Expeditious and highly efficient protocol for the synthesis of novel diversely substituted thieno[2,3-b]thiophene

Article abstract of DOI:10.1016/j.molstruc.2012.05.056

1,1′-(3-Methyl-4-phenylthieno[2,3-b]thiophene-2,5-diyl)bis(4,4,4 triethoxybut-2-en-1-one)-3 has been reported by one-pot reaction of enaminone derivative 2 with triethylorthoformate in fairly high yields. The hitherto unknown bis-hydroxyl amine derivatives 4 via N-nucleophile under basic conditions is described. Additionally, the novel Compound 5 were synthesized by the cyclization of enaminone derivative 2 using AcOH with the aid of catalytic amount of AcONH_4. Nevertheless, facile reaction sequences for the preparation of 6, 7, 8a-c, and 9a-c starting with 1,1′-(3-methyl-4- phenylthieno[2,3-b]thiophene-2,5-diyl)diethanone 1 have been developed. Finally, several bis-heterocycles 10a-f were synthesized through a stepwise formation of hydrazone followed by a Michael 1,4-addition of the nucleophile nitrogen atom and provides a convenient access to an important class of nitrogen heterocycles.

Full text of DOI:10.1016/j.molstruc.2012.05.056

Journal of Molecular Structure 1027 (2012) 15–19
Contents lists available at SciVerse ScienceDirect
Journal of Molecular Structure
journal homepage: www.elsevier.com/locate/molstruc
Expeditious and highly efficient protocol for the synthesis of novel diversely
substituted thieno[2,3-b]thiophene
⇑
⇑
Yahia Nasser Mabkhot , Assem Barakat , Saeed Alshahrani
Department of Chemistry, Faculty of Science, King Saud University, P.O. Box 2455, Riyadh 11451, Saudi Arabia
a r t i c l e i n f o
a b s t r a c t
1,10-(3-Methyl-4-phenylthieno[2,3-b]thiophene-2,5-diyl)bis(4,4,4 triethoxybut-2-en-1-one)-3 has been
reported by one-pot reaction of enaminone derivative 2 with triethylorthoformate in fairly high yields.
The hitherto unknown bis-hydroxyl amine derivatives 4 via N-nucleophile under basic conditions is
described. Additionally, the novel Compound 5 were synthesized by the cyclization of enaminone deriv-
ative 2 using AcOH with the aid of catalytic amount of AcONH4. Nevertheless, facile reaction sequences for
the preparation of 6, 7, 8a-c, and 9a-c starting with 1,10-(3-methyl-4-phenylthieno[2,3-b]thiophene-2,5-
diyl)diethanone 1 have been developed. Finally, several bis-heterocycles 10a-f were synthesized through a
stepwise formation of hydrazone followed by a Michael 1,4-addition of the nucleophile nitrogen atom and
provides a convenient access to an important class of nitrogen heterocycles.
Article history:
Received 6 May 2012
Received in revised form 23 May 2012
Accepted 23 May 2012
Available online 7 June 2012
Keywords:
Thienothiophene
Enaminones
Bis-heterocycles
Intramolecular cyclization
Ó 2012 Elsevier B.V. All rights reserved.
1. Introduction
are of interest as potential biologically active compounds or phar-
maceuticals. To the best of our knowledge, no such any of those
More recently thienothoiphene, in particular the thieno[2,3-
b]thiophene scaffold, have attracted considerable attention as the
moieties comprise some significant advantages. Thienothiophene
derivatives represent important building blocks in organic and
medicinal chemistry. They have been developed for different phar-
maceutical purposes and have been tested as potential antitumor,
antiviral, antibiotic, and antiglaucoma drugs, or as inhibitors of
platelet aggregation [1,2]. On the other hand, hydrazone deriva-
tives are reported to possess antimicrobial [3], antitubercular [4],
anticonvulsant [5] and anti-inflammatory [6] activities. Mabkhot
and others [7–22] have reported a variety of syntheses of hetero-
aromatics developed using functionally substituted thieno[2,3-
b]thiophenes as readily obtainable building blocks possessing mul-
tiple electrophilic and nucleophilic moieties. Nitrogen-containing
heterocycles are undoubtedly one of the most important funda-
mentals in organic chemistry. They are widely distributed in
natural products and in pharmaceuticals, and numerous studies
for their chemistry and synthesis have been reported. Pyrazole
derivatives are a very interesting class of heterocyclic compounds
that have remarkable pharmacological activities as antibacterial,
antifungal, and hypoglycemic compounds, as tumor necrosis inhib-
itor, and in the treatment of thromboembolic disorders [23–29]. In
continuation of these findings, we report herein the synthesis of
analogs of thieno[2,3-b]thiophene moiety as a base unit which
molecules had been reported so far.
