorably with the calculated values. Infrared spectra were measured from KBr disk using a Thermo Nicolet 8700 FT-IR spectrometer and frequencies were reported in cm−1. 1H NMR and 13C NMR spectra were recorded on a Bruker DRX-300 AVANCE instrument at 300 and 75 MHz, respectively, using TMS as internal standard and DMSO-d6 or CDCl3 as solvent. Chemical shifts and coupling constants were reported in ppm and Hz, respectively. Thin-layer chromatography was performed on “Silufol-UV 254” plates. Mass spectra were obtained by using an Agilent HP 5973 mass spectrometer operating at an ionization potential of 70 eV.

2.2. Materials

Ethyl benzoylpyruvate was prepared from diethyl oxalate (6.0 mmol) and acetophenone (4.0 mmol) in the presence of sodium ethoxide (8.4 mmol) in absolute ethanol (30 mL) under N2 atmosphere [28]. 4-Benzoyl-5-phenylamino-2,3-dihydrothiophene-2,3-dione (1) was obtained by careful addition of phenyl isothiocyanate (10 mmol) to benzoylpyruvate (10 mmol) in KOH (10 mmol) and DMF (20 mL) with stirring for 24 h at room temperature [16].

2.3. Reactions of Compound 1 with Amines
2.3.1. General Procedure

To a stirred solution of 1 (0.309 g, 1.0 mmol) in THF/H2O (1 : 1, 10 mL) at room temperature or ethanol (10 mL) at 70°C was added either aminopyridines, lamotrigine, hydroxylamine, DL-1-phenylethylamine, metformin, and 1-naphthylamine (1.0 mmol), or 2,6-diaminopyridine, 2,4-diamino-6-phenyl-1,3,5-triazine, 2,4,6-triamino-1,3,5-triazine, 4,6-diamino-2-mercaptopyrimidine, dapsone, 4,4′-bipyridine, 1,5-naphthalenediamine, and 1,3-phenylenediamine (0.5 mmol). The reaction mixture was then stirred for 6 h. The progress of the reaction was determined by TLC (eluent AcOEt/hexane 4 : 1). The solid in THF/H2O (1 : 1) was separated by filtration (or the ethanol was evaporated) and then was crystallized from a suitable solvent (ethanol, 2-propanol, H2O or EtOH/H2O (1 : 1)) or was washed with EtOH/H2O (1 : 1) to give 28, respectively.

2.4. Characterization Data of the Compounds 28
2.4.1. (2E)-N-2-Pyridyl-2-hydroxy-4-oxo-4-phenyl-3-(N-phenylthiocarbamoyl)-2-butenamide (2a)

Brownish yellow powder (crystallized from ethanol); yield: 0.28 g (69%); mp 195°C–197°C; IR (KBr): 3436 (NH), 3050 (OH, enol), 1728 (C=O, amide), 1633 (C=O, ketone), 1619 (C=C), 1588 (NH), 1536, 1394, 1132 (C-N, NH, C=S, thioamide) cm−1; 1H NMR (DMSO-d6): δ 6.84 (1H, t, J = 6.7 Hz, CHmeta of C5H5N), 6.95 (1H, d, J = 8.8 Hz, CHmeta of C5H5N), 7.21 (2H, d, J = 7.5 Hz, 2CHortho of Ph-NH), 7.32–7.42 (6H, m, 2Ph), 7.43 (1H, t, J = 7.4 Hz, CHpara of C5H5N), 7.62 (2H, d, J = 7.4 Hz, 2CHortho of Ph-CO), 7.89 (2H, br s, OH, NH), 7.91 (1H, d, J = 6.9 Hz, CHortho of C5H5N), 12.24 (1H, br s, NH); 13C NMR (DMSO-d6): δ 112.1 (C3), 113.1 (=C), 113.3 (C5), 127.3, 127.4, 128.0, 128.9, 129.4, 130.6 (10C, 2Ph), 134.9 (Cipso of Ph-CO), 136.2 (C4), 140.7 (Cipso of Ph-NH), 144.0 (C6), 154.0 (C2), 163.2 (=C-OH), 172.9 (C=O, amide), 189.1 (C=S), 197.1 (C=O, ketone) ppm; EI-MS: m/z (%) = 403 (M+, 3), 309 (58), 280 (12), 252 (19), 220 (6), 162 (8), 105 (100), 77 (72), 51 (24). Anal. Calcd for C22H17N3O3S (403.45): C, 65.49%; H, 4.25%; N, 10.42%; found: C, 65.26%; H, 3.98%; N, 10.65%.

