Synthesis and reactions of some heterocyclic candidates based on 2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene moiety as anti-arrhythmic agents

Article abstract of DOI:10.1002/jhet.1554

In continuation of our previous work, a series of novel thiophene derivatives 4-16 were synthesized by the reaction of ethyl 2-amino-4,5,6,7- tetrahydrobenzo[b]thiophene-3-carboxylate (1) or 2-amino-4,5,6,7- tetrahydrobenzo[b]thiophene-3-carbonitrile (2)

Full text of DOI:10.1002/jhet.1554

766
Synthesis and Reactions of Some Heterocyclic Candidates Based on
2-Amino-4,5,6,7-tetrahydrobenzo[b]thiophene Moiety as
Anti-Arrhythmic Agents
Vol 50
Mohamed G. Assy,a Mohamed H. Sherif,a Abd El-Galil E. Amr,b,c* Osama I. Abdelsalam,c Mohamed A. Al-Omar,d
Mohamed M. Abdalla,e and Islam Ragaba
aDepartment of Chemistry, Faculty of Science, Zagazig University, Zagazig, Egypt
bDrug Exploration and Development Chair, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia
cApplied Organic Chemistry Department, National Research Center, Cairo, Dokki, Egypt
dDepartment of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia
eResearch Unit, Saco Pharm. Co., Giza, Egypt
*
E-mail: aamr1963@yahoo.com
Received August 27, 2011
DOI 10.1002/jhet.1554
Published online 24 June 2013 in Wiley Online Library (wileyonlinelibrary.com).
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CN
NC
O
N
O
O
N
O
O
N
O
O
N
O
S
S
S
S
In continuation of our previous work, a series of novel thiophene derivatives 4–16 were synthesized
by the reaction of ethyl 2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate (1) or 2-amino-
4,5,6,7-tetrahydrobenzo[b]thiophene-3-carbonitrile (2) with different organic reagents. Fusion of 1 with
ethylcyanoacetate or maleic anhydride afforded the corresponding thienooxazinone derivative 4 and N-
thienylmalimide derivative 5, respectively. Acylation of 1 with chloroacetylchloride afforded the amide
6, which was cyclized with ammonium thiocyanate to give the corresponding N-theinylthiazole deriv-
ative 8. On the other hand, reaction of 1 with substituted aroylisothiocyanate derivatives gave the
corresponding thiourea derivatives 9a–e, which were cyclized by the action of sodium ethoxide to
afford the corresponding N-substituted thiopyrimidine derivatives 10a–e. Condensation of 2 with acid
anhydrides in refluxing acetic acid afforded the corresponding imide carbonitrile derivatives 11–13.
Similarly, condensation of 1 with the previous acid anhydride yielded the corresponding imide ethyl ester
1
derivatives 14–16, respectively. The structures of newly synthesized compounds were confirmed by IR, H
NMR, 13C NMR, MS spectral data, and elemental analysis. The detailed synthesis, spectroscopic data,
LD50, and pharmacological activities of the synthesized compounds are reported.
J. Heterocyclic Chem., 50, 766 (2013).
INTRODUCTION
anticancer activities [23–25]. In addition, in our previous
work, the newly substituted heterocyclic compounds exhib-
ited anti-androgenic [26], anti-inflammatory [27], anticancer
[28], anticonvulsant [29], and antiarrhythmic [30] activities.
Recently, some thienopyrimidinone and p-methoxyphenyl
pyrrolidine derivatives were synthesized, which exhibit
analgesic, antiparkinsonian, anti-inflammatory, serotonin an-
tagonist, and anti-anxiety activities [31–33]. In view of the
aforementioned facts and continuation of our previous work
[34] on tetrahydrobenzothiophene, it seemed most interesting
to synthesize some new heterocyclic thiophene derivatives
with the aim to evaluate their anti-arrhythmic activity.
Thiophene derivatives are very important compounds
because of their high reactivity usefulness in organic
chemistry as key starting materials to form various classes
of biological-active compounds. Also, they play a part in
animal metabolism. For example, in Figure 1, BiotinW,
one of the vitamins (Vitamin H), is a tetrahydrothiophene;
however, aromatic thiophenes do occur in some plants, in
association with polyacetylenes with which they are
biogenetically linked, and BanminthW (pyrantel), available
anthelmintic used in animal husbandry, is one of the
thiophene compounds in chemotherapy.
In the previous work, several of thiophene derivatives are
known as analgesic [1,2], anticonvulsant, anti-inflammatory
and antibacterial [3–6], antipyretic [7], antitumor [8,9], anti-
parasitic [10], antimicrobial [11], antihistaminic (H1) [12],
anti-anxiety [13], anti-arrhythmic [14], and serotonin
antagonist [15] agents. Also, we reported the synthesis of
substituted heterocyclic derivatives as antimicrobial [16],
anti-inflammatory [17–19], and antitumor [20–22]
agents. On the other hand, thioxopyrimidine and thiazolo-
pyrimidine derivatives have promising biological and
RESULTS AND DISCUSSION
Chemistry. Ethyl 2-amino-4,5,6,7-tetrahydrobenzo[b]
thiophene-3-carboxylate (1) and 2-amino-4,5,6,7-tetrahydrobenzo
[b]thiophene-3-carbonitrile (2) were synthesized according to
the reported procedures [35–38] as starting materials
(Scheme 1).