2. General experimental
General: All melting points were measured on a Gallenkamp
melting point apparatus. IR spectra were measured as KBr pellets
on a perking elmer FT 1000 spectrophotometer. The NMR spectra
were recorded on a Varian Mercury Jeol-400 NMR spectrometer.
1H NMR (400 MHz) and 13C NMR were run in dimethylsulfoxide
(DMSO-d6). Chemical shifts (d) are referred in terms of ppm and J
-coupling constants are given in Hz. Abbreviations for multiplicity
is as follows: s (singulet), d (doublet), t (triplet), q (quadruplet), m
(multiplet). Mass spectra were recorded on a Shimadzu GCMS-QP
1000 EX mass spectrometer at 70 eV. Elemental analysis was car-
ried out on an Elementar Vario EL analyzer.
2.1. 1,10-(3-Methyl-4-phenylthieno[2,3-b]thiophene-2,5-
diyl)bis(4,4,4-triethoxybut-2-en-1-one) (3)
Compound 3 was prepared by fusion of enaminone derivative 2
(212 mg, 0.5 mmol) with triethylorthoformate (TEOF) (148 mg,
1 mmol). Ethanol was added and then the formed solid product
was filtered off affording 3 as pale red crystals. Yield: 57%; m.p.
315–317 °C; IR mmax (KBr): 1641 (C@O) cmꢀ1 1H NMR (400 MHz,
;
DMSO-d6) (ppm): 1.05 (t, 3H, J = 6.6 Hz, CH3), 1.96 (s, 3H, CH3),
⇑
Corresponding authors. Tel.: +966 14675884; fax: +966 14675992.
E-mail addresses: Yahia@ksu.edu.sa (Y.N. Mabkhot), ambarakat@ksu.edu.sa
a
2.84–3.13 (q, 2H, J = 8.0 Hz, CH2), 5.69 (d, 1H, J = 12 Hz, CH),
(A. Barakat).
6.53 (d, 1H, J = 12 Hz, bCH), 7.42–7.52 (m, 5H, ArAH); 13C NMR
0022-2860/$ - see front matter Ó 2012 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.molstruc.2012.05.056

16
Y.N. Mabkhot et al. / Journal of Molecular Structure 1027 (2012) 15–19
(100 MHz, DMSO-d6) (ppm): 14.2, 22.3, 44.0, 129.3, 129.8, 130.4,
131.5, 133.3, 142.0, 182.41; MS m/z(%): 630 [M+, 35%]; Anal. calcd.
for C33H42O8S2: C, 62.83; H, 6.71; O, 20.21; S, 10.17; Found: C,
62.80; H, 6.75; S, 20.18.
179.7, 140.6, 137.0, 135.0, 134.2, 129.1, 128.4, 115.8, 100.8, 72.5,
44.7, 13.9; MS m/z (%): 520[M+, 5%]; Anal. calcd. for C29H24N6S2:
C, 66.90; H, 4.65; N, 16.14; S, 12.32; Found: C, 66.85; H, 4.72; N,
16.17; S, 12.39.