2.4.2. (2E)-N-4-Methyl-2-pyridyl-2-hydroxy-4-oxo-4-phenyl-3-(N-phenylthiocarbamoyl)-2-butenamide (2b)

Orange powder (crystallized from ethanol); yield: 0.30 g (71%); mp 202°C (decomposition); IR (KBr): 3414, 3309 (NH), 3061 (OH, enol), 2920 (CH, aliphatic), 1718 (C=O, amide), 1660 (C=O, ketone), 1626 (C=C), 1598 (NH), 1534, 1392, 1137 (C-N, NH, C=S, thioamide) cm−1; 1H NMR (CDCl3): δ 2.35 (3H, s, CH3), 6.55 (1H, d, J = 6.1 Hz, CHmeta of C5H5N), 6.86 (1H, s, CHmeta of C5H5N), 7.33 (2H, d, J = 7.3 Hz, 2CHortho of Ph-NH), 7.43–7.56 (6H and 1H, m, 2Ph and OH), 7.63 (2H, d, J = 7.4 Hz, 2CHortho of Ph-CO), 7.85 (1H, d, J = 6.1 Hz, CHortho of C5H5N), 7.86, 14.28 (2H, 2br s, 2NH); 13C NMR (CDCl3): δ 22.1 (CH3), 113.1 (=C), 114.5 (C3), 120.7 (C5), 128.0, 128.2, 128.6, 129.5, 129.8, 129.9 (10C, 2Ph), 134.1 (Cipso of Ph-CO), 139.2 (Cipso of Ph-NH), 154.4 (C6), 156.4 (C4), 160.1 (C2), 163.8 (=C-OH), 174.9 (C=O, amide), 189.2 (C=S), 200.0 (C=O, ketone) ppm; EI-MS: m/z (%) = 417 (M+, 3), 309 (10), 280 (3), 252 (5), 220 (3), 162 (3), 105 (93), 77 (100), 51 (38). Anal. Calcd for C23H19N3O3S (417.48): C, 66.17%; H, 4.59%; N, 10.07%; found: C, 65.95%; H, 4.78%; N, 10.31%.

2.4.3. N-5-Amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl-(2E)-2-hydroxy-4-oxo-4-phenyl-3-(N-phenylthiocarbamoyl)-2-butenamide (2c)

Orange powder (crystallized from 2-propanol); yield 0.42 g (74%); mp 236°C–238°C; IR (KBr): 3466, 3270, 3182 (NH), 1725 (C=O, amide), 1637 (C=O, ketone), 1595 (C=C), 1578 (NH), 1535, 1386, 1140 (C-N, NH, C=S, thioamide) cm−1; 1H NMR (DMSO-d6): δ 7.22 (2H, d, 3J = 7.3 Hz, 2CHortho of Ph-NH), 7.31–7.46 (6H, m, 2Ph), 7.52 (2H, 2d, 3J = 5.1 Hz, CHortho and CHpara of Ph-triazine), 7.63 (2H, d, 3J = 7.6 Hz, 2CHortho of Ph-CO), 7.82 (1H, t, 3J = 5.1 Hz, CHmeta of Ph-triazine), 8.19, 9.17, 13.75 (5H, 3br s, OH, 2NH, NH2); 13C NMR (DMSO-d6): δ 113.1 (=C), 127.4, 127.5, 128.1, 129.0, 129.1, 129.5, 130.6, 130.7, 131.3, 132.2, 132.4, 132.5 (16C, 3Ph), 134.9 (Cipso of Ph-CO), 138.5 (C6), 140.6 (Cipso of Ph-NH), 154.3 (C5), 155.9 (C3), 163.3 (=C-OH), 173.0 (C=O, amide), 189.2 (C=S), 197.2 (C=O, ketone) ppm; EI-MS: m/z (%) 551 (1), 495 (8), 368 (6), 309 (42), 280 (8), 255 (30), 220 (5), 185 (55), 105 (100), 77 (75), 43 (42). Anal. Calcd for C26H18Cl2N6O3S (565.43): C, 55.23; H, 3.21; N, 14.86. Found: C, 55.49; H, 2.98; N, 14.61.