Fusion of ethyl aminothiophene carboxylate 1 with ethyl-
cyanoacetate afforded the corresponding thienooxazinone
© 2013 HeteroCorporation

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Synthesis and Reactions of Some Heterocyclic Candidates
767
dry acetone gave the corresponding thiourea derivatives
9a–e, which were cyclized by refluxing in ethanolic
sodium ethoxide to afford the corresponding N-substituted
thiopyrimidine derivatives 10a–e (Scheme 3).
Condensation of 2-amino-4,5,6,7-tetrahydrobenzo[b]
thiophene-3-carbonitrile (2) with acid anhydrides, namely,
3,4,5,6-tetrachlorophthalic anhydride, 1,2,4,5-benzenete-
tracarboxylic dianhydride, and 1,4,5,8-naphthalene tetra-
carboxylic dianhydride in refluxing acetic acid afforded
the corresponding imide 11 and bis-imide 12 and 13
carbonitrile derivatives, respectively (Scheme 4). The IR
spectra of compounds 11–13 showed the absence of n
(NH2) at 3455–3320 cmꢀ1 for compound 2 and the presence
of bands at 1696–1688 cmꢀ1 corresponding to n (C═O,
imide) and at 2220–2210cmꢀ1 corresponding to n (CN).
Similarly, condensation of 1 with the previous acid anhy-
drides in refluxing acetic acid yielded the corresponding
imide 14 and bis-imide 15 and 16 ethyl ester derivatives,
respectively (Scheme 5). The IR spectra of compounds
14–16 showed the absence of n (NH2) at 3460–3400 cmꢀ1
for compound 1 and the presence of bands at 1680–1675 cmꢀ1
and 1725–1715 cmꢀ1 corresponding to n (C═O, imide)
and n (C═O, ester), respectively.
Figure 1. Chemical structure of (+)-biotin and banminth.
Scheme 1. Synthetic routes for starting materials 1 and 2.
Pharmacological screening. Anti-arrhythmic activity.
Procaine amide 5 mg kgꢀ1 i.v. and lidocaine 5 mg kgꢀ1
i.v. lead to an increase in LD100 by 65%, which
corresponds to an LD100 of approximately 9 mg/100 mg
(Fig. 2).
In Table 1 and Figure 2, all the tested compounds
showed potent anti-arrhythmic activities, where the com-
pounds 4, 6, 9c, 10b, 10c, 11, and 15 are more potent than
derivative 4 via the non-isolable cyanoacetamide 3.
Condensation of amino ester 1 with maleic anhydride in
refluxing glacial acetic acid afforded the corresponding
N-thienylmalimide 5 (Scheme 2).
Acylation of amino ester 1 with chloroacetylchloride
afforded chloroacetamide derivative 6, which was cyclized
with ammonium thiocyanate to give the corresponding N-
theinylthiazole derivative 8 via the non-isolable thiocya-
nate derivative 7. On the other hand, reaction of 1 with
substituted aroylisothiocyanate derivatives in refluxing
procaine amide and lidocaine.
Determination of acute toxicity (LD50). The LD50 was
determined by using rats. They were injected with
different increasing doses of the synthesized compounds.
Scheme 2. Synthetic routes for compounds 3–5.
Journal of Heterocyclic Chemistry
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768
M. G. Assy, M. H. Sherif, A. E.-G. E. Amr, M. A. Al-Omar, M. M. Abdalla, and I. Ragab
Vol 50
Scheme 3. Synthetic routes for compounds 6a–e to 10a–e.
CONCLUSION
A series of new thiophene heterocyclic candidates were
synthesized as anti-arrhythmic agent by using 2-amino-tet-
rahydrobenzo[b]thiophene derivatives as starting materials.
The anti-arrhythmic screening showed that many of these
obtained compounds have good activities comparable with
the reference controls. The detailed synthesis, spectroscopic
data, LD50, and pharmacological activities of the synthesized
compounds are reported herein.
EXPERIMENTAL
All melting points are uncorrected and measured using an
Electrothermal IA 9100 apparatus (Shimadzu, Tokyo, Japan). IR
spectra were recorded as potassium bromide pellets on a Perkin-
Elmer 1650 spectrophotometer (Perkin-Elmer, Norwalk, CT,
USA). 1H NMR was determined on a Jeol-Ex-270 NMR
spectrometer (JEOL, Tokyo, Japan), and chemical shifts were
expressed as parts per million, ppm (d values), against TMS as
internal reference. Mass spectra were recorded on VG 2AM-3F
mass spectrometer (Thermo Electron Corporation, USA).
Microanalyses were operated using a Mario El Mentar apparatus,
Organic Microanalysis Unit (NRC), and the results were within
the accepted range (ꢁ0.2%) of the calculated values. Follow-up
of the reactions and checking the purity of the compounds were
made by TLC on silica gel-coated aluminum sheets (Type
60F254, Merck, Darmstadt, Germany).
Synthesis of 3-cyanomethyl-4,5,6,7,-tetrahydrobenzo[b]
The dose that killed 50% of the animal was calculated
thiono[2,3-d]oxazine-4-(3H)-one (4).