2.2. 1,10-(3-Methyl-4-phenylthieno[2,3-b]thiophene-2,5-diyl)bis(3-
2.6. General procedure for the synthesis of compounds 8a,b (GP1)
(hydroxyamino)prop-2-en-1-one) (4)
A mixture of compound 1 (157 mg, 0.5 mmol) with hydrazine
derivatives (1 mL) in absolute ethanol (15 mL) was heated under
reflux for 8 h afforded the corresponding derivatives 8a,b respec-
tively. The solid product was collected by filtration and recrystal-
lized from (EtOH).
A
mixture of compound
2
(212 mg, 0.5 mmol) with
(NH2OHꢁHCl) (70 mg, 1 mmol) in dioxan (15 mL) was refluxed for
7 h in the presence of TEA (triethyl amine). The reaction mixture
was left to cool to RT. The formed solid product was filtered off,
washed with ethanol, dried and recrystallized from (EtOH) to af-
ford the corresponding hydroxyl mine derivatives 4 as white crys-
2.6.1. 1,10-(1,10-(3-Methyl-4-phenylthieno[2,3-b]thiophene-2,5-
diyl)bis(ethan-1-yl-1-ylidene))bis(hydrazine) (8a)
tal. Yield (59%); m.p. 165–166 °C; IR
mmax (KBr): 1653 (C@O), 3420
(OH) cmꢀ1 1H NMR (400 MHz, DMSO-d6) (ppm): 2.2 (brs, 2H,
;
Compound 8a was prepared from hydrazine hydrate (1 mL) fol-
lowed GP1 as a deep yellow crystals; Yield (89%); m.p. 186–187 °C;
OH&NH), 1.96 (s, 3H, CH3), 4.53 (d, 1H, J = 12 Hz, CH), 5.38 (d,
1H, J = 12 Hz, CH), 7.41–7.65 (m, 5H, C6H5); 13C NMR (100 MHz,
DMSO-d6) (ppm): 180, 153.9, 109.8, 44.79, 14.9; MS m/z (%):
400[M+, 15%]; Anal. calcd. for C19H16N2O4S2: C, 56.98; H, 4.03; N,
7.00; O, 15.98; S, 16.01; Found: C, 56.91;H, 4.09; N, 7.02; S, 16.04.
IR mmax (KBr): 3350–3385 (NH2), 1598 (C@N) cmꢀ1 1H NMR
;
(400 MHz, DMSO-d6) (ppm): 1.34–1.71–2.01 (s, 9H, CH3), 6.38–
6.39 (s, 2H, NH2) 7.36–7.45 (m, 5H, ArAH); 13C NMR(100 MHz,
DMSO-d6) (ppm): 148.3, 141.7, 140.1, 132.6, 129.8, 129.2, 126.8,
15.1, 12.0; MS m/z (%): 342 [M+, 43%]; Anal. calcd. for C17H18N4S2:
C, 59.62; H, 5.30; N, 16.36; S, 18.73; Found: C, 59.65; H, 5.26; N,
16.31; S, 18.76.
2.3. 3-(Dimethylamino)-1-(5-(6-(5-((E)-3-(dimethylamino)acryloyl)-
3-methyl-4-phenylthieno[2,3-b]thiophen-2-yl)nicotinoyl)-3-methyl-
4-phenylthieno[2,3-b]thiophen-2-yl)prop-2-en-1-one (5)
2.6.2. 2,20-(1,10-(3-Methyl-4-phenylthieno[2,3-b]thiophene-2,5-
diyl)bis(ethan-1-yl-1-ylidene))bis(1-phenylhydrazine). (8b)
Compound 8b was prepared from phenyl hydrazine (1 mL) fol-
lowed GP1 as a yellow crystals; Yield (88%); m.p. 192–193 °C; IR
A mixture of compound 2 (212 mg, 0.5 mmol) with acetic acid
glacial (15 mL) was refluxed for 3 h in the presence of ammonium
acetate. The solid product formed was filtered off, washed with
ethanol, dried and recrystallized from (DMF/EtOH) to afford 5 as
deep yellow powder crystal. Yield (77%); m.p. >330 °C; IR mmax
mmax (KBr): 3442 (NAH), 1598 (C@N) cmꢀ1 1H NMR(400 MHz,
;
DMSO-d6) (ppm): 1.30–1.67–1.98 (s, 9H, CH3), 7.67 (s, 1H, NH)
7.24–7.57 (m, 15H, ArAH); 13C NMR(100 MHz, DMSO-d6) (ppm):
148.2, 141.7, 140.2, 132.6, 129.2, 127.6, 122.4, 113.2, 15.1, 14.0;
MS m/z (%): 494 [M+, 1%]; Anal. calcd. for C29H26N4S2: C, 70.41;
H, 5.30; N, 11.33; S, 12.96; Found: C, 70.36; H, 5.33; N, 11.40; S,
12.93.