2.4.4. 2,6-Bis((2E)-2-hydroxy-4-oxo-4-phenyl-3-(N-phenylthiocarbamoyl)-2-butenamido)pyridine (3a)

Yellowish orange powder (crystallized from ethanol); yield: 0.27 g (73%); mp 190°C–192°C; IR (KBr): 3481, 3391 (NH), 3050 (OH, enol), 1727 (C=O, amide), 1634 (C=O, ketone), 1596 (C=C), 1577 (NH), 1518, 1381, 1139 (C-N, NH, C=S, thioamide) cm−1; 1H NMR (DMSO-d6): δ 5.88 (2H, d, J = 8.2 Hz, 2CHmeta of C5H5N), 7.13 (2 (2H), br s, 2OH, 2NH), 7.22 (2 (2H), d, J = 7.6 Hz, 4CHortho of Ph-NH), 7.34–7.51 (2 (6H) and 1H, m, 4Ph and CHpara of C5H5N), 7.63 (2 (2H), d, J = 7.5 Hz, 4CHortho of Ph-CO), 12.06 (2 (1H), br s, 2NH); 13C NMR (DMSO-d6): δ 95.0 (C3 and C5), 113.1 (2=C), 127.3, 127.4, 128.1, 128.9, 129.4, 130.6 (2 (10C), 4Ph), 134.9 (2Cipso of Ph-CO), 140.6 (2Cipso of Ph-NH), 145.1 (C4), 151.9 (C2 and C6), 163.3 (2=C-OH), 172.8 (2C=O, amide), 189.1 (2C=S), 197.2 (2C=O, ketone) ppm; EI-MS: m/z (%) = 309 (64), 280 (13), 252 (21), 221 (7), 162 (9), 105 (100), 77 (86), 51 (27). Anal. Calcd for C39H29N5O6S2 (727.81): C, 64.36%; H, 4.02%; N, 9.62%; found: C, 64.58%; H, 3.88%; N, 9.84%.

2.4.5. 2,4-Bis((2E)-2-hydroxy-4-oxo-4-phenyl-3-(N-phenylthiocarbamoyl)-2-butenamido)-6-phenyl-1,3,5-triazine (3b)

Orange-yellow powder (crystallized from EtOH/H2O (1 : 1)); yield: 0.31 g (76%); mp 243°C (decomposition); IR (KBr): 3484, 3143 (NH), 1733, 1716 (C=O, amide), 1649 (C=O, ketone), 1618 (C=C), 1529, 1380, 1137 (C-N, NH, C=S, thioamide) cm−1; 1H NMR (DMSO-d6): δ 7.24 (2 (2H), d, J = 7.3 Hz, 4CHortho of Ph-NH), 7.33–7.49 (2 (6H), m, 4Ph), 7.62 (2H, t, J = 7.5 Hz, 2CHmeta of Ph-6-triazine), 7.68 (2 (2H), d, J = 7.2 Hz, 4CHortho of Ph-CO), 7.72 (1H, t, J = 7.5 Hz, CHpara of Ph-6-triazine), 8.09 (2H, d, J = 7.5 Hz, 2CHortho of Ph-6-triazine), 8.48 (2 (3H), br s, 2OH, 4NH); 13C NMR (DMSO-d6): δ 113.5 (2=C), 127.6, 127.7, 128.2, 128.3, 129.0, 129.1, 129.4, 130.6, 131.3 (25C, 5Ph), 133.9 (Cipso of Ph-6-triazine), 134.5 (2Cipso of Ph-CO), 139.7 (2Cipso of Ph-NH), 160.6 (C2 and C4), 163.1 (C6), 163.7 (2=C-OH), 170.1 (2C=O, amide), 189.0 (2C=S), 197.6 (2C=O, ketone) ppm; EI-MS: m/z (%) = 309 (39), 280 (9), 252 (16), 220 (5), 187 (50), 162 (6), 144 (10), 105 (100), 77 (95), 51 (27). Anal. Calcd for C43H31N7O6S2 (805.88): C, 64.09%; H, 3.88%; N, 12.17%; found: C, 64.28%; H, 4.05%; N, 11.96%.

2.4.6. 2,4-Bis((2E)-2-hydroxy-4-oxo-4-phenyl-3-(N-phenylthiocarbamoyl)-2-butenamido)-6-amino-1,3,5-triazine (3c)

Orange powder (crystallized from ethanol); yield: 0.29 g (79%); mp 225°C–227°C; IR (KBr): 3319, 3209 (NH), 1725, 1704 (C=O, amide), 1651 (C=O, ketone), 1579, 1396, 1143 (C-N, NH, C=S, thioamide) cm−1; 1H NMR (DMSO-d6): δ 7.22 (2 (2H), d, J = 7.3 Hz, 4CHortho of Ph-NH), 7.31–7.47 (2 (6H), m, 4Ph), 7.64 (2 (2H), d, J = 7.7 Hz, 4CHortho of Ph-CO), 7.67 (2 (3H) and 2H, br s, 2OH, 4NH, and NH2); 13C NMR (DMSO-d6): δ 113.2 (2=C), 127.5, 127.5, 128.2, 129.0, 129.4, 130.9 (2 (10C), 4Ph), 134.8 (2Cipso of Ph-CO), 140.4 (2Cipso of Ph-NH), 159.4 (C2 and C4), 160.2 (C6), 163.5 (2=C-OH), 172.2 (2C=O, amide), 189.2 (2C=S), 197.4 (2C=O, ketone) ppm; EI-MS: m/z (%) = 309 (11), 280 (3), 252 (6), 220 (3), 162 (4), 126 (25), 105 (96), 77 (100), 51 (31). Anal. Calcd for C37H28N8O6S2 (744.80): C, 59.67%; H, 3.79%; N, 15.04%; found: C, 59.49%; H, 3.98%; N, 15.23%.