A mixture of amino
according to Austen et al. [39] and summarized in Table 2.
ester derivative 1 (2.25 g, 0.01 mol) and ethyl cyanoacetate
Scheme 4. Synthetic routes for compounds 11–13 (color figure can be viewed in the online issue which is available at www.interscience.wiley.com).
Journal of Heterocyclic Chemistry
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Synthesis and Reactions of Some Heterocyclic Candidates
769
Scheme 5. Synthetic routes for compounds 14–16 (color figure can be viewed in the online issue which is available at www.interscience.wiley.com).
Table 1
Antiarrhythmic activities of known and newly synthesized compounds.
Compound (5 mg kgꢀ1
)
Percentage increase in LD100
Lidocaine
63
Procaine amide
65
1
4
6
8
70.00
76.60
75.00
69.10
72.50
75.50
68.50
74.60
76.00
70.10
75.60
70.00
68.00
69.50
76.10
68.00
9b
9c
9d
10b
10c
10d
11
12
13
14
15
16
Figure 2. Antiarrhythmic activities of known and newly synthesized
compounds (color figure can be viewed in the online issue which is
available at www.interscience.wiley.com).
(1.13 g, 0.01 mol) was fused together for 1 h at 120ꢂC. The solid
obtained was crystallized from acetic acid to give the
corresponding oxazinonone derivative 4 as brown crystals. Yield
90%; mp 260–262ꢂC; IR (KBr): n = 2216–2210 (CN), 1690–1682
Synthesis of ethyl 2-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-
4,5,6,7-tetrahydrobenzo[b]-thiophene-3-carboxylate (5).
A
solution of 1 (2.25g, 0.01 mol) and maleic anhydride (~0.1 g,
0.01mol) in glacial acetic acid (20 mL) was refluxed for 3 h. The
reaction mixture was evaporated under reduced pressure, and the
obtained residue was solidified with diethyl ether. The obtained
solid was collected by filtration, dried, and crystallized from
ethanol to give dioxopyrrolo derivative 5 as yellow crystals. Yiꢀel1d
(C═O), 1605 (C═C)cmꢀ1 1H NMR (270 MHz, DMSO-d6):
;
d = 1.70–2.88 (m, 8H, cyclohexane), 4.55 (s, 2H, CH2); 13C NMR
(67.5 MHz, DMSO-d6): d = 20.08 (CH2), 22.88, 23.15, 23.62,
24.78 (4CH2), 128.88, 139.03, 139.65, 151.45 (thiophene-C),
116.32 (CN), 154.15 (C═O), 164.96 (C═N); ms: m/z 246 (M+,
8), 220 (32), 164 (100), 136 (10), 108 (12), 79 (76); Anal. Calcd
for C12H10N2O2S (246.28): C, 58.52; H, 4.09; N, 11.37; S, 13.02.
Found: C, 58.45; H, 4.00; N, 11.30; S, 12.95.
94%; mp 110–112ꢂC; IR (KBr): n = 1688, 1740 (2C═O) cm
;
1H NMR (270MHz, DMSO-d6): d = 1.32 (t, 3H, J = 7.3 Hz, CH3),
1.62–2.88 (m, 8H, cyclohexane), 4.18 (q, 2H, J = 7.3 Hz, CH2),
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M. G. Assy, M. H. Sherif, A. E.-G. E. Amr, M. A. Al-Omar, M. M. Abdalla, and I. Ragab
Vol 50
1668 (C═N) cmꢀ1; H NMR (270 MHz, DMSO-d6): d = 1.28 (t,
3H, J = 7.3 Hz, CH3), 1.60–2.92 (m, 8H, cyclohexane), 4.20 (q,
2H, J = 7.3 Hz, CH2), 7.02 (s, 1H, thiazol-H), 10.90 (s, 1H, NH
exchangeable with D2O), 12.60 (s, 1H, OH exchangeable with
D2O); 13C NMR (67.5 MHz, DMSO-d6): d = 14.18 (CH3), 23.18,
23.24, 23.82, 24.52 (4CH2), 60.58 (CH2), 112.45, 127.97, 132.45,
138.06 (thiophene-C), 148.64 (C═O), 75.10, 151.44, 198.35
(thiazol-C); ms: m/z 324 (M+, 24), 164 (100); Anal. Calcd for
C14H16N2O3S2 (324.42): C, 51.83; H, 4.97; N, 8.63; S, 19.77.
Found: C, 51.76; H, 4.92; N, 8.58; S, 19.70.
Synthesis of ethyl-2-(aroylisothiocyanate)amino-5,6,7,8-
tetrahydrobenzo[b]thiophene-3-carboxylate (9a–e). A mixture
of 1 (2.25 g, 0.01 mol) and aroylisothiocyante derivatives, namely,
benzoyl, p-methoxybenzoyl, p-chlorobenzoyl, p-fluorobenzoyl, or
4-bromobenzoyl-isothiocyanate (0.01 mol) in dry acetone (20 mL)
was refluxed for 3 h. The reaction mixture was concentrated
under reduced pressure, and the obtained solid was filtered,
dried, and crystallized from ethanol to give thiourea
derivatives 9a–e, respectively.
1
Table 2
Acute toxicity (LD50) of known compounds and newly synthesized
compounds.
Compound no.
