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

Article abstract of DOI:10.1155/2020/5945796

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 tempe

Full text of DOI:10.1155/2020/5945796

Hindawi
Heteroatom Chemistry
Volume 2020, Article ID 5945796, 9 pages
https://doi.org/10.1155/2020/5945796
Research Article
Synthesis of Organic Ligands via Reactions of
4
2
-Benzoyl-5-phenylamino-
,3-dihydrothiophene-2,3-dione with N-Nucleophiles
Hassan Kabirifard , Pardis Hafez Taghva, Hossein Teimouri, Niloofar Koosheshi,
Parastoo Javadpour, Hanieh Bagherinejad, Soheila Seyfi, Maryam Hossein Roodbari,
and Elaheh Golabian
Department of Chemistry, North Tehran Branch, Islamic Azad University, Tehran, Iran
Correspondence should be addressed to Hassan Kabirifard; h_kabirifard@iau-tnb.ac.ir
Received 5 March 2020; Accepted 10 June 2020; Published 8 July 2020
Academic Editor: Mariateresa Giustiniano
Copyright © 2020 Hassan Kabirifard et al. *is is an open access article distributed under the Creative Commons Attribution
License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is
properly cited.
*
e reaction of 4-benzoyl-5-phenylamino-2,3-dihydrothiophene-2,3-dione (1) with aminoheteroaryls, lamotrigine, 1,3-dia-
minoheteroaryls, dapsone, NH R (hydroxylamine, DL-1-phenylethylamine, and metformin), and 4,4′-bipyridine in THF/H O (1 :1)
2
2
at room temperature led to 3-N-phenylthiocarbamoyl-2-butenamides 2–5, while that with naphthylamines and 1,3-phenyl-
enediamine 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.
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].
Recently, effective methods for the synthesis of 4-ac-
ylated-5-substituted thiophene-2,3-diones through acyla-
tion 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
1
. Introduction
Lamotrigine (3,5-diamino-6-(2,3-dichlorophenyl)-1,2,4-tri-
azine) 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 [1–4]. 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 [7–9]. *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].

2
Heteroatom Chemistry
2.3. Reactions of Compound 1 with Amines
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 [17–19]. In addition,
2
.3.1. General Procedure. To a stirred solution of 1 (0.309 g,
1
.0 mmol) in THF/H O (1 :1, 10 mL) at room temperature or
2
°
ethanol (10 mL) at 70 C was added either aminopyridines,
lamotrigine, hydroxylamine, DL-1-phenylethylamine, met-
formin, and 1-naphthylamine (1.0 mmol), or 2,6-dia-
minopyridine, 2,4-diamino-6-phenyl-1,3,5-triazine, 2,4,6-
4
-benzoyl-5-phenylamino-2,3-dihydrothiophene-2,3-
triamino-1,3,5-triazine,
4,6-diamino-2-mercaptopyr-
dione (1) has been recognized as a particularly significant
starting material or intermediate for the synthesis of di-
verse sulfur- and nitrogen-containing heterocyclic com-
pounds [16, 20–23]. In the previous study, we found that
the reactions of 4-benzoyl-5-phenylamino-2,3-dihy-
drothiophene-2,3-dione (1) with N-nucleophiles such as
primary and secondary aliphatic amines and tertiary ar-
imidine, dapsone, 4,4′-bipyridine, 1,5-naphthalenediamine,
and 1,3-phenylenediamine (0.5 mmol). *e reaction mixture
was then stirred for 6 h. *e progress of the reaction was
determined by TLC (eluent AcOEt/hexane 4 :1). *e solid in
THF/H O (1 :1) was separated by filtration (or the ethanol
2
was evaporated) and then was crystallized from a suitable
solvent (ethanol, 2-propanol, H O or EtOH/H O (1 :1)) or
omatic and aliphatic amines in THF/H O (1 :1) at room
2
2
2
was washed with EtOH/H O (1 :1) to give 2–8, respectively.
temperature gave amide derivatives that have N-phenyl-
thiocarbamoyl group [20] while those with primary aro-
matic 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 [24–27], 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
2
2
2
.4. Characterization Data of the Compounds 2–8
.4.1. (2E)-N-2-Pyridyl-2-hydroxy-4-oxo-4-phenyl-3-(N-phe-
nylthiocarbamoyl)-2-butenamide (2a). Brownish yellow
powder (crystallized from ethanol); yield: 0.28 g (69%); mp
°
°
1
95 C–197 C; IR (KBr): v 3436 (NH), 3050 (OH, enol), 1728
(
C�O, amide), 1633 (C�O, ketone), 1619 (C�C), 1588 (NH),
−
1 1
1
536, 1394, 1132 (C-N, NH, C�S, thioamide) cm ; H NMR
1
,3-phenylenediamine for the first time (Scheme 2 and
(
DMSO-d ): δ 6.84 (1H, t, J � 6.7 Hz, CH
of C H N), 6.95
6
meta
5
5
Scheme 3).
(
1H, d, J � 8.8 Hz, CH
of C H N), 7.21 (2H, d, J � 7.5 Hz,
meta
5
5
2
CH
of Ph-NH), 7.32–7.42 (6H, m, 2Ph), 7.43 (1H, t,
ortho
J � 7.4 Hz, CH
of C H N), 7.62 (2H, d, J � 7.4 Hz,
2
. Materials and Methods
para
5
5
2
CH
of Ph-CO), 7.89 (2H, br s, OH, NH), 7.91 (1H, d,
ortho
13
2
.1. General Information. *e reagents were purchased from
J � 6.9 Hz, CH
of C H N), 12.24 (1H, br s, NH);
C
ortho
5
5
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 fa-
vorably with the calculated values. Infrared spectra were
measured from KBr disk using a *ermo Nicolet 8700 FT-IR
NMR (DMSO-d ): δ112.1 (C ), 113.1 (�C), 113.3 (C ), 127.3,
6
3
5
127.4, 128.0, 128.9, 129.4, 130.6 (10C, 2Ph), 134.9 (C
of
ipso
Ph-CO), 136.2 (C ), 140.7 (C of Ph-NH), 144.0 (C ), 154.0
4
ipso
6
(C ), 163.2 (�C-OH), 172.9 (C�O, amide), 189.1 (C�S),
2
+
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 C H N O S (403.45): C, 65.49%; H,
−1 1
spectrometer and frequencies were reported in cm . H
22
17 3 3
1
3
NMR and C NMR spectra were recorded on a Bruker
DRX-300 AVANCE instrument at 300 and 75 MHz, re-
4.25%; N, 10.42%; found: C, 65.26%; H, 3.98%; N, 10.65%.
spectively, using TMS as internal standard and DMSO-d or
6
2
3
.4.2. (2E)-N-4-Methyl-2-pyridyl-2-hydroxy-4-oxo-4-phenyl-
CDCl as solvent. Chemical shifts and coupling constants
3
-(N-phenylthiocarbamoyl)-2-butenamide
(2b). Orange
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
powder (crystallized from ethanol); yield: 0.30 g (71%); mp
°
2
02 C (decomposition); IR (KBr): v 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
7
0 eV.