(KBr): 1640 (C@O) cmꢀ1 1H NMR (400 MHz, DMSO-d6) (ppm):
;
1.96 (s, 3H, CH3), 2.2 (s, 3H, CH3), 3.00 (s, 12H, CH3), 4.55 (d, 1H,
J = 12 Hz, CH), 5.43 (d, 1H, J = 12 Hz, CH), 7.41–7.65 (m, 5H,
C6H5), 7.98–8.10 (m, 3H, C5H3N), 13C NMR (100 MHz, DMSO-d6)
(ppm): 14.2, 22.3, 44.0, 129.3, 129.8, 130.4, 131.5, 133.3, 142.0,
182.41, 183.5; MS m/z (%): 758[M+, 1.2%]; Anal. calcd. for
C
42H35N3O3S4: C, 66.55; H, 4.65; N, 5.54; O, 6.33; S, 16.92; Found:C,
2.7. General procedure for the synthesis of compounds 9a-c (GP2)
A mixture of compound 1 (314 mg, 1 mmol) with aromatic
66.58; H, 4.60; N, 5.58; S, 16.89.
2.4. 2,20-(1,10-(3-Methyl-4-phenylthieno[2,3-b]thiophene-2,5-
diyl)bis(ethan-1-yl-1-ylidene)) dimalononitrile (6)
aldehyde derivatives (2 mmol, 2 equiv.) in absolute ethanol
(15 mL) was heated under reflux for 6–7 h in the presence of mix-
ture of (TEA) and ZnCl2. The reaction mixture was cooled to RT and
the formed solid product was collected by filtration, and recrystal-
lized from (EtOH) afford the corresponding derivatives 9a-c.
A mixture of compound 1)314 mg, 1 mmol(with malononitril
(132 mg, 2 mmol, 2.0 equiv.) in absolute ethanol (15 mL) was
heated under reflux for 4 h, The solid product was collected by fil-
tration afford 6 as a deep red crystals; Yield (65%); m.p. >320 °C; IR
2.7.1. 1,10-(3-Methyl-4-phenylthieno[2,3-b]thiophene-2,5-diyl)bis(3-
phenylprop-2-en-1-one). (9a)
Compound 9a was prepared from benzaldehyde followed GP2
as a white fine needles crystals; yield (76%); m.p. 239–240 °C; IR
mmax (KBr): 2191 (CN) cmꢀ1 1H NMR (400 MHz, DMSO-d6) (ppm):
;
1.63 (s, 6H, CH3), 1.84 (s, 3H, CH3), 7.29–7.55 (m, 5H, ArAH); 13C
NMR (100 MHz, DMSO-d6) (ppm):178.6, 137.0, 136.5, 135.2,
132.1, 129.0, 128.1, 125.4, 112.4, 45.5, 22.2; MS m/z (%): 410[M+,
2%]; Anal. calcd. for C23H14N4S2: C, 67.29; H, 3.44; N, 13.65; S,
15.62; Found: C, 67.12; H, 3.49; N, 13.68; S, 15.59.