LD50 / mg kgꢀ1
Buspirone
Diazepam
1
4
6
8
9a
9b
9c
113 ꢁ 0.18
102 ꢁ 0.10
184 ꢁ 0.17
233 ꢁ 0.15
208 ꢁ 0.19
128 ꢁ 0.18
222 ꢁ 0.18
295 ꢁ 0.15
276 ꢁ 0.18
236 ꢁ 0.17
125 ꢁ 0.10
226 ꢁ 0.19
245 ꢁ 0.11
232 ꢁ 0.15
198 ꢁ 0.19
245 ꢁ 0.17
248 ꢁ 0.16
156 ꢁ 0.12
175 ꢁ 0.15
188 ꢁ 0.18
276 ꢁ 0.17
142 ꢁ 0.15
9d
9e
10a
10b
10c
10d
10e
11
12
13
14
15
Ethyl
thiophene-3-carboxylate (9a). Yield 97%; mp 173–175ꢂC; IR
(KBr): n = 3416 (NH), 1742, 1686 (2C═O)cmꢀ1 1H NMR
2-(3-benzoylthioureido)-4,5,6,7-tetrahydrobenzo[b]
;
(270 MHz, DMSO-d6): d = 1.26 (t, 3H, J = 7.3 Hz, CH3), 1.58–
2.90 (m, 8H, cyclohexane), 4.24 (q, 2H, J = 7.3 Hz, CH2), 7.25–
7.86 (m, 5H, Ar–H), 8.45, 9.15 (2s, 2H, 2NH exchangeable with
D2O); 13C NMR (67.5 MHz, DMSO-d6): d = 14.22 (CH3), 23.16,
23.26, 23.78, 24.46 (4CH2), 60.66 (CH2), 113.55, 128.05,
138.01, 164.10 (thiophene-C), 148.66, 165.12 (2C═O), 176.56
(C═S), 127.32, 128.05, 132.13, 133.02 (Ph–C); ms: m/z 388
(M+, 6), 343 (12), 238 (8), 105 (76), 164 (100); Anal. Calcd for
C19H20N2O3S2 (388.50): C, 58.74; H, 5.19; N, 7.21; S, 16.51.
Found: C, 58.70; H, 5.16; N, 7.15; S, 16.42.
16
6.75 (d, 2H, pyrrol-H); 13C NMR (67.5MHz, DMSO-d6): d = 14.20
(CH3), 22.95, 23.10, 23.65, 24.85 (4CH2), 60.45 (CH2), 97.12,
142.05, 125.96, 127.35 (thiophene-C), 147.95, 162.03 (3C═O),
135.66 (2C, pyrrol-C); ms: m/z 305 (M+, 12), 279 (100); Anal.
Calcd for C15H15NO4S (305.35): C, 59.00; H, 4.95; N, 4.59; S,
10.50. Found: C, 58.94; H, 4.90; N, 4.54; S, 10.44.
Ethyl 2-(3-(4-methoxybenzoyl)thioureido)-4,5,6,7-tetrahydrobenzo
[b]thiophene-3-carboxylate (9b). Yield 92%; mp 190–192ꢂC;
1
IR (KBr): n = 3422 (NH), 1737, 1686 (2C═O) cmꢀ1; H NMR
(270 MHz, DMSO-d6): d = 1.30 (t, 3H, J = 7.4 Hz, CH3), 1.64–
2.88 (m, 8H, cyclohexane), 3.65 (s, 3H, OCH3), 4.18 (q, 2H,
J = 7.4 Hz, CH2), 6.95–7.78 (m, 4H, Ar–H), 8.52, 9.05 (2s, 2H,
2NH exchangeable with D2O); 13C NMR (67.5 MHz, DMSO-
d6): d = 14.18 (CH3), 22.97, 23.10, 23.67, 24.12 (4CH2), 60.64
(CH2), 60.45 (OCH3), 112.95, 128.05, 138.45, 164.12
(thiophene-C), 148.64, 165.18 (2C═O), 176.88 (C═S), 106.86,
127.98, 142.35, 153.08 (Ar–C); ms: m/z 418 (M+, 12), 311 (46),
267 (18), 195 (100), 167 (76); Anal. Calcd for C20H22N2O4S2
(418.10): C, 57.39; H, 5.30; N, 6.69; S, 15.32. Found: C, 57.25;
H, 5.18; N, 6.58; S, 15.24.
Synthesis of ethyl 2-(2-chloroacetamido)-4,5,6,7-tetrahydro-
benzo[b]thiophene-3-carboxylate (6). A mixture of 1 (2.25 g,
0.01 mol) and chloroacetylchloride (1.12g, 0.01mol) in acetic
acid (20 mL) was stirred for 2 h at room temperature. The
separated solid formed upon dilution with water (40 mL),
filtered off, dried, and crystallized from acetic acid to give
chloroacetamide 6 as brown crystals. Yield 80%; mp 80–82ꢂC;
IR (KBr): n = 3388 (NH), 1742, 1664 (2C═O) cmꢀ1
;
1H
NMR (270MHz, DMSO-d6): d = 1.25 (t, 3H, J = 7.5 Hz, CH3),
1.68–2.85 (m, 8H, cyclohexane), 4.24 (q, 2H, J = 7.5 Hz, CH2),
4.32 (s, 2H, CH2), 8.84 (s, 1H, NH exchangeable with D2O);
13C NMR (67.5MHz, DMSO-d6): d = 14.18 (CH3), 23.14, 23.54,
23.88, 24.86 (4CH2), 42.76, 60.55 (2CH2), 99.12, 1126.08,
127.15, 175.12 (thiophene-C), 148.44, 164.94 (2C═O); ms: m/z
303 (M+ + 2, 12), 301 (M+, 37), 207 (100); Anal. Calcd for
C13H16ClNO3S (301.79): C, 51.74; H, 5.34; Cl, 11.75; N,
4.64; S, 10.62. Found: C, 51.68; H, 5.28; Cl, 11.70; N, 4.59;
S, 10.58.