−
1 1
C-N, NH, C�S, thioamide) cm ; H NMR (CDCl ): δ 2.35
3
3H, s, CH ), 6.55 (1H, d, J � 6.1 Hz, CH
of C H N), 6.86
5 5
3
meta
2
.2. Materials. Ethyl benzoylpyruvate was prepared from
(1H, s, CH
of C H N), 7.33 (2H, d, J � 7.3 Hz, 2CH
of
ortho
meta
5
5
diethyl oxalate (6.0 mmol) and acetophenone (4.0 mmol) in
the presence of sodium ethoxide (8.4 mmol) in absolute
Ph-NH), 7.43–7.56 (6H and 1H, m, 2Ph and OH), 7.63 (2H,
d, J � 7.4 Hz, 2CH of Ph-CO), 7.85 (1H, d, J � 6.1 Hz,
ortho
13
ethanol (30 mL) under N atmosphere [28]. 4-Benzoyl-5-
CH
of C H N), 7.86, 14.28 (2H, 2br s, 2NH); C NMR
2
ortho 5 5
phenylamino-2,3-dihydrothiophene-2,3-dione (1) was ob-
(CDCl ): δ 22.1 (CH ), 113.1 (�C), 114.5 (C ), 120.7 (C ),
3
3
3
5
tained by careful addition of phenyl isothiocyanate
128.0, 128.2, 128.6, 129.5, 129.8, 129.9 (10C, 2Ph), 134.1
(C of Ph-CO), 139.2 (C of Ph-NH), 154.4 (C ), 156.4
(
10 mmol) to benzoylpyruvate (10 mmol) in KOH (10 mmol)
ipso
ipso
6
and DMF (20 mL) with stirring for 24 h at room temperature
16].
(C ), 160.1 (C ), 163.8 (�C-OH), 174.9 (C�O, amide), 189.2
4
2
[
(C�S), 200.0 (C�O, ketone) ppm; EI-MS: m/z (%) � 417

Heteroatom Chemistry
3
+
(
M , 3), 309 (10), 280 (3), 252 (5), 220 (3), 162 (3), 105 (93),
2CH
of Ph-6-triazine), 8.48 (2 (3H), br s, 2OH, 4NH);
ortho
13
7
6
1
7 (100), 51 (38). Anal. Calcd for C H N O S (417.48): C,
6.17%; H, 4.59%; N, 10.07%; found: C, 65.95%; H, 4.78%; N,
0.31%.
C NMR (DMSO-d ): δ 113.5 (2�C), 127.6, 127.7, 128.2,
23
19
3
3
6
128.3, 129.0, 129.1, 129.4, 130.6, 131.3 (25C, 5Ph), 133.9
(C
of Ph-6-triazine), 134.5 (2Cipso of Ph-CO), 139.7
ipso
(
2Cipso of Ph-NH), 160.6 (C and C ), 163.1 (C ), 163.7 (2�C-
2
4
6
OH), 170.1 (2C�O, amide), 189.0 (2C�S), 197.6 (2C�O,
2
.4.3. N-5-Amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl-
ketone) ppm; EI-MS: m/z (%) � 309 (39), 280 (9), 252 (16),
(
2E)-2-hydroxy-4-oxo-4-phenyl-3-(N-phenylthiocarbamoyl)-
2
20 (5), 187 (50), 162 (6), 144 (10), 105 (100), 77 (95), 51 (27).
2
-butenamide (2c). Orange powder (crystallized from 2-
Anal. Calcd for C H N O S (805.88): C, 64.09%; H,
43
31 7 6 2
°
°
propanol); yield 0.42 g (74%); mp 236 C–238 C; IR (KBr): v
466, 3270, 3182 (NH), 1725 (C�O, amide), 1637 (C�O,
3.88%; N, 12.17%; found: C, 64.28%; H, 4.05%; N, 11.96%.
3
ketone), 1595 (C�C), 1578 (NH), 1535, 1386, 1140 (C-N,
−
1 1
NH, C�S, thioamide) cm ; H NMR (DMSO-d ): δ 7.22
2.4.6. 2,4-Bis((2E)-2-hydroxy-4-oxo-4-phenyl-3-(N-phenyl-
thiocarbamoyl)-2-butenamido)-6-amino-1,3,5-triazine (3c).
Orange powder (crystallized from ethanol); yield: 0.29 g
6
3
(
2
2H, d, J � 7.3 Hz, 2CH
of Ph-NH), 7.31–7.46 (6H, m,
ortho
3
Ph), 7.52 (2H, 2d, J � 5.1 Hz, CH
and CH
ortho
of Ph-
para
of Ph-CO), 7.82
ortho
3
°
°
triazine), 7.63 (2H, d, J � 7.6 Hz, 2CH
(79%); mp 225 C–227 C; IR (KBr): v 3319, 3209 (NH), 1725,
1704 (C�O, amide), 1651 (C�O, ketone), 1579, 1396, 1143
3
(
(
(
1H, t, J � 5.1 Hz, CH
of Ph-triazine), 8.19, 9.17, 13.75
meta
13
−1
1
5H, 3br s, OH, 2NH, NH ); C NMR (DMSO-d ): δ 113.1
(C-N, NH, C�S, thioamide) cm ; H NMR (DMSO-d ): δ
2
6
6
�C), 127.4, 127.5, 128.1, 129.0, 129.1, 129.5, 130.6, 130.7,
7.22 (2 (2H), d, J � 7.3 Hz, 4CH
of Ph-NH), 7.31–7.47 (2
ortho
1
1
1
31.3, 132.2, 132.4, 132.5 (16C, 3Ph), 134.9 (C of Ph-CO),
(6H), m, 4Ph), 7.64 (2 (2H), d, J � 7.7 Hz, 4CH
of Ph-
ortho
13
ipso
38.5 (C ), 140.6 (C
of Ph-NH), 154.3 (C ), 155.9 (C ),
CO), 7.67 (2 (3H) and 2H, br s, 2OH, 4NH, and NH );
C
6
ipso
5
3
2
63.3 (�C-OH), 173.0 (C�O, amide), 189.2 (C�S), 197.2
NMR (DMSO-d ): δ 113.2 (2�C), 127.5, 127.5, 128.2, 129.0,
6
(
C�O, ketone) ppm; EI-MS: m/z (%) 551 (1), 495 (8), 368 (6),
129.4, 130.9 (2 (10C), 4Ph), 134.8 (2C
of Ph-CO), 140.4
ipso
3
09 (42), 280 (8), 255 (30), 220 (5), 185 (55), 105 (100), 77
(2Cipso of Ph-NH), 159.4 (C and C ), 160.2 (C ), 163.5
2 4 6
(
75), 43 (42). Anal. Calcd for C H Cl N O S (565.43): C,
(2�C-OH), 172.2 (2C�O, amide), 189.2 (2C�S), 197.4
26
18
2 6 3
5
5.23; H, 3.21; N, 14.86. Found: C, 55.49; H, 2.98; N, 14.61.