mmax (KBr): 1699 (C@O) cmꢀ1
;
1H NMR(400 MHz, DMSO-d6)
a
(ppm): 2.40 (s, 3H, CH3), 6.89 (d, 1H, J = 8.8 Hz, CH), 7.00–7.77
(m, 15H, ArAH), 7.87 (d, 1H, J = 8.8 Hz, bCH); 13C NMR (100 MHz,
DMSO-d6) (ppm): 183.9, 144.8, 141.0, 137.5, 136.2, 131.2, 130.3,
129.6, 128.8, 128.6, 127.7, 124.8, 122.0, 114.1, 113.2, 15.2; MS m/
z (%): 490[M+, 1%]; Anal. calcd. for C31H22O2S2: C, 75.89; H, 4.52;
O, 6.52; S, 13.07; Found: C, 75.94; H, 4.49; S, 13.10.
2.5. 2,20-1,10-(3-Methyl-4-phenylthieno[2,3-b]thiophene-2,5-
diyl)bis(3-(dimethylamino) prop-2-ene-1-yl-1-
ylidene)dimalononitrile (7)
A mixture of compound 6) 205 mg, 0.5 mmol (with (DMF–DMA)
(1 mmol, 2 equiv.) in absolute ethanol (15 mL) was heated under
reflux for 4 h. The formed solid product was collected by filtration
afford 7 as a deep brown powder crystals; Yield (64%); m.p.
2.7.2. 1,10-(3-Methyl-4-phenylthieno[2,3-b]thiophene-2,5-diyl)bis(3-
(4-chlorophenyl)prop-2-en-1-one). (9b)
Compound 9b was prepared from p-chlorobenzaldehyde fol-
lowed GP2 as a yellow crystals; yield (82%); m.p. 222–223 °C; IR
>320 °C; IR mmax (KBr): 2193 (CN) cmꢀ1
;
1H NMR (400 MHz,
mmax (KBr): 1654 (C@O cmꢀ1
(ppm): 2.40 (s, 3H, CH3), 6.35(d, 1H, J = 8.8 Hz, CH), 7.34–7.56
(m, 15H, ArAH), 7.85 (d, 1H, J = 8.8 Hz, bCH); 13C NMR(100 MHz,
DMSO-d6) (ppm): 183.9, 144.8, 141.1, 137.5, 136.2, 131.2, 130.3,
;
1H NMR(400 MHz, DMSO-d6)
a
DMSO-d6) (ppm): 1.83 (s, 3H, CH3), 3.24–3.13 (s, 12H, CH3),
a
7.90–7.95 (d, 1H, J = 12.0 Hz, CH), 7.39–7.52 (m, 5H, ArAH), 8.15
(d, 1H, J = 12.0 Hz, bCH); 13C NMR (100 MHz, DMSO-d6) (ppm):

Y.N. Mabkhot et al. / Journal of Molecular Structure 1027 (2012) 15–19
17
129.7, 128.8, 127.7, 124.8, 122.1, 114.1, 113.3, 15.2; MS m/z (%):
559[M+, 1.5%]; Anal. calcd. for C31H20Cl2O2S2: C, 66.54; H, 3.60;
O, 5.72; S, 11.46; Found: C, 66.63; H, 3.57; S, 11.43.
NMR(100 MHz, DMSO-d6) (ppm): 151.2, 141.2, 129.5, 126, 128.1,
61.8, 42.1, 13.8; MS m/z (%): 739[M+, 3%]; Anal. calcd. for
C43H32Cl2N4S2: C, 69.81; H, 4.36; N, 7.57; S, 8.67; Found: C,
69.89; H, 4.29; N, 7.61; S, 8.62.