Synthesis of ethyl 4,5,6,7-tetrahydro-2-(4-hydroxy-2-imino-
thiazol-3(2H)-yl)benzo[b]-thiophene-3-carboxylate (8). A mixture
of compound 6 (3.01 g, 0.01 mol) and ammonium thiocyante
(0.76 g, 0.01 mol) in ethanol (20 mL) was refluxed for 3 h. The
separated solid formed upon dilution with water (20 mL),
filtered off, dried, and crystallized form acetic acid to give
hydroxythiazole derivative 8 as light brown crystals. Yield 80%;
mp 278–280ꢂC; IR (KBr): n = 3434 (NH), 1742 (C═O, ester),
Ethyl 2-(3-(4-chlorobenzoyl)thioureido)-4,5,6,7-tetrahydrobenzo
[b]thiophene-3-carboxylate (9c). Yield 86%; mp 194–196ꢂC; IR
(KBr): n = 3408 (NH), 1745, 1686 (2C═O) cmꢀ1 1H NMR
;
(270 MHz, DMSO-d6): d = 1.28 (t, 3H, J = 7.5 Hz, CH3), 1.64–
2.84 (m, 8H, cyclohexane), 4.25 (q, 2H, J = 7.5 Hz, CH2), 7.75
(d, 2H, J = 8.6 Hz, Ar–H), 7.92 (d, 2H, J = 8.6 Hz, Ar–H), 8.65,
9.45 (2s, 2H, 2NH exchangeable with D2O); 13C NMR
(67.5 MHz, DMSO-d6): d = 14.15 (CH3), 23.12, 23.32, 23.80,
24.56 (4CH2), 60.49 (CH2), 113.56, 128.15, 138.12, 164.34
(thiophene-C), 148.56, 165.32 (2C═O), 176.64 (C═S), 128.02,
130.15, 131.15, 137.32 (Ph–C); ms: m/z 424 (M+ + 2, 7), 422
(M+, 20), 139 (100); Anal. Calcd for C19H19ClN2O3S2
(422.95): C, 53.96; H, 4.53; Cl, 8.38; N, 6.62; S, 15.16. Found:
C, 53.90; H, 4.47; Cl, 8.32; N, 6.55; S, 15.12.
Ethyl 2-(3-(4-fluorobenzoyl)thioureido)-4,5,6,7-tetrahydrobenzo
[b]thiophene-3-carboxylate (9d). Yield 82%; mp 188–190ꢂC;
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IR (KBr): n = 3412 (NH), 1737, 1690 (2C═O) cmꢀ1
;
1H NMR
D2O); 13C NMR (67.5MHz, DMSO-d6): d = 22.96, 23.33, 23.35,
24.16 (4CH2), 117.48, 124.95, 139.76, 155.35 (thiophene ring),
128.12, 129.08, 130.16, 136.86 (Ph–C), 168.35, 169.45 (2C═O),
165.06 (C–SH); ms: m/z 376 (M+, 64), 164 (100); Anal. Calcd
for C17H13ClN2O2S2 (376.88): C, 54.18; H, 3.48; Cl, 9.41; N,
7.43; S, 17.02. Found: C, 54.08; H, 3.40; Cl, 9.35; N, 7.36; S,
16.96.
(270MHz, DMSO-d6): d = 1.25 (t, 3H, J = 7.3 Hz, CH3), 1.65–
2.80 (m, 8H, cyclohexane), 4.24 (q, 2H, J = 7.3 Hz, CH2), 7.65
(d, 2H, J = 8.5 Hz, Ar–H), 8.05 (d, 2H, J = 8.5 Hz, Ar–H), 8.76,
9.65 (2s, 2H, 2NH exchangeable with D2O); 13C NMR
(67.5 MHz, DMSO-d6): d = 14.05 (CH3), 22.98, 23.24, 23.75,
24.50 (4CH2), 60.59 (CH2), 113.66, 128.32, 138.24, 164.30
(thiophene-C), 148.60, 165.38 (2C═O), 176.75 (C═S), 115.46,
128.76, 129.01, 166.30 (Ph–C); ms: m/z 406 (M+, 20), 311 (100);
Anal. Calcd for C19H19FN2O3S2 (406.49): C, 56.14; H, 4.71; N,
6.89; S, 15.78. Found: C, 56.10; H, 4.65; N, 6.83; S, 15.70.