2.4.7. 4,6-Bis((2E)-2-hydroxy-4-oxo-4-phenyl-3-(N-phenylthiocarbamoyl)-2-butenamido)-2-mercaptopyrimidie (3d)

Dark orange crystal (crystallized from EtOH/H2O (1 : 1)); yield: 0.25 g (67%); mp 135°C–137°C; IR (KBr): 3500, 3396, 3287 (NH), 1730 (C=O, amide), 1664 (C=O, ketone), 1579 (C=C), 1552, 1382, 1141 (C-N, NH, C=S, thioamide) cm−1; 1H NMR (DMSO-d6): δ 5.29 (1H, s, CH of pyrimidine), 7.20 (2 (2H), d, J = 7.6 Hz, 4CHortho of Ph-NH), 7.32–7.44 (2 (6H), 1H and 2 (1H), m, 4Ph, SH and 2OH), 7.62 (2 (2H), d, J = 7.5 Hz, 4CHortho of Ph-CO), 12.73 (2 (2H), br s, 4NH); 13C NMR (DMSO-d6): δ 73.40 (C5), 113.1 (2=C), 127.4, 127.4, 128.1, 129.0, 129.5, 130.7 (2 (10C), 4Ph), 134.9 (2Cipso of Ph-CO), 140.6 (2Cipso of Ph-NH), 155.2 (C4 and C6), 163.3 (2=C-OH), 172.8 (C2), 173.0 (2C=O, amide), 189.2 (2C=S), 197.2 (2C=O, ketone) ppm; EI-MS: m/z (%) = 309 (29), 252 (7), 142 (5), 122 (39), 105 (23), 77 (100), 51 (36). Anal. Calcd for C38H28N6O6S3 (760.86): C, 59.99%; H, 3.71%; N, 11.05%; found: C, 59.81%; H, 3.94%; N, 11.24%.

2.4.8. 4,4′-Bis((2E)-2-hydroxy-4-oxo-4-phenyl-3-(N-phenylthiocarbamoyl)-2-butenamido) Biphenylsulfone (3e)

Orange powder (washed with EtOH/H2O (1 : 1)); yield 0.30 g (69%); mp 192°C–194°C; IR (KBr): 3448 (NH), 1736 (C=O, amide), 1618 (C=O, ketone), 1592 (C=C), 1560, 1314, 1152 (C-N, NH, C=S, thioamide), 1384, 1106 (SO2) cm−1; 1H NMR (DMSO-d6): δ 7.11 (2 (2H), d, 3J = 7.7 Hz, 4CHortho of Ph-NHCS), 7.32–7.52 (2 (10H), 2 (1H) and 2 (1H), m, 6Ph, 2OH and 2NH), 7.74 (2 (2H), d, 3J = 5.7 Hz, 4CHortho of Ph-CO), 13.42 (2 (1H), br s, 2NH); 13C NMR (DMSO-d6): δ 113.2 (2=C), 125.5, 127.5, 127.7, 128.3, 128.6, 129.1, 129.4, 131.3 (2 (14C), 4Ph), 134.7 (2Cipso of Ph-CO), 139.9 (2Cipso of Ph-SO2), 141.1 (2Cipso of Ph-NHCS), 153.7 (2Cipso of Ph-NHCO), 163.5 (2=C-OH), 170.4 (2C=O, amide), 188.9 (2C=S), 197.5 (2C=O, ketone) ppm; EI-MS: m/z (%) 357 (1), 309 (9), 255 (20), 222 (15), 105 (100), 77 (81), 43 (69). Anal. Calcd for C46H34N4O8S3 (866.98): C, 63.73; H, 3.95; N, 6.46. Found: C, 63.48; H, 4.21; N, 6.21.