(2C�O, ketone) ppm; EI-MS: m/z (%) � 309 (11), 280 (3),
2
52 (6), 220 (3), 162 (4), 126 (25), 105 (96), 77 (100), 51 (31).
Anal. Calcd for C H N O S (744.80): C, 59.67%; H,
37
28 8 6 2
2
.4.4. 2,6-Bis((2E)-2-hydroxy-4-oxo-4-phenyl-3-(N-phenyl-
3.79%; N, 15.04%; found: C, 59.49%; H, 3.98%; N, 15.23%.
thiocarbamoyl)-2-butenamido)pyridine (3a). Yellowish or-
ange powder (crystallized from ethanol); yield: 0.27 g (73%);
°
°
mp 190 C–192 C; IR (KBr): v 3481, 3391 (NH), 3050 (OH,
enol), 1727 (C�O, amide), 1634 (C�O, ketone), 1596 (C�C),
2.4.7. 4,6-Bis((2E)-2-hydroxy-4-oxo-4-phenyl-3-(N-phenyl-
thiocarbamoyl)-2-butenamido)-2-mercaptopyrimidie (3d).
1
577 (NH), 1518, 1381, 1139 (C-N, NH, C�S, thioamide)
Dark orange crystal (crystallized from EtOH/H O (1 :1));
2
−
1
1
°
°
cm ; H NMR (DMSO-d ): δ 5.88 (2H, d, J � 8.2 Hz,
yield: 0.25 g (67%); mp 135 C–137 C; IR (KBr): v 3500, 3396,
6
2
(
CHmeta of C H N), 7.13 (2 (2H), br s, 2OH, 2NH), 7.22 (2
3287 (NH), 1730 (C�O, amide), 1664 (C�O, ketone), 1579
5 5
−
1
2H), d, J � 7.6 Hz, 4CH
of Ph-NH), 7.34–7.51 (2 (6H)
(C�C), 1552, 1382, 1141 (C-N, NH, C�S, thioamide) cm ;
ortho
1
and 1H, m, 4Ph and CH
of C H N), 7.63 (2 (2H), d,
H NMR (DMSO-d ): δ 5.29 (1H, s, CH of pyrimidine), 7.20
para
5
5
6
13
J � 7.5 Hz, 4CH
of Ph-CO), 12.06 (2 (1H), br s, 2NH); C
(2 (2H), d, J � 7.6 Hz, 4CH
of Ph-NH), 7.32–7.44 (2 (6H),
ortho
ortho
NMR (DMSO-d ): δ 95.0 (C and C ), 113.1 (2�C), 127.3,
1H and 2 (1H), m, 4Ph, SH and 2OH), 7.62 (2 (2H), d,
J � 7.5 Hz, 4CH of Ph-CO), 12.73 (2 (2H), br s, 4NH);
6
3
5
1
27.4, 128.1, 128.9, 129.4, 130.6 (2 (10C), 4Ph), 134.9 (2C
ipso
ortho
13
of Ph-CO), 140.6 (2Cipso of Ph-NH), 145.1 (C ), 151.9 (C
C NMR (DMSO-d ): δ 73.40 (C ), 113.1 (2�C), 127.4,
4
2
6
5
and C ), 163.3 (2�C-OH), 172.8 (2C�O, amide), 189.1
127.4, 128.1, 129.0, 129.5, 130.7 (2 (10C), 4Ph), 134.9 (2C
ipso
6
(
(
(
4
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 C H N O S (727.81): C, 64.36%; H,
of Ph-CO), 140.6 (2C of Ph-NH), 155.2 (C and C ), 163.3
ipso 4 6
(2�C-OH), 172.8 (C ), 173.0 (2C�O, amide), 189.2 (2C�S),
2
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 C H N O S (760.86): C, 59.99%; H, 3.71%; N, 11.05%;
39
29 5 6 2
.02%; N, 9.62%; found: C, 64.58%; H, 3.88%; N, 9.84%.
38
28 6 6 3
found: C, 59.81%; H, 3.94%; N, 11.24%.
2
.4.5. 2,4-Bis((2E)-2-hydroxy-4-oxo-4-phenyl-3-(N-phenyl-
thiocarbamoyl)-2-butenamido)-6-phenyl-1,3,5-triazine (3b).
Orange-yellow powder (crystallized from EtOH/H O (1 :1));
2.4.8. 4,4′-Bis((2E)-2-hydroxy-4-oxo-4-phenyl-3-(N-phenyl-
2
°
yield: 0.31 g (76%); mp 243 C (decomposition); IR (KBr): v
thiocarbamoyl)-2-butenamido)
Biphenylsulfone
(3e).