Ethyl (4-oxo-2-mercapto-4,5,6,7-terahydrobenzo[b]thieno[2,3-
d]pyrimidin-3(4H)-yl)-(4-fluorophenyl) carboxylate (10d). Yield
82%; mp 248–250ꢂC; IR (KBr): n = 1705, 1685 (2C═O), 1660
1
(C═N) cmꢀ1; H NMR (270 MHz, DMSO-d6): d =1.65–2.78 (m,
Ethyl 2-(3-(4-bromobenzoyl)thioureido)-4,5,6,7-tetrahydrobenzo
8H, cyclohexane), 7.36 (d, 2H, J=8.6Hz, Ar–H), 8.05 (d, 2H,
J = 8.6 Hz, Ar–H), 9.98 (s, 1H, SH exchangeable with D2O);
13C NMR (67.5 MHz, DMSO-d6): d = 22.94, 23.16, 23.45,
24.10 (4CH2), 117.52, 124.98, 139.36, 155.42 (thiophene
ring), 115.45, 127.08, 128.36, 165.86 (Ph–C), 167.82,
169.55 (2C═O), 165.14 (C–SH); ms: m/z 360 (M+, 32), 132
(100); Anal. Calcd for C17H13FN2O2S2 (360.43): C, 56.65;
H, 3.64; N, 7.77; S, 17.79. Found: C, 56.60; H, 3.60; N, 7.70; S,
17.73.
[b]thiophene-3-carboxylate (9e).
IR (KBr): n = 3418 (NH), 1746, 1686 (2C═O) cmꢀ1
Yield 86%; mp 216–218ꢂC;
;
1H NMR
(270MHz, DMSO-d6): d = 1.22 (t, 3H, J = 7.4 Hz, CH3), 1.70–
2.75 (m, 8H, cyclohexane), 4.18 (q, 2H, J = 7.4 Hz, CH2), 7.68 (d,
2H, J = 8.6 Hz, Ar–H), 7.90 (d, 2H, J = 8.6 Hz, Ar–H), 8.85, 9.76
(2s, 2H, 2NH exchangeable with D2O); 13C NMR (67.5MHz,
DMSO-d6): d = 14.05 (CH3), 23.16, 23.28, 23.69, 24.45 (4CH2),
60.62 (CH2), 113.67, 128.29, 138.32, 164.18 (thiophene-C), 148.55,
165.26 (2C═O), 176.78 (C═S), 126.24, 129.46, 131.14, 132.34
(Ph–C); ms: m/z 406 (M+, 20), 311 (100); Anal. Calcd for
C19H19BrN2O3S2 (467.40): C, 48.82; H, 4.10; N, 5.99; S, 13.72.
Found: C, 48.75; H, 4.02; N, 5.94; S, 13.68.
Ethyl (4-oxo-2-mercapto-4,5,6,7-terahydrobenzo[b]thieno[2,3-
d]pyrimidin-3(4H)-yl)-(4-bromophenyl) carboxylate (10e). Yield
62%; mp >300ꢂC; IR (KBr): n = 1708, 1686 (2C═O), 1664
1
(C═N) cmꢀ1; H NMR (270 MHz, DMSO-d6): d =1.72–2.72 (m,
8H, cyclohexane), 7.46 (d, 2H, J=8.6Hz, Ar–H), 7.94 (d, 2H,
J=8.6Hz, Ar–H), 10.14 (s, 1H, SH exchangeable with D2O);
13C NMR (67.5MHz, DMSO-d6): d = 23.04, 23.18, 23.34, 24.18
(4CH2), 117.48, 124.92, 139.24, 155.16 (thiophene ring), 126.15,
129.12, 130.03, 131.55 (Ph–C), 167.90, 169.65 (2C═O), 164.18
(C–SH); ms: m/z 421 (M+, 24), 255 (100); Anal. Calcd for
C17H13BrN2O2S2 (421.33): C, 48.46; H, 3.11; N, 6.65; S, 15.22.
Found: C, 48.40; H, 3.05; N, 6.60; S, 15.16.
Synthesis of 3-arylmethanone-2-thio-5,6,7,8,-tetrahydrobenzo
[b]thieno[2,3-d]pyrimidin-4-(3H)-one (10a–e).
A mixture of
compounds 9a–e (0.01 mol) and sodium ethoxide (0.68 g,
0.01 mol) in ethanol (20 mL) was refluxed for 3 h. The reaction
mixture was acidified with HCl (10 mL, 20%) and diluted with
water. The obtained solid was filtered off, dried, and crystallized
from ethanol to give thiopyrimidine derivatives 10a–e, respectively.
Ethyl (4-oxo-2-mercapto-4,5,6,7-terahydrobenzo[b]thieno[2,3-
d]pyrimidin-3(4H)-yl)-(phenyl) carboxylate (10a). Yield 95%;
mp 280–282ꢂC; IR (KBr): n = 1707, 1678 (2C═O), 1660
Synthesis of tetrachlorodioxoisoindolyl derivatives 11 and
14.
A mixture of compound 2 or 1 (1 mmol) and 1,2,3,4-
1
(C═N)cmꢀ1; H NMR (270MHz, DMSO-d6): d = 1.62–2.88 (m,
tetrachlorophthalic anhydride (0.285 g, 1 mmol) in glacial acetic
acid (50 mL) was refluxed for 6 h. The solvent was evaporated
under reduced pressure, the obtained residue was solidified with
dry ether, and the crude product was collected by filtration and
purified by recrystallization from the proper solvent to yield the
corresponding compounds 11 and 14, respectively.