2.4.9. (2E)-N-Hydroxy-2-hydroxy-4-oxo-4-phenyl-3-(N-phenylthiocarbamoyl)-2-butenamide (4a)

Brownish yellow powder (crystallized from 2-propanol); yield: 0.20 g (58%); mp 249°C (decomposition); IR (KBr): 3384 (NH), 3030 (OH, enol), 1761 (C=O, amide), 1712 (C=O, ketone), 1598 (C=C), 1583 (NH), 1541, 1354, 1133 (C-N, NH, C=S, thioamide) cm−1; 1H NMR (DMSO-d6): δ 7.21 (2H, d, J = 7.8 Hz, 2CHortho of Ph-NH), 7.32–7.43 (6H and 1H, m, 2Ph and OH), 7.61 (2H, d, J = 7.6 Hz, 2CHortho of Ph-CO), OH and 2NH protons are missing in spectrum; 13C NMR (DMSO-d6): δ 113.2 (=C), 127.4, 127.5, 128.1, 128.9, 129.4, 130.7 (10C, 2Ph), 134.9 (Cipso of Ph-CO), 140.4 (Cipso of Ph-NH), 163.3 (=C-OH), 172.4 (C=O, amide), 189.1 (C=S), 197.2 (C=O, ketone) ppm; EI-MS: m/z (%) = 342 (M+, 2), 309 (31), 280 (8), 252 (14), 220 (5), 187 (59), 162 (5), 144 (12), 105 (100), 77 (93), 51 (26). Anal. Calcd for C17H14N2O4S (342.37): C, 59.64%; H, 4.12%; N, 8.18%; found: C, 59.79%; H, 3.98%; N, 8.35%.

2.4.10. DL-(2E)-N-1-Phenylethyl-2-hydroxy-4-oxo-4-phenyl-3-(N-phenylthiocarbamoyl)-2-butenamide (4b)

Orange crystal (crystallized from ethanol); yield: 0.33 g (76%); mp 186°C–188°C; IR (KBr): 3447 (NH), 3045 (OH, enol), 2940 (CH, aliphatic), 1733 (C=O, amide), 1648 (C=O, ketone), 1622 (C=C), 1596 (NH), 1537, 1380, 1141 (C-N, NH, C=S, thioamide) cm−1; 1H NMR (DMSO-d6): δ 1.48 (3H, d, J = 6.8 Hz, CH3), 4.41 (1H, q, J = 6.8 Hz, CH), 7.21 (2H, d, J = 7.7 Hz, 2CHortho of Ph-NH), 7.32–7.47 (11H, m, 3Ph), 7.62 (2H, d, J = 7.9 Hz, 2CHortho of Ph-CO), 8.19 (3H, br s, OH, 2NH); 13C NMR (DMSO-d6): δ 20.6 (CH3), 50.0 (CH), 113.1 (=C), 126.7, 127.3, 127.4, 128.1, 128.5, 128.7, 128.9, 129.4, 130.6 (15C, 2Ph), 134.9 (Cipso of Ph-CO), 139.1 (Cipso of Ph-CH), 140.7 (Cipso of Ph-NH), 163.2 (=C-OH), 172.9 (C=O, amide), 189.2 (C=S), 197.2 (C=O, ketone) ppm; EI-MS: m/z (%) = 430 (M+, 2), 309 (60), 280 (11), 252 (19), 220 (6), 162 (7), 144 (5), 105 (100), 77 (79), 51 (27). Anal. Calcd for C25H22N2O3S (430.52): C, 69.75%; H, 5.15%; N, 6.51%; found: C, 69.89%; H, 5.41%; N, 6.39%.

2.4.11. (2E)-1,1-Dimethylbiguanido-5-yl-2-hydroxy-4-oxo-4-phenyl-3-(N-phenylthiocarbamoyl)-2-butenamide (4c)

Orange powder (crystallized from 2-propanol); yield 0.31 g (71%); mp 98°C–100°C; IR (KBr): 3397 (NH), 1700 (C=O, amide), 1638 (C=O, ketone), 1596 (C=C), 1579 (NH), 1542, 1387, 1138 (C-N, NH, C=S, thioamide) cm−1; 1H NMR (DMSO-d6): δ 3.00 (6H, s, 2CH3), 5.19 (3H, br s, 3NH), 7.25 (2H, d, 3J = 7.3 Hz, 2CHortho of Ph-NH), 7.33–7.52 (6H, m, 2Ph), 7.68 (2H, d, 3J = 7.5 Hz, 2CHortho of Ph-CO), 7.80, 8.37 (3H, 2br s, 2NH, OH); 13C NMR (DMSO-d6): δ 39.50 (2CH3), 113.3 (=C), 126.9, 127.3, 128.5, 128.7, 129.4, 131.1 (10C, 2Ph), 134.7 (Cipso of Ph-CO), 140.1 (Cipso of Ph-NH), 154.7, 155.9 (2C=NH), 163.5 (=C-OH), 171.2 (C=O, amide), 189.1 (C=S), 197.5 (C=O, ketone) ppm; EI-MS: m/z (%) 309 (1), 282 (2), 149 (7), 113 (13), 85 (57), 57 (100), 41 (39). Anal. Calcd for C21H22N6O3S (438.50): C, 57.52; H, 5.06; N, 19.17. Found: C, 57.26; H, 5.29; N, 19.43.