3
484, 3143 (NH), 1733, 1716 (C�O, amide), 1649 (C�O,
Orange powder (washed with EtOH/H O (1 :1)); yield 0.30 g
2
°
°
ketone), 1618 (C�C), 1529, 1380, 1137 (C-N, NH, C�S,
(69%); mp 192 C–194 C; IR (KBr): v 3448 (NH), 1736 (C�O,
−
1 1
thioamide) cm ; H NMR (DMSO-d ): δ 7.24 (2 (2H), d,
amide), 1618 (C�O, ketone), 1592 (C�C), 1560, 1314, 1152
6
−
1 1
J � 7.3 Hz, 4CH
of Ph-NH), 7.33–7.49 (2 (6H), m, 4Ph),
(C-N, NH, C�S, thioamide), 1384, 1106 (SO ) cm ; H
ortho
2
3
7
(
.62 (2H, t, J � 7.5 Hz, 2CH
of Ph-6-triazine), 7.68 (2
NMR (DMSO-d ): δ 7.11 (2 (2H), d, J � 7.7 Hz, 4CH
of
meta
6
ortho
2H), d, J � 7.2 Hz, 4CH
of Ph-CO), 7.72 (1H, t,
Ph-NHCS), 7.32–7.52 (2 (10H), 2 (1H) and 2 (1H), m, 6Ph,
ortho
3
J � 7.5 Hz, CH
of Ph-6-triazine), 8.09 (2H, d, J � 7.5 Hz,
2OH and 2NH), 7.74 (2 (2H), d, J � 5.7 Hz, 4CH
of Ph-
para
ortho

4
Heteroatom Chemistry
Ph
N
S
RNH2
H
O
O
Ph
NHR
O
O
H
H
Ph
N
S
THF/H O,r.t.[20]
R2NH
H
2
Ph
NR2
O
O
Ph
N
Ph
N
S
H
O
N
S
O
H
Ph
O
O
N
O
Ph
O
O
1
Ph
N
0.5 N
N
S
H
Ph
N
O
O
O
O
N
Ph
H
Ph
N
O
S
N
ArNH2
S
Ph
EtOH, Δ [16]
Ph
O
O
N
H
Ar
Scheme 1: Earlier works of reactions of 1 with N-nucleophiles.
CO), 13.42 (2 (1H), br s, 2NH); 13C NMR (DMSO-d ): δ
130.7 (10C, 2Ph), 134.9 (C of Ph-CO), 140.4 (C of Ph-
ipso ipso
6
1
1
13.2 (2�C), 125.5, 127.5, 127.7, 128.3, 128.6, 129.1, 129.4,
NH), 163.3 (�C-OH), 172.4 (C�O, amide), 189.1 (C�S),
+
31.3 (2 (14C), 4Ph), 134.7 (2C of Ph-CO), 139.9 (2C of
197.2 (C�O, ketone) ppm; EI-MS: m/z (%) � 342 (M , 2),
ipso
ipso
Ph-SO ), 141.1 (2C
of Ph-NHCS), 153.7 (2C of Ph-
ipso
309 (31), 280 (8), 252 (14), 220 (5), 187 (59), 162 (5), 144 (12),
105 (100), 77 (93), 51 (26). Anal. Calcd for C H N O S
2
ipso
NHCO), 163.5 (2�C-OH), 170.4 (2C�O, amide), 188.9
17
14 2 4
(
2C�S), 197.5 (2C�O, ketone) ppm; EI-MS: m/z (%) 357 (1),
09 (9), 255 (20), 222 (15), 105 (100), 77 (81), 43 (69). Anal.
Calcd for C H N O S (866.98): C, 63.73; H, 3.95; N, 6.46.
(342.37): C, 59.64%; H, 4.12%; N, 8.18%; found: C, 59.79%;
H, 3.98%; N, 8.35%.
3
4
6
34 4 8 3
Found: C, 63.48; H, 4.21; N, 6.21.
2
3
.4.10. DL-(2E)-N-1-Phenylethyl-2-hydroxy-4-oxo-4-phenyl-
-(N-phenylthiocarbamoyl)-2-butenamide (4b). Orange
2
.4.9. (2E)-N-Hydroxy-2-hydroxy-4-oxo-4-phenyl-3-(N-phe-
crystal (crystallized from ethanol); yield: 0.33 g (76%);
°
°
nylthiocarbamoyl)-2-butenamide (4a). Brownish yellow
mp 186 C–188 C; IR (KBr): v 3447 (NH), 3045 (OH,
enol), 2940 (CH, aliphatic), 1733 (C�O, amide), 1648
(C�O, ketone), 1622 (C�C), 1596 (NH), 1537, 1380, 1141
powder (crystallized from 2-propanol); yield: 0.20 g (58%);
mp 249 C (decomposition); IR (KBr): v 3384 (NH), 3030
°
−
1 1
(
(
OH, enol), 1761 (C�O, amide), 1712 (C�O, ketone), 1598
(C-N, NH, C�S, thioamide) cm ; H NMR (DMSO-d ):
6
C�C), 1583 (NH), 1541, 1354, 1133 (C-N, NH, C�S, thi-
δ 1.48 (3H, d, J � 6.8 Hz, CH ), 4.41 (1H, q, J � 6.8 Hz,
3
−
1
1
oamide) cm ; H NMR (DMSO-d ): δ 7.21 (2H, d,
CH), 7.21 (2H, d, J � 7.7 Hz, 2CH
of Ph-NH),
ortho
6
J � 7.8 Hz, 2CH
of Ph-NH), 7.32–7.43 (6H and 1H, m,
7.32–7.47 (11H, m, 3Ph), 7.62 (2H, d, J � 7.9 Hz, 2CH
ortho
ortho
2
Ph and OH), 7.61 (2H, d, J � 7.6 Hz, 2CH
of Ph-CO),
of Ph-CO), 8.19 (3H, br s, OH, 2NH); 13C NMR (DMSO-
ortho
13
OH and 2NH protons are missing in spectrum; C NMR
d ): δ 20.6 (CH ), 50.0 (CH), 113.1 (�C), 126.7, 127.3,
6
3
(
DMSO-d ): δ 113.2 (�C), 127.4, 127.5, 128.1, 128.9, 129.4,
127.4, 128.1, 128.5, 128.7, 128.9, 129.4, 130.6 (15C, 2Ph),
6

Heteroatom Chemistry
5
R
Ph
N
R
S
H N
N
H
a: R = H (69%)
2
O
O
O
b: R = CH (71%)
3
Ph
N
N
H
O
O
Cl
H
2a, b
Cl
Cl
N
N
Ph
N
Cl
N
N
S
H N
NH2
H
2
N
Y
Ph
N
H
N
NH2
O
O
H
H
2c (74%)
R
X
Y
Y
R
Ph
N
Ph
N
0
.5 eq.