2.7.3. 1,10-(3-Methyl-4-phenylthieno[2,3-b]thiophene-2,5-diyl)bis(3-
(4-methoxyphenyl)prop-2-en-1-one). (9c)
Compound 9c was prepared from p-methoxybenzaldehyde fol-
lowed GP2 as a yellow crystals; yield (48%); m.p. >320 °C; IR mmax
2.8.5. 5,50-(3-Methyl-4-phenylthieno[2,3-b]thiophene-2,5-diyl)bis(3-
(4-methoxyphenyl)-1H-pyrazole). (10e)
Compound 10e was prepared from 9c and hydrazine hydrate
followed GP3 as a White crystals; yield (60%); m.p. >320 °C; mmax
(KBr): 1636 (C@Ocmꢀ1
;
1H NMR(400 MHz, DMSO-d6) (ppm): 2.40
a
(KBr): 3417 (NAH), 1571 (C@N) cmꢀ1 1H NMR(400 MHz, DMSO-
;
(s, 3H, CH3) 6.88 (d, 1H, J = 8.8 Hz, CH), 7.12–7.57 (m, 15H, ArAH),
7.86 (d, 1H, J = 8.8 Hz, bCH); 13C NMR(100 MHz, DMSO-d6) (ppm):
183.9, 144.8, 141.1, 137.5, 136.2, 131.2, 130.3, 129.6, 128.6,
127.7, 124.8, 122.0, 114.1, 113.3, 15.2; MS m/z (%): 550[M+,
1.8%]; Anal. calcd. for C33H26O4S2: C, 71.97; H, 4.76; O, 11.62; S,
11.65; Found: C, 71.90; H, 4.73; S, 11.69.
d6) (ppm): 1.83 (s, 3H, CH3), 3.5 (d, 4H, J = 8.6 Hz, 2CH2), 3.90 (s,
6H, 2CH3) 4.8 (t, 2H, J = 7.1 Hz, 2CH), 6.85–7.4 (m, 25H, ArAH),
9.12(s, 1H, NH), 13C NMR(100 MHz, DMSO-d6) (ppm): 151.2,
141.2, 129.5, 126, 128.1, 61.8, 42.1, 13.8; MS m/z (%): 578[M+,
3%]; Anal. calcd. for C33H30N4O2S2: C, 68.48; H, 5.22; N, 9.68; O,
5.53; S, 11.08; Found: C, 68.54; H, 5.29; N, 9.60; S, 11.03.
2.8. General procedure for the synthesis of compounds 10a-f (GP3)
2.8.6. 5,50-(3-Methyl-4-phenylthieno[2,3-b]thiophene-2,5-diyl)bis(3-
(4-methoxyphenyl)-1-phenyl-1H-pyrazole). (10f)
A mixture of compound 9a-c (0.25 mmol) with hydrazine deriv-
atives (0.5 mmol) in absolute ethanol (10 mL) was heated under
reflux for 6–8 h. The reaction mixture was cooled to RT and the
formed solid product was collected by filtration, and recrystallized
from (MeOH) afford the corresponding derivatives 10a-f.
Compound 10f was prepared from 9c and phenyl hydrazine hy-
drate followed GP3 as a pale brown crystals; yield (57%); m.p. 222–
224 °C; mmax (KBr): 1589 (C@N) cmꢀ1 1H NMR(400 MHz, DMSO-
;
d6) (ppm): 1.83 (s, 3H, CH3), 3.5 (d, 4H, J = 8.6 Hz, 2CH2), 3.90 (s,
6H, 2CH3) 4.8 (t, 2H, J = 7.1 Hz, 2CH), 6.85–7.4 (m, 25H, ArAH);
13C NMR(100 MHz, DMSO-d6) (ppm): 151.2, 141.2, 129.5, 126,
128.1, 61.8, 42.1, 13.8; MS m/z (%): 730[M+, 3%]; Anal. calcd. for
2.8.1. 5,50-(3-Methyl-4-phenylthieno[2,3-b]thiophene-2,5-diyl)bis(3-
phenyl-1H-pyrazole). (10a)
Compound 10a was prepared from 9a and hydrazine hydrate
followed GP3 as a yellow crystals; yield (57%); m.p. 202–203 °C;
C45H38N4O2S2: C, 73.94; H, 5.24; N, 7.67; O, 4.38; S, 8.77; Found:
C, 73.88; H, 5.30; N, 7.61; S, 8.71.