2-(4,5,6,7-Tetrachloro-1,3-dioxoisoindolin-2-yl)-4,5,6,7-
tetrahydrobenzo[b]thiophene-3-carbo-nitrile (11). Yield 66%;
mp 236–238ꢂC (DMF/H2O); IR (KBr): n = 2218 (CN), 1690
(C═O, imide), 1640 (C═N) cmꢀ1; 1H NMR (270 MHz, DMSO-d6):
d = 1.65–2.76 (m, 8H, CH2, cyclohexyl-H); 13C NMR
(67.5 MHz, DMSO-d6): d = 22.96, 23.32, 23.88, 24.46
(4CH2), 77.52, 128.12, 128.76, 146.14 (thiophene-C), 116.54
(CN), 167.32 (2C═O), 127.92, 133.12, 135.08 (Ph–C); ms:
m/z 446 (M+, 65), 204 (100); Anal. Calcd for
C17H8Cl4N2O2S (446.13): C, 45.77; H, 1.81; Cl, 31.79; N,
6.28; S, 7.19. Found: C, 45.70; H, 1.78; Cl, 31.73; N, 6.22;
S, 7.15.
8H, cyclohexane), 7.10–7.86 (m, 5H, Ar–H), 10.10 (s, 1H, SH
exchangeable with D2O); 13C NMR (67.5 MHz, DMSO-d6):
d = 23.15, 23.45, 23.85, 24.66 (4CH2), 117.54, 124.25, 138..85,
155.40 (thiophene ring), 127.10, 128.08, 131.16, 131.76 (Ph-C),
168.75, 170.35 (2C═O), 164.95 (C–SH); ms: m/z 342 (M+, 16),
265 (100); Anal. Calcd for C17H14N2O2S2 (342.43): C, 59.63;
H, 4.12; N, 8.18; S, 18.73. Found: C, 59.56; H, 4.06; N, 8.10;
S, 18.66.
Ethyl
(4-oxo-2-mercapto-4,5,6,7-terahydrobenzo[b]thieno
[2,3-d]pyrimidin-3(4H)-yl)-(4-methoxyphenyl) carboxylate (10b).
Yield 95%; mp 118–120ꢂC; IR (KBr): n = 1705, 1676
(2C═O), 1662 (C═N) cmꢀ1 1H NMR (270MHz, DMSO-d6):
;
d = 1.65–2.92 (m, 8H, cyclohexane), 3.62 (s, 3H, OCH3), 7.36–
7.82 (m, 4H, Ar–H), 10.12 (s, 1H, SH exchangeable with D2O);
13C NMR (67.5 MHz, DMSO-d6): d = 23.08, 23.48, 23.80, 24.65
(4CH2), 60.36 (OCH3), 117.45, 124.15, 138..75, 155.32
(thiophene ring), 107.10, 128.22, 141.56, 153.06 (Ph–C),
168.64, 169.85 (2C═O), 164.55 (C–SH); ms: m/z 372 (M+, 12),
195 (100); Anal. Calcd for C18H16N2O3S2 (372.06): C, 58.04;
H, 4.33; N, 7.52; S, 17.22. Found: C, 57.92; H, 4.25; N, 7.42;
S, 17.08.
Ethyl 2-(4,5,6,7-tetrachloro-1,3-dioxoisoindolin-2-yl)-4,5,6,7-
tetrahydrobenzo[b]-thiophene-3-carboxylate (14).
Yield 75%;
mp 218–220ꢂC (EtOH); IR (KBr): n = 1745 (C═O, ester), 1690
1
(C═O, imide), 1640 (C═N) cmꢀ1; H NMR (270 MHz, DMSO-
Ethyl (4-oxo-2-mercapto-4,5,6,7-terahydrobenzo[b]thieno[2,3-
d]pyrimidin-3(4H)-yl)-(4-chlorophenyl) carboxylate (10c). Yield
76%; mp 288–290ꢂC; IR (KBr): n = 1704, 1682 (2C═O), 1662
d6): d = 1.24 (t, 3H, CH3), 1.72–2.96 (m, 8H, cyclohexane), 3.80
(q, 2H, CH2); 13C NMR (67.5 MHz, DMSO-d6): d = 14.05
(CH3), 23.14, 23.28, 23.76, 24.36 (4CH2), 60.65 (CH2), 97.55,
126.05, 127.01, 142.10 (thiophene-C), 148.65, 167.12
(3C═O), 127.32, 133.05, 135.13 (Ph–C); ms: m/z 493 (M, 8),
495 (M+ + 2, 3), 251 (100); Anal. Calcd for C19H13Cl4NO4S
(C═N) cmꢀ1 1H NMR (270 MHz, DMSO-d6): d =1.60–2.84
;
(m, 8H, cyclohexane), 7.56 (d, 2H, J = 8.5 Hz, Ar–H), 7.88
(d, 2H, J = 8.5 Hz, Ar–H), 10.05 (s, 1H, SH exchangeable with
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

772
M. G. Assy, M. H. Sherif, A. E.-G. E. Amr, M. A. Al-Omar, M. M. Abdalla, and I. Ragab
Vol 50
(493.19): C, 46.27; H, 2.66; Cl, 28.75; N, 2.84; S, 6.50. Found:
C, 46.22; H, 2.60; Cl, 28.68; N, 2.80; S, 6.45.