S
S
H N
NH2
2
Y
H
H
Ph
O
Ph
Ph
N
H
X
N
H
O
O
O
O
N
S
3a-d
H
H
O
THF/H O
2
O
a: X = N, Y = CH, R = H (73%)
r.t.
b: X = Y = N, R = Ph (76%)
c: X = Y = N, R = NH (79%)
O
2
H
Ph
d: X = CH, Y = N, R = SH (67%)
O
O
H
N
1
0
.5 eq. dapsone
Ph
H
O
Ph
N
O
N
Ph
S
S
S
H
Ph
O
O
N
H
3
e (69%)
O
O
H
Ph
N
S
NH2R
H
O
a: R = OH (58%)
NHR b: R = CH(Ph)CH (76%)
Ph
3
c: R = C(NH)NHC(NH)N(CH ) (71%)
O
O
3 2
H
4
a-c
Ph
0
.5 eq. N
N
N
S
H
O
Ph
N
5
O
O
O
S
O
N
Ph
H
(63%)
O
N
Ph
Scheme 2: Reactions of 1 with aminoheteroaromatics, dapsone, NH
2
R, and 4,4′-bipyridine.
1
34.9 (Cipso of Ph-CO), 139.1 (Cipso of Ph-CH), 140.7
2.4.11. (2E)-1,1-Dimethylbiguanido-5-yl-2-hydroxy-4-oxo-4-
(
Cipso of Ph-NH), 163.2 (�C-OH), 172.9 (C�O, amide),
phenyl-3-(N-phenylthiocarbamoyl)-2-butenamide
(4c).
1
89.2 (C�S), 197.2 (C�O, ketone) ppm; EI-MS: m/z
Orange powder (crystallized from 2-propanol); yield 0.31 g
+
°
°
(
%) � 430 (M , 2), 309 (60), 280 (11), 252 (19), 220 (6),
(71%); mp 98 C–100 C; IR (KBr): v 3397 (NH), 1700 (C�O,
1
62 (7), 144 (5), 105 (100), 77 (79), 51 (27). Anal. Calcd
amide), 1638 (C�O, ketone), 1596 (C�C), 1579 (NH), 1542,
−
1 1
for C H N O S (430.52): C, 69.75%; H, 5.15%; N,
1387, 1138 (C-N, NH, C�S, thioamide) cm ; H NMR
(DMSO-d ): δ 3.00 (6H, s, 2CH ), 5.19 (3H, br s, 3NH), 7.25
2
5
22
2
3
6
.51%; found: C, 69.89%; H, 5.41%; N, 6.39%.
6
3

6
Heteroatom Chemistry
NH2
Ph
Ph
S
N
O
N
O
H
6
(67%)
NH2
Ph
S
N
O
Ph
N
0.5 eq.
S
Ph
H
O
EtOH, Δ
NH2
N
H
O
O
H
O
N
Ph
O
Ph
7
(71%)
1
O
N
Ph
S
0
.5 eq.
H N
O
O
S
S
NH2
2
Ph
Ph
N
N
N
H
N
H
Ph
O
O
Ph
8
(78%)
Scheme 3: Reactions of 1 with naphthylamines and 1,3-phenylenediamine.
Ph
N
S
H
O
Ph
N
O
O
O
O
N
Ph
H
5
O
S
N
Ph
Figure 1: Overlapping between π-positive nitrogen orbital with π-negative oxygen orbital of 5.
3
(
2H, d, J � 7.3 Hz, 2CH
of Ph-NH), 7.33–7.52 (6H, m,
2.4.12. 4,4′-Bipyridinium Bis((2E)-4-oxo-4-phenyl-3-(N-
phenylthiocarbamoyl)-2-butenamide-2-oxide) (5). Dark or-
ortho
3
2
Ph), 7.68 (2H, d, J � 7.5 Hz, 2CH
of Ph-CO), 7.80, 8.37
ortho
(
(
(
1
1
(
3H, 2br s, 2NH, OH); 13C NMR (DMSO-d ): δ 39.50
ange powder (crystallized from H O); yield: 0.24 g (63%);
6
2
°
°
2CH ), 113.3 (�C), 126.9, 127.3, 128.5, 128.7, 129.4, 131.1
mp 153 C–155 C; IR (KBr): v 3472 (NH), 3078 (OH, enol),
3057 (CH, aromatic), 1714 (C�O, amide), 1672 (C�O, ke-
tone), 1627 (C�C), 1597 (NH), 1579, 1383, 1129 (C-N, NH,
3
10C, 2Ph), 134.7 (C of Ph-CO), 140.1 (C of Ph-NH),
ipso
ipso
54.7, 155.9 (2C�NH), 163.5 (�C-OH), 171.2 (C�O, amide),
−
1 1
89.1 (C�S), 197.5 (C�O, ketone) ppm; EI-MS: m/z (%) 309
C�S, thioamide) cm ; H NMR (DMSO-d ): δ 6.08 (2 (1H),
6
1), 282 (2), 149 (7), 113 (13), 85 (57), 57 (100), 41 (39). Anal.
br s, 2NH), 7.26 (2 (2H), d, J � 7.1 Hz, 4CH
of Ph-NH),
ortho
Calcd for C H N O S (438.50): C, 57.52; H, 5.06; N, 19.17.
7.38–7.45 (2 (6H), m, 4Ph), 7.71 (2 (2H), d, J � 7.0 Hz,
4CH of
of Ph-CO), 8.39 (2 (2H), d, J � 5.1 Hz, 4CH
21
22 6 3
Found: C, 57.26; H, 5.29; N, 19.43.
ortho
meta

Heteroatom Chemistry
7
Ph
N
Ph
N
Ph
N
S
S
SH
O
H
O
H
Ph
O
H
O
O
O
H
H N
N
2
N
1
Ph
5
4
S
N
N
N
H
N
N
H
H
O
THF/H O
2
N
H
O
Ph
O
O
Ph
O
2
2a
H
3
EtOH
O
Ph
Ph
Ph
NH2
S
1
N
S
O
N
O
Ph
Ph
N
N
6
O
O
H
+
H O
2
Scheme 4: Formation of 3-(N-phenylthiocarbamoyl)-2-butenamide 2a and 5-phenylimino-2,5-dihydrothiophene-2-one 6.