2.4.12. 4,4′-Bipyridinium Bis((2E)-4-oxo-4-phenyl-3-(N-phenylthiocarbamoyl)-2-butenamide-2-oxide) (5)

Dark orange powder (crystallized from H2O); yield: 0.24 g (63%); mp 153°C–155°C; IR (KBr): 3472 (NH), 3078 (OH, enol), 3057 (CH, aromatic), 1714 (C=O, amide), 1672 (C=O, ketone), 1627 (C=C), 1597 (NH), 1579, 1383, 1129 (C-N, NH, C=S, thioamide) cm−1; 1H NMR (DMSO-d6): δ 6.08 (2 (1H), br s, 2NH), 7.26 (2 (2H), d, J = 7.1 Hz, 4CHortho of Ph-NH), 7.38–7.45 (2 (6H), m, 4Ph), 7.71 (2 (2H), d, J = 7.0 Hz, 4CHortho of Ph-CO), 8.39 (2 (2H), d, J = 5.1 Hz, 4CHmeta of C5H5N), 9.05 (2 (2H), d, J = 5.1 Hz, 4CHortho of C5H5N); 13C NMR (DMSO-d6): δ 113.4 (2=C), 124.5 (2 (2C3) of C5H5N), 127.6, 127.7, 128.3, 129.1, 129.4, 131.3 (2 (10C), 4Ph), 134.6 (2Cipso of Ph-CO), 139.8 (2Cipso of Ph-NH), 145.2 (2C4 of C5H5N), 148.8 (2 (2C2) of C5H5N), 163.7 (2=C-O), 170.4 (2C=O, amide), 189.1 (2C=S), 197.6 (2C=O, ketone) ppm; EI-MS: m/z (%) = 309 (79), 280 (16), 252 (24), 221 (7), 193 (4), 162 (10), 105 (100), 77 (90), 51 (27). Anal. Calcd for C44H30N4O6S2 (774.86): C, 68.20%; H, 3.90%; N, 7.23%; found: C, 68.35%; H, 3.78%; N, 7.42%.

2.4.13. 4-Benzoyl-3-(1-naphthylamino)-5-phenylimino-2,5-dihydrothiophene-2-one (6)

Brownish yellow powder (crystallized from 2-propanol); yield: 0.29 g (67%); mp 203°C–205°C; IR (KBr): 3448 (NH), 3032 (CH, aromatic), 1750 (C=O, thioester), 1698 (C=O, ketone), 1606 (C=N), 1588 (C=C), 1548 (NH) cm−1; 1H NMR (CDCl3): δ 6.88 (1H, d, J = 7.6 Hz, CH2 of naphthyl), 7.18–7.39 (8H, m, 2Ph), 7.50 (1H, t, J = 7.6 Hz, CH3 of naphthyl), 7.56 (1H, t, J = 7.9 Hz, CH6 of naphthyl), 7.60 (2H, d, J = 8.0 Hz, 2CHortho of Ph-CO), 7.67 (1H, t, J = 7.9 Hz, CH7 of naphthyl), 7.71 (1H, d, J = 7.6 Hz, CH4 of naphthyl), 7.88 (1H, d, J = 7.9 Hz, CH5 of naphthyl), 8.17 (1H, d, J = 7.9 Hz, CH8 of naphthyl), 14.28 (1H, br s, NH); 13C NMR (CDCl3): δ 105.1 (=C), 121.9, 124.8, 124.9, 127.0, 127.8, 128.2, 128.3, 128.5, 128.6, 128.9, 129.2, 129.3, 129.6, 130.0, 130.7, 132.1 (20C, 2Ph, naphthyl), 132.9 (Cipso of naphthyl-NH), 133.9 (Cipso of Ph-N=C), 160.0 (=C–NH), 167.5 (C=N), 175.5 (C=O, thioester), 198.6 (C=O, ketone) ppm; EI-MS: m/z (%) = 434 (20), 345 (71), 243 (18), 230 (18), 127 (86), 104 (15), 77 (100), 51 (29). Anal. Calcd for C27H18N2O2S (434.51): C, 74.63%; H, 4.18%; N, 6.45%; found: C, 74.85%; H, 4.37%; N, 6.23%.

2.4.14. 1,5-Bis(4-benzoyl-2-oxo-5-phenylimino-2,5-dihydrothiophene-3-ylamino)naphthalene (7)

Green powder (crystallized from 2-propanol); yield: 0.26 g (71%); mp 235°C–237°C; IR (KBr): 3497 (NH), 3059 (CH, aromatic), 1758 (C=O, thioester), 1698 (C=O, ketone), 1605 (C=N), 1584 (C=C), 1559 (NH) cm−1; 1H NMR (CDCl3): δ 6.99 (2H, d, J = 7.0 Hz, CH2 and CH6 of naphthylene), 7.16–7.56 (2 (10H) and 2H, m, 4Ph and, CH3 and CH7 of naphthylene), 8.02 (2H, d, J = 7.0 Hz, CH4 and CH8 of naphthylene), 14.23 (2 (1H), br s, 2NH); 13C NMR (DMSO-d6): δ 105.6 (2=C), 122.2, 126.6, 127.4, 127.6, 128.0, 128.0, 128.6, 128.7, 128.8, 130.0, 130.1 (2 (15C), 4Ph, naphthylene), 132.4 (2Cipso of naphthylene-NH), 133.3 (2Cipso of Ph-N=C), 159.8 (2=C–NH), 166.9 (2C=N), 175.7 (2C=O, thioester), 198.1 (2C=O, ketone) ppm; EI-MS: m/z (%) = 740 (7), 594 (2), 522 (5), 450 (5), 408 (5), 227 (7), 165 (10), 123 (11), 105 (22), 91 (26), 77 (44), 57 (72), 43 (100). Anal. Calcd for C44H28N4O4S2 (740.85): C, 71.33%; H, 3.81%; N, 7.56%; found: C, 71.58%; H, 4.08%; N, 7.74%.

2.4.15. 1,3-Bis(4-benzoyl-2-oxo-5-phenylimino-2,5-dihydrothiophene-3-ylamino)benzene (8)

Lemon yellow powder (washed with EtOH/H2O (1 : 1)); yield: 0.27 g (78%); mp 317°C–319°C; IR (KBr): 3446 (NH), 1754 (C=O, thioester), 1699 (C=O, ketone), 1617 (C=N), 1600 (C=C), 1581 (NH) cm−1; 1H NMR (DMSO-d6): δ 6.71 (2(1H), d, J = 8.0 Hz, 2CHortho of Ph-NH), 6.78 (1H, s, CHortho of Ph-NH), 7.02 (1H, t, J = 8.0 Hz, CHmeta of Ph-NH), 7.23 (2 (2H), d, J = 7.3 Hz, 4CHortho of Ph-N), 7.33–7.56 (2 (8H), m, 4Ph), 13.24 (2 (1H), br s, 2NH); 13C NMR (DMSO-d6): δ 105.1 (2=C), 122.3, 124.0, 128.1, 128.3, 128.8, 129.0, 129.1, 129.4, 129.8, 130.2 (26C, 5Ph), 133.5 (2Cipso of Ph-NH), 136.6 (2Cipso of Ph-N=C), 159.8 (2=C-NH), 164.6 (2C=N), 175.8 (2C=O, thioester), 197.5 (2C=O, ketone) ppm; EI-MS: m/z (%) = 690 (M+, 1), 667 (2), 387 (2), 190 (4), 123 (7), 105 (13), 91 (19), 77 (60), 57 (48), 43 (100). Anal. Calcd for C40H26N4O4S2 (690.79): C, 69.55%; H, 3.79%; N, 8.11%; found: C, 69.74%; H, 3.58%; N, 8.39%.

3. Results and Discussion

Interaction of 1 with aminoheteroaromatics and lamotrigine in THF/H2O (1 : 1) at room temperature provided the corresponding N-2-pyridyl and N-1,2,4-triazin-3-yl-2-hydroxy-4-oxo-4-phenyl-3-(N-phenylthiocarbamoyl)-2-butenamides 2ac, while that with 1,3-diaminoheteroaromatics and dapsone in a 1 : 0.5 ratio afforded bis(2-hydroxy-4-oxo-4-phenyl-3-(N-phenylthiocarbamoyl)-2-butenamido) pyridine 3a, 1,3,5-triazine 3b and 3c, pyrimidine 3d, and diphenyl sulfone 3e (Scheme 2). Treatment of 1 with NH2R (hydroxylamine, DL-1-phenylethylamine, and metformin) in THF/H2O (1 : 1) at room temperature provided the corresponding 2-hydroxy-4-oxo-4-phenyl-3-(N-phenylthiocarbamoyl)-2-butenamides 4ac (Scheme 2). Moreover, the reaction of 1 with 4,4′-bipyridine in THF/H2O (1 : 1) at room temperature in a 1 : 0.5 ratio led to stable 1,4-diionic nitrogen betaine 5 (Scheme 2). Reaction of 1 with α-naphthylamine in boiling ethanol yielded 4-benzoyl-3-(1-naphthylamino)-5-phenylimino-2,5-dihydrothiophene-2-one (6), while that with 1,5-naphthylenediamine and 1,3-phenylenediamine in a 1 : 0.5 ratio provided bis(4-benzoyl-2-oxo-5-phenylimino-2,5-dihydrothiophene-3-ylamino)naphthalene and benzene (7, 8) (Scheme 3). Similar to primary and secondary aliphatic amines and tertiary aromatic and aliphatic amine [20], it has been reported that primary heteroaromatic amines and dapsone reacted with compound 1 in THF/H2O (1 : 1) at room temperature to produce 3-N-phenylthiocarbomoyl-2-butenamides 2 and 3. The products of 28 were gained in moderate to good yields.

The structures of 28 were characterized by elemental analyses, IR, 1H, and 13C NMR spectroscopy and as well as mass spectrometry. The mass spectra of some products exhibited fairly weak molecular ion peaks. The structural analogy of 25 can easily be observed from their IR and 13C NMR spectra. Absorption bands of the enolic OH moiety (except 5), amide C=O, and thioamide C-N, NH, and C=S groups at 3078–3030, 1761–1700, 1579–1518, 1396–1314, and 1152–1129 cm−1, respectively, are structural characteristics. Their 13C NMR spectra also revealed signals at δ 163.20-163.75, 170.13–174.87, and 188.99–189.21 ppm due to the carbon atoms of the = C-OH (in Case 5, =C-O), amide C=O, and thioamide C=S. In the 13C NMR spectra of compound 5, there was no decrease in the chemical shift of the =C and ketonic C=O groups denoting that the negative charge is not distributed on the central carbon atom and two oxygen atoms, and in this, the structure conjugation of negative oxygen with the benzoyl group due to overlapping between π-positive nitrogen orbital with π-negative oxygen orbital was absent (Figure 1) [20]. The 1H NMR spectra of 25 exhibited a broad singlet at δ 6.08–8.48 ppm for the NH and enolic OH protons. In the IR and 13C NMR spectra of products 68, the absorptions of the carbonyl group (C-3) were absent. IR and 13C NMR absorptions of the C=N group in 68 are found at 1617–1605 cm−1 and δ 164.62–167.52 ppm, respectively. Their 1H NMR spectra exhibited a broad singlet at δ 13.24–14.28 ppm for the enaminic NH proton and multiplet signals integrated for 17–26 protons of aromatic rings at δ 6.71–8.17 ppm.

These indicate the nucleophilic attacks of heteroaromatic amines, lamotrigine, dapsone, and metformin similar to primary and secondary aliphatic amines and tertiary aromatic and aliphatic amines [20] on thioester carboxyl group (C-2) of the thiophenedione ring 1, because of the extremely high reactivity of the thioester carboxyl group in the polar aprotic solvent-water mixture (THF/H2O (1 : 1)) with high ionic strength. However, the nucleophilic attacks of primary aromatic amines insoluble in THF/H2O (1 : 1) such as naphthylamines and 1,3-phenylenediamine in polar protic solvent (ethanol) occur on the carbonyl group (C-3) [16] (Scheme 4). Therefore, nucleophile reaction pathways and selectivity of thiophene-2,3-dione 1 depend on the nucleophile and solvent.

4. Conclusion

The nucleophilic attacks of N-nucleophiles soluble in THF/H2O (1 : 1) such as aminoheteroaryls, lamotrigine, dapsone, and metformin occur on thioester carboxyl group (C-2) and N-nucleophiles insoluble in THF/H2O (1 : 1) likely primary aromatic amines on the carbonyl group (C-3) of thiophene-2,3-dione 1 for the synthesis of the corresponding amide and thiophene derivatives 28 as convenient organic ligands with medium to good yields.

Data Availability

The data used to support the findings of this study are included within the article and the supplementary information file(s).

Conflicts of Interest

The authors declare that they have no conflicts of interest.

Acknowledgments

The authors are thankful to the North Tehran Branch, Islamic Azad University, for partial support of this work.

Supplementary Materials

Samples 2a–c, 3a–e, 4a–c, 5, 6, 7 and 8: IR, 1H NMR, 13C NMR and MS. (Supplementary Materials)

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