(2CH2), 97.55, 126.24, 127.16, 142.32 (2 thiophene-C), 148.62,
167.44 (6C═O), 129.75, 133.86, 135.03 (naphth-C); ms: m/z
682 (M+, 18), 264 (100); Anal. Calcd for C36H30N2O8S2
(682.76): C, 63.33; H, 4.43; N, 4.10; S, 9.39. Found: C, 63.26;
H, 4.35; N, 4.02; S, 9.33.
Synthesis of bis[substituted cyclohexa[b]thien]pyrroloisoin
dolyl derivatives 12 and 15. A mixture of compound 2 or 1
(2mmol) and 1,2,4,5-benzenetetracarboxylic dianhydride (0.218g,
1 mmol) in glacial acetic acid (50mL) was heated under reflux
for 6 h. The residue formed was filtered off and crystallized from
the proper solvent to yield the corresponding compounds 12 and
15, respectively.
Pharmacological screening.
Antiarrhythmic activity
[40–42]. Purpose and rational.
The plant alkaloid
aconitine persistently activates sodium channel. Infusion of
aconitine in the anesthetized rat causes ventricular arrhythmias.
Drugs considered to have anti-arrhythmic properties can be
tested in aconitine-intoxicated rats.
2,20-(1,3,5,7-Tetraoxopyrrolo[3,4-f]isoindole-2,6(1H,3H,5H,7H)-
diyl)bis(4,5,6,7-tetrahydro-benzo[b]thiophene-3-carbonitrile)
(12).
Yield 72%; mp >300ꢂC (AcOH/H2O); IR (KBr):
Procedure.
Male Ivanovas rats weighing 300–350 g are
n =2218 (CN), 1692 (C═O, imide), 1656 (C═N) cmꢀ1; H NMR
(270 MHz, DMSO-d6): d =1.70–2.90 (m, 16H, CH2, cyclohexyl-
H), 7.79 (s, 2H, Ar-H); 13C NMR (67.5 MHz, DMSO-d6):
d = 23.26, 23.42, 23.66, 24.34 (8CH2), 97.38, 126.25, 127.24,
142.25 (2 thiophene-C), 116.45 (2CN), 148.62, 167.45
(6C═O), 125.03, 135.26 (Ph–C); ms: m/z 538 (M+, 16), 350
(100); Anal. Calcd for C28H18N4O4S2 (538.60): C, 62.44; H,
3.37; N, 10.40; S, 11.91. Found: C, 62.40; H, 3.32; N, 10.33;
S, 11.86.
1
used. The animals are anesthetized by intraperitoneal injection
of 1.25 g kgꢀ1 urethane: 5 mg kgꢀ1 aconitine dissolved in 0.1 N
HNO3 is administered by continuous infusion into the
saphenous vein of 0.1 mL minꢀ1 and the electrocardiogram in
leadII is recorded every 30 s. The test compound is injected IV
at a screening dose of 5 mg kgꢀ1 5 min before the start of the
aconitine infusion; 24 animals are used per compound.
Evaluation. The anti-arrhythmic effect of a test compound
is measured by the amount of aconitine/100 g animal (duration
of infusion), which was induced.
Diethyl
(1H,3H,5H,7H)-diyl)bis-(4,5,6,7-tetra-hydrobenzo[b]thiophene-
3-carboxylate) (15).
Yield 65%; mp >300ꢂC (AcOH); IR
2,20-(1,3,5,7-tetraoxopyrrolo[3,4-f]isoindole-2,6-
• Ventricular extra systoles
• Ventricular tachycardia
• Ventricular fibrillation
(KBr): n = 1748 (C═O, ester), 1688 (C═O, imide), 1654
1
(C═N) cmꢀ1; H NMR (270 MHz, DMSO-d6): d = 1.25 (t, 6H,
CH3), 1.62–2.86 (m, 16H, CH2, cyclohexyl-H), 3.84 (q, 4H,
CH2); 7.84 (s, 2H, Ar-H); 13C NMR (67.5 MHz, DMSO-d6):
d = 13.95 (2CH3), 23.22, 23.32, 23.77, 24.42 (8CH2), 60.72
(2CH2), 97.45, 126.15, 127.12, 142.22 (2 thiophene-C), 148.58,
167.34 (6C═O), 124.95, 135.23 (Ph–C); ms: m/z 632 (M+, 8),
423 (15), 214 (45), 209 (100); Anal. Calcd for C32H28N2O8S2
(632.70): C, 60.75; H, 4.46; N, 4.43; S, 10.14. Found: C, 60.70;
H, 4.38; N, 4.36; S, 10.06.
Higher doses of aconitine in the treated group compared with
the untreated control group are an indication of anti-arrhythmic
activity. Statistical significance between the groups is assessed
by the student’s T-test.
Acknowledgment. The authors extend their appreciation to the
Deanship of Scientific Research at King Saud University for
funding the work through the research group project no. RGP-
VPP-172.
Synthesis of 2,7-bis-[substituted cyclohexa[b]thien]benzo[l,
m,n][3,8]phenanthrolines 13 and 16. A mixture of compound
2 or 1 (2 mmol) and 1,4,5,8-naphthalenetetracarboxylic dianhydride
(0.268 g, 1 mmol) in glacial acetic acid (50 mL) was heated
under reflux for 6 h. The obtained solid was filtered off,
washed with acetic acid, dried, and crystallized from the proper
solvent to afford the corresponding derivatives 13 and 16,
respectively.
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Journal of Heterocyclic Chemistry
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet