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

*e 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 2–5, while that with naphthylamines and 1,3-phenylenediamine in ethanol at high temperature led to 5-phenylamino-2,5-dihydrothiophene-2-ones 6–8 as organic ligands in the medium to good yields. *ese 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.


Introduction
Lamotrigine (3,5-diamino-6-(2,3-dichlorophenyl)-1,2,4-triazine) is a member of the phenyltriazine drug category. is category has its main utility in the adjunctive treatment of partial seizures in epilepsy and generalized seizures of Lennox-Gastaut syndrome [1][2][3][4]. Maintenance treatment of bipolar I disorder and depression is an additional important use of the phenyltriazine category [5,6]. Metformin (N,Ndimethylimidodicarbonimidic diamide) is a member of the biguanide class of compound. Currently, metformin is a US Food and Drug Administration approved drug for the firstline treatment of type 2 diabetes [7][8][9]. e 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. is 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].

General Information.
e 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. ese results agree favorably with the calculated values. Infrared spectra were measured from KBr disk using a ermo Nicolet 8700 FT-IR spectrometer and frequencies were reported in cm −1 . 1 H NMR and 13 C NMR spectra were recorded on a Bruker DRX-300 AVANCE instrument at 300 and 75 MHz, respectively, using TMS as internal standard and DMSO-d 6 or CDCl 3 as solvent. Chemical shifts and coupling constants were reported in ppm and Hz, respectively.
in-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.
e products of 2-8 were gained in moderate to good yields. e structures of 2-8 were characterized by elemental analyses, IR, 1 H, and 13 C NMR spectroscopy and as well as mass spectrometry. e mass spectra of some products exhibited fairly weak molecular ion peaks. e structural analogy of 2-5 can easily be observed from their IR and 13 C 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. eir 13 C 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 13 C 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]. e 1 H NMR spectra of 2-5 exhibited a broad singlet at δ 6.08-8.48 ppm for the NH and enolic OH protons. In the IR and 13 C NMR spectra of products 6-8, the absorptions of the carbonyl group (C-3) were absent. IR and 13 C NMR absorptions of the C�N group in 6-8 are found at 1617-1605 cm −1 and δ 164.62-167.52 ppm, respectively. eir 1 H 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. ese 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/H 2 O (1 : 1)) with high ionic strength. However, the nucleophilic attacks of primary aromatic amines insoluble in THF/H 2 O (1 : 1) such as naphthylamines and 1,3-phenylenediamine in polar protic solvent (ethanol) occur on the carbonyl group (C-3) [16] (Scheme 4). erefore, nucleophile reaction pathways and selectivity of thiophene-2,3-dione 1 depend on the nucleophile and solvent.

Conclusion
e nucleophilic attacks of N-nucleophiles soluble in THF/ H 2 O (1 : 1) such as aminoheteroaryls, lamotrigine, dapsone, and metformin occur on thioester carboxyl group (C-2) and N-nucleophiles insoluble in THF/H 2 O (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 2-8 as convenient organic ligands with medium to good yields.

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

Conflicts of Interest
e authors declare that they have no conflicts of interest.