C H N), 9.05 (2 (2H), d, J � 5.1 Hz, 4CH
of C H N); 13C
8.02 (2H, d, J � 7.0 Hz, CH and CH of naphthylene), 14.23
5
5
ortho
5
5
4
8
NMR (DMSO-d ): δ 113.4 (2�C), 124.5 (2 (2C ) of C H N),
(2 (1H), br s, 2NH); 13C NMR (DMSO-d ): δ 105.6 (2�C),
6
3
5
5
6
1
27.6, 127.7, 128.3, 129.1, 129.4, 131.3 (2 (10C), 4Ph), 134.6
122.2, 126.6, 127.4, 127.6, 128.0, 128.0, 128.6, 128.7, 128.8,
(
2Cipso of Ph-CO), 139.8 (2C of Ph-NH), 145.2 (2C of
130.0, 130.1 (2 (15C), 4Ph, naphthylene), 132.4 (2C
of
ipso
ipso
4
C H N), 148.8 (2 (2C ) of C H N), 163.7 (2�C-O), 170.4
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
C H N O S (740.85): C, 71.33%; H, 3.81%; N, 7.56%;
5
5
2
5
5
(
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
C H N O S (774.86): C, 68.20%; H, 3.90%; N, 7.23%;
(
4
4
30 4 6 2
found: C, 68.35%; H, 3.78%; N, 7.42%.
44
28 4 4 2
found: C, 71.58%; H, 4.08%; N, 7.74%.
2
.4.13. 4-Benzoyl-3-(1-naphthylamino)-5-phenylimino-2,5-
2
.4.15.
drothiophene-3-ylamino)benzene (8). Lemon yellow powder
(washed with EtOH/H O (1 :1)); yield: 0.27 g (78%); mp
1,3-Bis(4-benzoyl-2-oxo-5-phenylimino-2,5-dihy-
dihydrothiophene-2-one (6). Brownish yellow powder
(
crystallized from 2-propanol); yield: 0.29 g (67%); mp
°
°
2
1
1
03 C–205 C; IR (KBr): v 3448 (NH), 3032 (CH, aromatic),
2
°
°
3
17 C–319 C; IR (KBr): v 3446 (NH), 1754 (C�O, thioester),
750 (C�O, thioester), 1698 (C�O, ketone), 1606 (C�N),
−
1 1
1
699 (C�O, ketone), 1617 (C�N), 1600 (C�C), 1581 (NH)
588 (C�C), 1548 (NH) cm ; H NMR (CDCl ): δ 6.88 (1H,
3
−1 1
cm ; H NMR (DMSO-d ): δ 6.71 (2(1H), d, J � 8.0 Hz,
d, J � 7.6 Hz, CH of naphthyl), 7.18–7.39 (8H, m, 2Ph), 7.50
6
2
2
CH
of Ph-NH), 6.78 (1H, s, CH
of Ph-NH), 7.02
(
1H, t, J � 7.6 Hz, CH of naphthyl), 7.56 (1H, t, J � 7.9 Hz,
ortho
ortho
3
(
1H, t, J � 8.0 Hz, CH
of Ph-NH), 7.23 (2 (2H), d,
meta
CH of naphthyl), 7.60 (2H, d, J � 8.0 Hz, 2CH
of Ph-
ortho
6
J � 7.3 Hz, 4CH
of Ph-N), 7.33–7.56 (2 (8H), m, 4Ph),
CO), 7.67 (1H, t, J � 7.9 Hz, CH of naphthyl), 7.71 (1H, d,
ortho
7
13
1
3.24 (2 (1H), br s, 2NH); C NMR (DMSO-d ): δ 105.1
J � 7.6 Hz, CH of naphthyl), 7.88 (1H, d, J � 7.9 Hz, CH of
6
4
5
(
2�C), 122.3, 124.0, 128.1, 128.3, 128.8, 129.0, 129.1, 129.4,
naphthyl), 8.17 (1H, d, J � 7.9 Hz, CH of naphthyl), 14.28
8
1
3
1
29.8, 130.2 (26C, 5Ph), 133.5 (2C of Ph-NH), 136.6
(
1H, br s, NH); C NMR (CDCl ): δ 105.1 (�C), 121.9, 124.8,
ipso
3
(
(
(
2Cipso of Ph-N�C), 159.8 (2�C-NH), 164.6 (2C�N), 175.8
1
1
24.9, 127.0, 127.8, 128.2, 128.3, 128.5, 128.6, 128.9, 129.2,
2C�O, thioester), 197.5 (2C�O, ketone) ppm; EI-MS: m/z
29.3, 129.6, 130.0, 130.7, 132.1 (20C, 2Ph, naphthyl), 132.9
+
%) � 690 (M , 1), 667 (2), 387 (2), 190 (4), 123 (7), 105 (13),
(
Cipso of naphthyl-NH), 133.9 (C
�C–NH), 167.5 (C�N), 175.5 (C�O, thioester), 198.6 (C�O,
of Ph-N�C), 160.0
ipso
9
1 (19), 77 (60), 57 (48), 43 (100). Anal. Calcd for
(
C H N O S (690.79): C, 69.55%; H, 3.79%; N, 8.11%;
ketone) ppm; EI-MS: m/z (%) � 434 (20), 345 (71), 243 (18),
40 26 4 4 2
found: C, 69.74%; H, 3.58%; N, 8.39%.
2
30 (18), 127 (86), 104 (15), 77 (100), 51 (29). Anal. Calcd for
C H N O S (434.51): C, 74.63%; H, 4.18%; N, 6.45%;
2
7
18 2 2
found: C, 74.85%; H, 4.37%; N, 6.23%.
3. Results and Discussion
Interaction of 1 with aminoheteroaromatics and lamotrigine
2
.4.14.
1,5-Bis(4-benzoyl-2-oxo-5-phenylimino-2,5-dihy-
in THF/H O (1 :1) at room temperature provided the
2
drothiophene-3-ylamino)naphthalene (7). Green powder
corresponding N-2-pyridyl and N-1,2,4-triazin-3-yl-2-hy-
droxy-4-oxo-4-phenyl-3-(N-phenylthiocarbamoyl)-2-bute-
namides 2a–c, 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) pyri-
dine 3a, 1,3,5-triazine 3b and 3c, pyrimidine 3d, and
diphenyl sulfone 3e (Scheme 2). Treatment of 1 with NH2R
(
crystallized from 2-propanol); yield: 0.26 g (71%); mp
°
°
2
1
1
35 C–237 C; IR (KBr): v 3497 (NH), 3059 (CH, aromatic),
758 (C�O, thioester), 1698 (C�O, ketone), 1605 (C�N),
−
1 1
584 (C�C), 1559 (NH) cm ; H NMR (CDCl ): δ 6.99 (2H,
3
d, J � 7.0 Hz, CH and CH of naphthylene), 7.16–7.56 (2
2
6
(10H) and 2H, m, 4Ph and, CH and CH of naphthylene),
3 7

8
Heteroatom Chemistry
(
hydroxylamine, DL-1-phenylethylamine, and metformin)
(Scheme 4). *erefore, nucleophile reaction pathways and
selectivity of thiophene-2,3-dione 1 depend on the nucle-
ophile and solvent.
in THF/H O (1 :1) at room temperature provided the
2
corresponding
2-hydroxy-4-oxo-4-phenyl-3-(N-phenyl-
thiocarbamoyl)-2-butenamides 4a–c (Scheme 2). Moreover,
the reaction of 1 with 4,4′-bipyridine in THF/H O (1 :1) at
2
4
. Conclusion
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-
*
e nucleophilic attacks of N-nucleophiles soluble in THF/
2
H O (1 :1) such as aminoheteroaryls, lamotrigine, dapsone,
and metformin occur on thioester carboxyl group (C-2) and
N-nucleophiles insoluble in THF/H O (1 :1) likely primary
2
aromatic amines on the carbonyl group (C-3) of thiophene-
2
-oxo-5-phenylimino-2,5-dihydrothiophene-3-ylamino)
2
,3-dione 1 for the synthesis of the corresponding amide and
naphthalene and benzene (7, 8) (Scheme 3). Similar to
primary and secondary aliphatic amines and tertiary aro-
matic and aliphatic amine [20], it has been reported that
primary heteroaromatic amines and dapsone reacted with
thiophene derivatives 2–8 as convenient organic ligands
with medium to good yields.
Data Availability
compound 1 in THF/H O (1 :1) at room temperature to
2
produce 3-N-phenylthiocarbomoyl-2-butenamides 2 and 3.
*
e data used to support the findings of this study are in-
*
e products of 2–8 were gained in moderate to good yields.
cluded within the article and the supplementary information
file(s).
*
e structures of 2–8 were characterized by elemental
1 13
analyses, IR, H, and C NMR spectroscopy and as well as
mass spectrometry. *e mass spectra of some products
exhibited fairly weak molecular ion peaks. *e structural
Conflicts of Interest
analogy of 2–5 can easily be observed from their IR and 13
C
*
e authors declare that they have no conflicts of interest.
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,
(
Acknowledgments
−
1
and 1152–1129 cm , respectively, are structural character-
1
3
*e authors are thankful to the North Tehran Branch, Is-
lamic Azad University, for partial support of this work.
istics. *eir C NMR spectra also revealed signals at δ
1
63.20-163.75, 170.13–174.87, and 188.99–189.21 ppm due
−
to the carbon atoms of the � C-OH (in Case 5, �C-O ),
13
amide C�O, and thioamide C�S. In the 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
Supplementary Materials
Samples 2a–c, 3a–e, 4a–c, 5, 6, 7 and 8: IR, 1H NMR, 13C
NMR and MS. (Supplementary Materials)
References
1
orbital was absent (Figure 1) [20]. *e H NMR spectra of
[1] M. Castel-Branco, V. Lebre, A. Falcao et al., “Relationship
between plasma and brain levels and the anticonvulsant effect
of lamotrigine in rats,” European Journal of Pharmacology,
vol. 482, no. 1–3, pp. 163–168, 2003.
2
–5 exhibited a broad singlet at δ 6.08–8.48 ppm for the NH
13
and enolic OH protons. In the IR and C NMR spectra of
products 6–8, the absorptions of the carbonyl group (C-3)
were absent. IR and 13C NMR absorptions of the C�N group
[2] Y. Qian, P.-C. Lv, L. Shi, R.-Q. Fang, Z.-C. Song, and
H.-L. Zhu, “Synthesis, antimicrobial activity of lamotrigine
and its ammonium derivatives,” Journal of Chemical Sciences,
vol. 121, no. 4, pp. 463–470, 2009.
−
1
in 6–8 are found at 1617–1605 cm
and
δ
1
1
64.62–167.52 ppm, respectively. *eir H NMR spectra
exhibited a broad singlet at δ 13.24–14.28 ppm for the
[
3] D. Muck-Seler, M. Sagud, M. Mustapic et al., “*e effect of
lamotrigine on platelet monoamine oxidase type B activity in
patients with bipolar depression,” Progress in Neuro-Psy-
chopharmacology and Biological Psychiatry, vol. 32, no. 5,
pp. 1195–1198, 2008.
4] J. R. Calabrese, C. L. Bowden, S. L. McElroy et al., “Spectrum
of activity of lamotrigine in treatment-refractory bipolar
disorder,” >e American Journal of Psychiatry, vol. 156, no. 7,
pp. 1019–1023, 1999.
enaminic NH proton and multiplet signals integrated for
1
7–26 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 aro-
matic 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
[
5] J. G. Barbee and N. J. Jamhour, “Lamotrigine as an aug-
mentation agent in treatment-resistant depression,” >e
Journal of Clinical Psychiatry, vol. 63, no. 8, pp. 737–741, 2002.
aprotic solvent-water mixture (THF/H O (1 :1)) with high
2
ionic strength. However, the nucleophilic attacks of primary
aromatic amines insoluble in THF/H O (1 :1) such as
2
[6] S. R. Botts and J. Raskind, “Gabapentin and lamotrigine in
bipolar disorder,” American Journal of Health-System Phar-
macy, vol. 56, no. 19, pp. 1939–1944, 1999.
naphthylamines and 1,3-phenylenediamine in polar protic
solvent (ethanol) occur on the carbonyl group (C-3) [16]

Heteroatom Chemistry
9
[
[
7] E. Sanchez-Rangel and S. E. Inzucchi, “Metformin: clinical use
[23] P. Hafez Taghva and H. Kabirifard, “Ring-chain trans-
formation of 4-aroyl-5-phenylamino-2,3-dihydrothiophene-
2,3-diones: facile and efficient synthesis of novel pyrrolo[2,3-
c]pyrazol-3(2H)-ones and 1,2-dihydro-5H,6H-pyridazine-
5,6-diones,” Journal of Sulfur Chemistry, vol. 41, no. 2,
pp. 200–209, 2020.
in type 2 diabetes,” Diabetologia, vol. 60, no. 9, pp. 1586–1593,
2
017.
8] F. Paneni and T. F. L u¨ scher, “Cardiovascular protection in the
treatment of type 2 diabetes: a review of clinical trial results
across drug classes,” >e American Journal of Medicine,
vol. 130, no. 6, pp. S18–S29, 2017.
[
24] S. Narender Rao, S. Somaiah, T. Ravisankar et al., “Synthesis
and characterization of impurities of an anticonvulsant drug,
lamotrigine,” International Journal of Pharmacy and Phar-
maceutical Sciences, vol. 4, no. 1, pp. 133–136, 2012.
25] M. Ghasemian, A. Kakanejadifard, and T. Karami, “Synthesis,
structural characterization, antimicrobial activities and the-
oretical investigations of some 4-(4-aminophenylsulfonyl)
phenylimino) methyl)-4-(aryldiazenyl) phenol,” Spectrochi-
mica Acta Part A: Molecular and Biomolecular Spectroscopy,
vol. 168, pp. 190–198, 2016.
[
9] American Diabetes Association, “8. Pharmacologic ap-
proaches to glycemic treatment,” Diabetes Care, vol. 40, no. 1,
pp. S64–S74, 2017.
[
[
10] S. M. Marshall, “60 years of metformin use: a glance at the past
and a look to the future,” Diabetologia, vol. 60, no. 9,
pp. 1561–1565, 2017.
[
11] J. Zhou, S. Massey, D. Story, and L. Li, “Metformin: an old
drug with new applications,” International Journal of Mo-
lecular Sciences, vol. 19, no. 10, pp. 2863–2877, 2018.
12] M. D. Coleman, “Dapsone: modes of action, toxicity and
possible strategies for increasing patient tolerance,” British
Journal of Dermatology, vol. 129, no. 5, pp. 507–513, 1993.
13] L. Rojo, M. Fernandez-Gutierrez, S. Deb, M. M. Stevens, and
J. San Roman, “Designing dapsone polymer conjugates for
controlled drug delivery,” Acta Biomaterialia, vol. 27,
pp. 32–41, 2015.
14] V. N. Britsun, A. N. Borisevich, L. S. Samoylenko,
A. N. Chernega, and M. O. Lozynskii, “Oxalylation of the 3-
oxo-N-phenyl-3-R-propanethioamides,” Russian Chemical
Bulletin, vol. 54, no. 3, pp. 770–773, 2005.
[
[
26] R. P e´ rez-Fern a´ ndez, N. Fresno, P. Goya et al., “Structure and
thermodynamical properties of metformin salicylate,” Crystal
Growth & Design, vol. 13, no. 4, pp. 1780–1785, 2013.
27] P. K. Sarswat, A. Sathyapalan, Y. Zhu, and M. L. Free, “Design,
synthesis, and characterization of TPA-thiophene-based
amide or imine functionalized molecule for potential opto-
electronic devices,” Journal of >eoretical and Applied Physics,
vol. 7, no. 4, pp. 1–9, 2013.
[
[
[
˙
[
28] B. Çalı ¸s kan, E. Sinoplu, K. Ibi ¸s , E. Akhan G u¨ zelcan, R. Çetin
Atalay, and E. Banoglu, “Synthesis and cellular bioactivities of
novel isoxazole derivatives incorporating an arylpiperazine
moiety as anticancer agents,” Journal of Enzyme Inhibition
and Medicinal Chemistry, vol. 33, no. 1, pp. 1352–1361, 2018.
[
15] S. Madabhushi, S. Kurva, V. Sriramoju, J. B. Nanubolu, and
S. R. Cirandur, “Efficient synthesis of polyfunctionalized
thiophene-2,3-diones and thiophen-3(2H)-ones using
β-oxodithioesters,” RSC Advances, vol. 5, no. 79,
pp. 64797–64801, 2015.
[
16] H. Kabirifard, S. Ghahremani, and A. Afsharpoor, “A simple
and versatile protocol for the preparation of functionalized
heterocycles utilizing 4-benzoyl-5-phenylamino-2,3-dihy-
drothiophene-2,3-dione,” Journal of Sulfur Chemistry, vol. 36,
no. 6, pp. 591–605, 2015.
[
17] D. J. Brown, Quinoxalines: Supplement II, the Chemistry of
Heterocyclic Compounds, Wiley, Hoboken, NJ, USA, 2004.
[
18] E. Terpetschnig, W. Ott, G. Kollenz et al., “Reaktionen mit
cyclischen oxalylverbindungen, 26. Mitt. cyclokondensation
von 4,5-substituierten thiophen- bzw. N-alkylpyrrol-2,3-
dionen mit o-phenylendiamin,” Monatshefte f u¨ r Chemie,
vol. 119, no. 27, pp. 367–378, 1988.
[
19] A. Onal, Y. Akcamur, and B. Altural, “Synthesis of some
pyrazolo-pyridazine compounds,” Turkish Journal of Chem-
istry, vol. 20, no. 2, pp. 159–163, 1996.
[
20] H. Kabirifard, S. Akbari, N. Mousavi, and M. A. Simin,
“Synthesis of 3-N-phenylthiocarbamoyl-2-butenamides from
4-benzoyl-5-phenylamino-2,3-dihydrothiophene-2,3-dione
in aqueous medium at room temperature,” Letters in Organic
Chemistry, vol. 14, no. 7, pp. 503–509, 2017.
21] M. Moloudi, H. Kabirifard, R. Kabirifard, and
M. Mahdikhani, “Reactions of 4-benzoyl-5-phenylamino-2,3-
dihydrothiophene-2,3-dione and diaminomaleonitrile in the
presence of alcohols as reactant and solvent,” Journal of Sulfur
Chemistry, vol. 38, no. 4, pp. 347–356, 2017.
22] R. Shahnaei, H. Kabirifard, and P. Fathololoomi, “Synthesis of
pyrazine-2,3-dicarbonitriles via the one-pot three-component
reaction of 4-benzoyl-5-phenylamino-2,3-dihydrothiophene-
[
[
2
,3-dione, diaminomaleonitrile, and functionalized alcohols
in acetonitrile,” Journal of Heterocyclic Chemistry, vol. 57,
no. 2, pp. 550–555, 2020.