IR mmax (KBr): 3283 (NAH), 1605 (C@N) cmꢀ1 1H NMR(400 MHz,
;
DMSO-d6) (ppm): 1.81 (s, 3H, CH3), 3.7 (d, 4H, J = 4.5 Hz, 2CH2),
4.8 (t, 2H, J = 7.1 Hz, 2CH), 6.95–7.40 (m, 15H, ArAH), 9.12(s, 1H,
NH); 13C NMR(100 MHz, DMSO-d6) (ppm): 151.7, 141.6, 129.5,
128.4, 128.3, 62.8, 44.1, 14.3; MS m/z (%): 518[M+, 3%]; Anal. calcd.
for C31H26N4S2: C, 71.78; H, 5.05; N, 10.80; S, 12.36; Found: C,
71.69; H, 5.10; N, 10.78; S, 12.39.
3. Results and discussion
The new 1,10-(3-methyl-4-phenylthieno[2,3-b]thiophene-2,5-
diyl)diethanone 1 and its bis(enaminones) derivatives 2 [30] being
2.8.2. 5,50-(3-Methyl-4-phenylthieno[2,3-b]thiophene-2,5-
diyl)bis(1,3-diphenyl-1H-pyrazole). (10b)
Compound 10b was prepared from 9a and phenyl hydrazine hy-
drate followed GP3 as a yellow crystals; yield (62%); m.p. 301 °C; IR
m
max (KBr): 1598 (C@N) cmꢀ1; 1H NMR(400 MHz, DMSO-d6) (ppm):
1.83 (s, 3H, CH3), 3.5 (d, 4H, J = 8.6 Hz, CH2), 4.8 (t, 2H, J = 7.1 Hz,
CH), 6.85–7.40 (m, 25H, ArAH); 13C NMR(100 MHz, DMSO-d6)
(ppm): 151.2, 141.2, 129.5, 126, 128.1, 61.8, 42.1, 13.8; MS m/z
(%): 670[M+, 8%]; Anal. calcd. for C43H34N4S2: C, 76.98; H, 5.11; N,
8.35; S, 9.56; Found: C, 76.91; H, 5.15; N, 8.30; S, 9.49.
2.8.3. 5,50-(3-Methyl-4-phenylthieno[2,3-b]thiophene-2,5-diyl)bis(3-
(4-chlorophenyl)-1H-pyrazole). (10c)
Compound 10c was prepared from 9b and hydrazine hydrate
followed GP3 as a yellow crystals; yield (67%); m.p. 315–316 °C;
IR mmax (KBr): 3284 (NAH), 1608 (C@N) cmꢀ1 1H NMR(400 MHz,
;
DMSO-d6) (ppm): 1.82 (s, 3H, CH3), 3.82 (d, 2H, J = 4.5 Hz, CH2),
4.9 (t, 1H, J = 7.1 Hz, CH), 6.96–7.49 (m, 25H, ArAH), 9.10 (s, 1H,
NH);; 13C NMR(100 MHz, DMSO-d6) (ppm): 151.7, 141.6, 129.5,
128.4, 128.3, 62.8, 44.1, 14.3; MS m/z (%): 587[M+, 3%]; Anal. calcd.
for C31H24Cl2N4S2: C, 63.37; H, 4.12; N, 9.54; S, 10.91; Found: C,
63.31; H, 4.16; N, 9.58; S, 10.89.
2.8.4. 5,50-(3-Methyl-4-phenylthieno[2,3-b]thiophene-2,5-diyl)bis(3-
(4-chlorophenyl)-1-phenyl-1H-pyrazole). (10d)
Compound 10d was prepared from 9b and phenyl hydrazine
hydrate followed GP3 as a pale brown crystals; yield (59%); m.p.
176–177 °C; IR (m ;
max): 1596 (C@N) cmꢀ1 1H NMR(400 MHz,
DMSO-d6) (ppm): 1.83 (s, 3H, CH3), 3.5 (d, 4H, J = 8.6 Hz, CH2),
4.8 (t, 2H, J = 7.1 Hz, CH), 6.85–7.49 (m, 23H, ArAH); 13C
Scheme 1. Synthesis of 3, 4, and 5.

18
Y.N. Mabkhot et al. / Journal of Molecular Structure 1027 (2012) 15–19
now available in our hand prompted us to study their synthetic
utility as key intermediate for a new class of molecules as well
as bis(5-membered) heterocycles with the thieno[2,3-b]thiophene
core. Thus, fusion the bis(enaminone) 2 with neat triethoxyme-
thane which is commercially available resulted in the formation
of the (2E,20E)-1,10-(3-methyl-4-phenylthieno[2,3-b]thiophene-
2,5-diyl)bis(4,4,4-triethoxybut-2-en-1-one) 3 after washing with
EtOH in 57% yield as depicted in Scheme 1.
The structure of compound 3 was determined from its elemen-
tal and spectroscopic analyses. The 1H NMR spectrum strongly sup-
ported this assignment where disappeared of singlet signal of
NMe2 Furthermore, the appearance two characteristic signals of
CH3CH2 group.
Our study is now extended to include the synthesis of new bis-
hydroxyl amine derivatives 4. Thus, reaction of 2 with hydroxyl
amine hydrochloride in refluxing dioxan for 7 h in the presence
of TEA afforded the corresponding bis-hydroxyl amine derivatives
4 in 59% yields. The formation of compound 4 would involve an ini-
tial addition of the amino group in hydroxylamine to the activated
double bond in enaminone derivative 2, followed by deamination
of NMe2 affording the final isolable product (Scheme 1).
When bis enaminone 2 was refluxed in AcOH 3 h in the pres-
ence of a catalytic amount of AcONH4 afforded 5 (Scheme 1). The
structure of the product was confirmed by elemental analysis were
consistent with isolated product 5 [31].
Refluxing of equimolar amounts of the 1,10-(3-methyl-4-phenyl-
thieno[2,3-b]thiophene-2,5-diyl)diethanone 1 and malononitrile in
ethanol afforded the corresponding dimalononitrile derivatives 6
(Scheme 2). The structure of the isolated product was identified
as 2,20-((3-methyl-4-phenylthieno[2,3-b]thiophene-2,5-diyl)-
bis(ethan-1-yl-1-ylidene))dimalononitrile 6 on the basis of its ele-
mental analyses and spectral data. The IR spectrum of the reaction
product exhibited absorption bands at 2191 cmꢀ1 due to the nitrile
group. The reactivity of compound 6 towards DMF–DMA was also
investigated. Thus, the treatment of compound 6 with DMF–DMA
in ethanol and refluxed for 4 h afforded bis-enamine derivatives 7.
The 1H NMR spectrum of compound 7 revealed two singlets at d
1.83, and 3.24 due to methyl, and NMe2 protons, respectively. Fur-
thermore, the appearance two doublets at d 7.90, and 8.15 due to
CH@CH protons.
Nevertheless, Phenylhydrazones 8a,b were next synthesized in
almost quantitative yields by the reaction between the hydrazine
derivatives and 1. The structure of hydrazone derivatives 8a,b
was established on the basis of their elemental analysis and spec-
tral data.
The reactivity of compound 1 towards some heterocyclic alde-
hydes was also investigated. Thus, the treatment of compound 1
Scheme 2. Synthesis of 6, 7, 8a,b, and 9a-c.
Scheme 3. Synthesis of 10a-f.

Y.N. Mabkhot et al. / Journal of Molecular Structure 1027 (2012) 15–19
19
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of hydrazone followed by a Michael 1,4-addition of the nucleophile
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of this strategy and focused on the preparation of thieno[2,3-
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In conclusion, the reactivity of 1,10-(3-methyl-4-phenylthie-
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amino)prop-2-en-1-one) (2) were investigated as a versatile and
readily accessible building block for the synthesis of new mole-
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may display potentially interesting biological activity in the field of
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Acknowledgment
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This project was supported by King Saud University, Deanship
of Scientific Research, College of Science Research Center.
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