3,4-Dimethyl-2,5-functionalized thieno[2,3-b[thiophenes: Versatile precursors for novel bis-thiazoles

Article abstract of DOI:10.1080/17415993.2014.975131

Synthesis of novel bis(thiazoles) 19-22, 24, 25, 30 and 31 is reported. Thus, reaction of the bis(α-bromoketones) 14 and 15 with the corresponding thioamide derivatives 16-18 in refluxing EtOH in the presence of triethylamine afforded 19-22 in good yields

Full text of DOI:10.1080/17415993.2014.975131

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3,4-Dimethyl-2,5-functionalized
thieno[2,3-b]thiophenes: versatile
precursors for novel bis-thiazoles
Osama M. Sayeda, Ahmed E.M. Mekkya, Ahmad M. Faraga & Ahmad
H.M. Elwahya
a Chemistry Department, Faculty of Science, Cairo University,
Giza, Egypt
Published online: 10 Nov 2014.
To cite this article: Osama M. Sayed, Ahmed E.M. Mekky, Ahmad M. Farag & Ahmad H.M. Elwahy
(2014): 3,4-Dimethyl-2,5-functionalized thieno[2,3-b]thiophenes: versatile precursors for novel bis-
thiazoles, Journal of Sulfur Chemistry, DOI: 10.1080/17415993.2014.975131
To link to this article: http://dx.doi.org/10.1080/17415993.2014.975131
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Journal of Sulfur Chemistry, 2014
http://dx.doi.org/10.1080/17415993.2014.975131
3,4-Dimethyl-2,5-functionalized thieno[2,3-b]thiophenes:
versatile precursors for novel bis-thiazoles
Osama M. Sayed, Ahmed E.M. Mekky, Ahmad M. Farag and Ahmad H.M. Elwahy∗
Chemistry Department, Faculty of Science, Cairo University, Giza, Egypt
(Received 2 September 2014; accepted 6 October 2014)
Synthesis of novel bis(thiazoles) 19–22, 24, 25, 30 and 31 is reported. Thus, reaction of the bis(α-
bromoketones) 14 and 15 with the corresponding thioamide derivatives 16–18 in refluxing EtOH in the
presence of triethylamine afforded 19–22 in good yields. On the other hand, the novel bis(thiazoles) 24 and
25 can be synthesized by the reaction of 14 and 15 with the corresponding p-chlorobenzaldehyde thiosemi-
carbazones 23 in refluxing EtOH. The novel isomeric bis(thiazoles) 30 and 31 can also be synthesized by
a reaction of the corresponding bis(benzaldehyde thiosemicarbazones) 27 and 28 with p-chlorophenacyl
bromide 29. Compounds 27 and 28 were obtained by condensation of the corresponding bis(aldehydes)
12 and 13 with thiosemicarbazide 26.
CI
CI
HN
N
NH
N
N
N
s
s
Me
O
O
Me
O
O
O
O
Etooc
cooEt
s
s
Etooc
cooEt
s
s
s
s
CI
CI
HN
NH
N
N
N
N
CHO
O
CHO
O
O
R
R
N
O
s
s
Etooc
cooEt
N
Etooc
cooEt
s
s
s
s
O
O
Etooc
cooEt
s
s
Keywords: bis(α-bromoketones); alkylation; cyclization; condensation; bis(thiazole); thieno[2,3-
b]thiophene
*Corresponding author. Email: aelwahy@hotmail.com
c
ꢀ 2014 Taylor & Francis

2
O.M. Sayed et al.
1. Introduction
Considerable attention has been focused on thienothiophenes due to their interesting biological
activities. They have been tested as potential antitumor, antiviral, antibiotic and antiglaucoma
drugs or as inhibitors of platelet aggregation.[1–5] In addition, thienothiophenes are of potential
interest as π-electron donors and have potential applications in a wide variety of optical and
electronic systems.[6–12]
Moreover, thiazole derivatives have attracted increasing attention due to their numerous
pharmacological applications and biological activities, such as anti-inflammatory, analgesic,
antimicrobial, anti-HIV , antihypertensive and herbicidal activity.[13–21]
Furthermore, attention has been increasingly paid to the synthesis of bis-heterocyclic com-
pounds in recent years, due to a wide array of diverse activities, especially, as antitumor and as
antimicrobial agents.[22–40]
2. Results and discussion
Recently, a technologically convenient one-pot synthesis of 2,5-functionalized thieno[2,3-
b]thiophenes 1 and 2 (Figure 1), starting from 1,3-diketones, has been reported. In this procedure,
carbon disulfide and alkylating agents containing electron-withdrawing groups are used. The
reaction proceeds in dry Dimethylformamide (DMF) in the presence of anhydrous potassium
fluoride as a promoter for condensation.[41]
The latter compounds can be used as starting materials for the synthesis of interest-
ing bis(heterocyces). In this respect, Mabkhot et al. reported the synthesis of 4,4’-(3,4-
dimethylthieno[2,3-b]thiophene-2,5-diyl)dithiazol-2-amine 4 from 1 firstly by bromination upon
treatment with Br2 in AcOH to give 1,1’-(3,4-dimethylthieno[2,3-b]thiophene-2,5-diyl)bis(2-
bromoethanone) 3 followed by reaction with thiourea in refluxing EtOH in the presence of
triethylamine (TEA) to give the corresponding bis-thiazole derivative 4 (Scheme 1).[42]
In continuation of these studies, we report herein on the synthesis of some novel (thieno[2,3-
b]thiophen-3,4-diyl)bis(thiazoles) 19–22, 24, 25, 30 and 31 in which the thiazoles are linked to
the thieno[2,3-b]thiophene core via phenoxymethyl groups.
For this purpose, ethyl 3,4-bis(bromomethyl)-5-(propionyloxy)thieno[2,3-b]thiophene-2-
carboxylate 5 was chosen as a key intermediate and could be readily obtained from the
Figure 1. Structures of 2,5-functionalized thieno[2,3-b]thiophenes 1 and 2.
Scheme 1. Synthesis of 4,4ꢁ-(3,4-dimethylthieno[2,3-b]thiophene-2,5-diyl)dithiazol-2-amine 4 from 1.

Journal of Sulfur Chemistry
3
O
Me
O
Me
O
Me
OH
6, 7
O
O
i)KOH/EtOH
ii)DMF,heat
EtOOC
COOEt
S
S
8, 9
Br
Br
COOEt
NBS
CCl4
2
CHO
CHO
EtOOC
CHO
S
S
5
OH
O
O
10, 11
i)KOH/EtOH
ii)DMF,heat
COOEt
EtOOC
S
S
12, 13
Scheme 2. Synthesis of bis(acetophenones) 8 and 9 as well as bis(aldehydes)12 and 13.
corresponding diethyl 3,4-dimethylthieno[2,3-b]thiophene-2,5-dicarboxylate 2 by radical bromi-
nation using N-Bromosuccinimide (NBS)/dibenzoyl peroxide (Scheme 2).[43,44]
The synthetic utility of 5 as building blocks for novel bis(acetophenones) 8 and 9 as well
as novel bis(aldehydes) 12 and 13 was investigated. Thus, the reaction of 5 with the potas-
sium salt (obtained upon treatment of 2-hydroxyacetophenone 6 and 4-hydroxyacetophenone
7, respectively, with ethanolic KOH), in boiling DMF afforded 8 and 9 in 83% and 78%
yields, respectively. Similarly, the bis(aldehydes) 12 and 13 were prepared in 70% and 75%
yields, respectively, by the reaction of 5 with the potassium salt (obtained upon treatment of
salicylaldehyde (10) and 4-hydroxybenzaldehyde (11) with ethanolic KOH) (Scheme 2).
α-Bromination of the side chain of 8 and 9 with NBS in the presence of p-toluenesulfonic acid
(p-TsOH) in acetonitrile afforded the corresponding bis(α-bromoketones) 14 and 15 as single
monobrominated ketones in most instances in high yield (Scheme 3). Reaction of the bis(α-
bromoketones) 14 and 15 with the thioamide derivatives 16–18 in refluxing EtOH/TEA afforded
the corresponding novel bis(thiazoles) 19–22 (Scheme 3). The reaction was completed within
5–8 h and the products were obtained in good yields.
Our study was extended to include the synthesis of the new bis(thiazolylhydrazones) 24 and
25 as outlined in Scheme 4. Thus reaction of the corresponding bis(α-bromoketones) 14 and 15
with p-chlorobenzaldehyde thiosemicarbazone 23 [45,46] in refluxing EtOH in the presence of
few drops of TEA as a catalyst afforded 24 and 25 in 82% and 83% yields, respectively.
The novel isomeric bis(thiazolylhydrazones) 30 and 31 were also successfully prepared, from
12 and 13 firstly by reaction with thiosemicarbazide 26 in refluxing EtOH containing few drops
of AcOH to give the corresponding bis(benzaldehyde thiosemicarbazones) 27 and 28. Subse-
quent reaction of the latter compounds with p-chlorophenacyl bromide 29 in refluxing ethanol
in the presence of few drops of TEA afforded 30 and 31 in 81% and 78% yields, respectively
(Scheme 5).
All of the isolated compounds were characterized by elemental analyses, as well as spectral
data that agree with the proposed structures. The structures of bis(aminothiazoles) 19 and 20
were confirmed by IR, 1H-NMR and mass spectral data. Thus, the IR spectrum of 19 as a rep-
resentative example showed absorption bands at 3165 and 3058 cm−1 due to NH2. Moreover,
the absence of the absorption band corresponding to carbonyl stretching frequency of the parent

4
O.M. Sayed et al.
R
R
S
Br
Br
S
N
O
O
O
N
S
NBS/p-TsOH
R
NH2
8, 9
O
O
O
CH3CN
EtOH/TEA
reflux,5-8h
COOEt
COOEt
EtOOC
EtOOC
S
S
S
S
16, R=NH2
17, R=NHCH3
18, RR=CH3
14, 15
19-22
19, R=NH2, o-isomer
20, R=NH2, p-isomer
21, R=NHMe, p-isomer
22, R=CH3, o-isomer
Scheme 3. Synthesis of bis(thiazoles) 19-22.
H
H
Cl
Cl
N
HN
NH
N
Br
Br
S
S
O
O
O
N
N
Cl
S
N
H2N
N
H
O
O
O
23
EtOOC
COOEt
EtOH/reflux, 3h
TEA
EtOOC
COOEt
S
S
S
S
24, 25
14, 15
24, o-isomer
25, p-isomer
Scheme 4. Synthesis of bis(thiazolylhydrazones)24 and 25.
S
S
N
N
H2N
HN
N
NH2
O
S
Br
NH2
H2N
N
H
Cl
29
26
1 2, 1 3
O
O
EtOH/drops ACOH
reflux, 3h
EtOOC
COOEt
S
S
27, 28
S
S
Cl
Cl
N
N
HN
N
NH
N
O
O
EtOOC
COOEt
S
S
30, 31 (30, o-isomer, 31, p-isomer)
Scheme 5. Synthesis of bis(thiazolylhydrazones)30 and 31.

Journal of Sulfur Chemistry
5
phenacyl bromide clearly confirmed the formation of bis(aminothiazole) 19. The 1H NMR spec-
trum of compound 19 showed a D2O-exchangeable signal at δ 6.93–7.69 due to NH2 protons
and a sharp singlet at δ 6.65 attributed to the C-5 proton of the thiazole ring. All other protons
were seen at the expected chemical shifts and integral values. The mass spectrum of compound
19 showed an intense molecular ion peak at m/z 693, in agreement with its molecular formulae.
On the other hand, the IR spectrum of bis(thiazolylhydrazone) 24 revealed an absorption band
at 3167 cm−1 due to (NH). Its 1H NMR spectrum showed the presence of a characteristic singlet
− =
−
at δ 7.98 due to one methine proton ( N CH ). The mass spectrum of compound 24 showed a
molecular ion peak at m/z 966 (M+, 21.04%) in agreement with its respective molecular formula.
The spectra of other bis(thiazoles) 25, 30 and 31 exhibited similar spectral data which are listed
in the experimental section.
3. Conclusions
We have developed an efficient synthesis of previously unreported bis(thiazoles) which are linked
to the 3- and 4-positions of thieno[2,3-b]thiophene core via phenoxymethyl groups. Full char-
acterization of these compounds is reported. The newly synthesized compounds are interesting
both in their own right as unusual molecules and for their promising pharmacological and biolog-
ical activities. Due to the mild reaction condition, good yields, easily accessible starting material
and straightforward product isolation, we think that this new synthetic approach discussed here
should provide access for novel new bis(functionalized) heterocycles with potentially potent
biological and pharmaceutical activities.
4. Experimental
4.1. General
Melting points were determined in open glass capillaries with a Gallenkamp apparatus and were
not corrected. The infrared spectra were recorded in potassium bromide disks on a Pye Uni-
cam SP 3–300 and Shimadzu FTIR 8101 PC infrared spectrophotometer. The 1H and 13C NMR
spectra were determined on a Varian Mercury VX 300 NMR spectrometer using tetramethyl-
silane as an internal standard and DMSO-d6 as a solvent. Mass spectra were measured on a
GCMS-QP1000 EX spectrometer at 70 eV.
4.2. Synthesis of the potassium salt of 6,7,10 and 11
To a solution of KOH (0.57 g, 10 mmol) in methanol (10 mL) was added the appropriate hydrox-
yketones 6 and 7 or the appropriate hydroxyaldehydes 10 and 11 (10 mmol). The mixture was
stirred at room temperature for 10 min. The solvent was then removed in vacuo. The remain-
ing solid was triturated with dry ether, collected, dried and used in the next step without further
purification.
4.3. Synthesis of 1,ω-bis(acetophenone) (8 and 9) and 1,ω-bis(aldehyed) (12 and 13)
A solution of the appropriate potassium salt of 6, 7, 10 or 11 (20 mmol) and the dibromo com-
pound 5 (10 mmol) in DMF (20 mL) was heated under reflux for 10 min, during which time, KBr
precipitated. The solvent was then removed in vacuo, and the remaining material was washed
with water (50 mL) and purified by crystallization from proper solvent.

6
O.M. Sayed et al.
4.3.1. Diethyl 3,4-bis((2-acetylphenoxy)methyl)thieno[2,3-b]thiophene-2,5-dicarboxylate (8)
1
Yield (78%, EtOH), mp. 150–152°C; IR (cm−1): 1714, 1670 (2 CO); H NMR (DMSO-d6):
δ 1.22 (t, 6H, CH2CH3, J = 6.9 Hz), 2.24 (s, 6H, CH3CO), 4.29 (q, 4H, CH2CH3, J = 6.9
Hz), 5.65 (s, 4H), 6.93–7.55 (m, 8H, ArH); 13C NMR (DMSO-d6): δ 14.32, 31.67, 61.55, 62.17,
113.45, 121.27, 128.29, 130.13, 134.13, 135.67, 135.81, 145.61, 145.97, 157.36, 161.62, 198.80;
MS: m/z 581 (M+, 28.51%); C30H28O8S2: Anal. Calcd C, 62.05; H, 4.86; S, 11.04. Found C,
62.08%; H, 4.81%; S, 11.01%.
4.3.2. Diethyl 3,4-bis((4-acetylphenoxy)methyl)thieno[2,3-b]thiophene-2,5-dicarboxylate (9)
1
Yield (83%, acetone), mp. 158–162°C; IR (cm−1): 1712, 1672 (2 CO); H NMR (CDCl3): δ
1.38 (t, 6H, CH2CH3, J = 7.2 Hz), 2.5 (s, 6H, CH3CO), 4.40 (q, 4H, CH2CH3, J = 7.2 Hz),
5.77 (s, 4H, OCH2), 6.81 (d, 4H, ArH, J = 8.7 Hz), 7.76 (d, 4H, ArH, J = 8.7 Hz); 13C NMR
(DMSO-d6): δ 14.35, 31.32, 61.32, 62.24, 114.47, 130.46, 130.86, 135.37, 136.14, 145.81,
146.17, 161.68, 161.84, 196.61; MS: m/z 581 (M+, 1.46%); C30H28O8S2: Anal. Calcd C, 62.05;
H, 4.86; S, 11.04. Found C, 62.08%; H, 4.81%; S, 11.01%.
4.3.3. Diethyl 3,4-bis((2-formylphenoxy)methyl)thieno[2,3-b]thiophene-2,5-dicarboxylate
(12)
Yield (73%, Dioxane), mp. 224–226°C [Lit.[44], 224–226°C].
4.3.4. Diethyl 3,4-bis((4-formylphenoxy)methyl)thieno[2,3-b]thiophene-2,5-dicarboxylate
(13)
Yield (65%, acetone), mp. 170–172°C; IR (cm−1): 2848, 2728(CHO),1670 (CO);1H NMR
(DMSO-d6): δ 1.27 (t, 6H, CH2CH3, J = 6.6 Hz), 4.33 (q, 4H, CH2CH3, J = 7.2 Hz), 5.67
(s, 4H), 6.99 (d, 4H, ArH, J = 8.4 Hz), 7.62 (d, 4H, ArH, J = 8.4 Hz), 9.77 (s, 2H,CHO);
13C NMR (DMSO-d6): δ 14.40, 61.89, 62.12, 113.41, 124.61, 128.54, 135.71, 136.69, 143.41,
146.07, 160.38, 161.66, 189.66; MS: m/z 552 (M+, 2.36%); C28H24O8S2: Anal. Calcd C, 60.86;
H, 4.38; S, 11.60. Found C, 60.82%; H, 4.35%; S, 11.55%.
4.4. Synthesis of bis(α-bromoacetophenones) 14 and 15
4.4.1. General procedure
To a stirred solution of bis(acetophenone) derivatives 8 or 9 (l0 mmol) and p-TsOH (5.6 g, 20
mmol) in acetonitrile (50 mL), NBS (3.6 g, 20 mmol) was slowly added. After addition of NBS
was complete, the reaction mixture was refluxed with stirring for 5 h. The solvent was then
evaporated in vacuo and the residue was dissolved in chloroform (50 mL), washed with water
(2 × 20 mL) and dried over MgSO4. After evaporation of the solvent, the resulting solid was
recrystallized from acetonitrile to afford the corresponding bis(α-bromoketone) derivative 15 as
white crystals. Compound 14 was used in the next step without further purification.

Journal of Sulfur Chemistry
7
4.4.1.1. Diethyl 3,4-bis((4-(2-bromoacetyl)phenoxy)methyl)thieno[2,3-b]thiophene-2,5-dicar-
boxylate (15) Yield (67%), mp. 148–150°C; IR (cm−1): 1702, 1658 (2 CO); 1H NMR (DMSO-
d6): δ 1.27 (t, 6H, CH2CH3, J = 6.9 Hz), 4.32 (q, 4H, CH2CH3, J = 6.9 Hz), 4.75 (s, 4H,
CH2Br), 5.68 (s, 4H, OCH2), 6.85 (d, 4H, ArH, J = 8.7 Hz), 7.82 (d, 4H, ArH, J = 8.7 Hz);
13C NMR (DMSO-d6): δ 14.40, 61.37, 62.19, 65.36, 113.37, 125.49, 128.58, 130.10, 136.06,
145.80, 146.70, 161.67, 166.22, 195.34; MS: m/z 736 (M+, 36.94%), 738 (M + 2, 18.89%);
C30H26Br2O8S2: Anal. Calcd C, 48.79; H, 3.55; S, 8.68. Found C, 48.82%; H, 3.49%; S, 8.62%.
4.5. Synthesis of bis(aminothiazole) derivatives (19–22)
4.5.1. General procedure
A solution of the appropriate bis(α-bromoacetophenones) compound 14 or 15 (10 mmol) and
the appropriate thioamide compound 16–18 (20 mmol) in ethanol, in the presence of TEA as a
catalyst, was heated under reflux for 5–8 h. The reaction mixture was then cooled and the solvent
was evaporated in vacuo and the solid residue was collected and recrystallized from ethanol to
give the corresponding bis(aminothiazole) products 19–22 as white crystals.
4.5.1.1. Diethyl 3,4-bis((2-(2-aminothiazol-4-yl)phenoxy)methyl)thieno[2,3-b]thiophene-2,5-
dicarboxylate (19) Yield (64%), mp. 188–190°C); IR (cm−1): 3165, 3058, (NH2), 1701 (CO),
1
=
1571 (C N); H NMR (DMSO-d6): δ 1.28 (t, 6H, CH2CH3, J = 6.9 Hz), 4.32 (q, 4H, CH2CH3,
J = 6.9 Hz), 5.70 (s, 4H, OCH2), 6.65 (s, 2H, thiazole-5-CH), 6.93–7.69 (m, 12H, ArH, NH2);
MS: m/z 693 (M+, 78.23%); C32H28N4O6S4: Anal. Calcd C, 55.47; H, 4.07; N, 8.09; S, 18.51.
Found C, 55.47%; H, 4.07%; N, 8.09%; S, 18.51%.
4.5.1.2. Diethyl 3,4-bis((4-(2-aminothiazol-4-yl)phenoxy)methyl)thieno[2,3-b]thiophene-2,5-
dicarboxylate (20) Yield (67%), mp. 230–235°C; IR (cm−1): 3192, 3076 (NH2), 1714 (CO),
1
=
1567 (C N); H NMR (DMSO-d6): δ 1.28 (t, 6H, CH2CH3, J = 6.9 Hz), 4.32 (q, 4H, CH2CH3,
J = 6.9 Hz), 5.66 (s, 4H, OCH3), 6.93 (s, 2H, thiazole-5-CH), 6.96–7.52 (m, 12H, ArH, NH2);
13C NMR (DMSO-d6): δ 14.50, 61.25, 62.22, 115.24, 127.56, 127.70, 129.60, 135.15, 136.96,
145.82, 146.23, 157.87, 158.89, 161.73, 170.34; MS: m/z 693 (M+, 10%); C32H28N4O6S4: Anal.
Calcd C, 55.47; H, 4.07; N, 8.09; S, 18.51.Found C, 55.4%2; H, 4.09%; N, 8.11%; S, 18.41%.
4.5.1.3. Diethyl 3,4-bis((4-(2-(methylamino)thiazol-4-yl)phenoxy)methyl)thieno[2,3-b]thio-
phene-2,5-dicarboxylate (21) Yield (62%), mp. 150–153°C; IR (cm−1): 3118 (NH), 1708 (CO),
1
=
1587 (C N); H NMR (DMSO-d6): δ 1.28 (t, 6H, CH2CH3, J = 6.9 Hz), 2.99 (s, 6H, NHCH3),
4.32 (q, 4H, CH2CH3, J = 6.9 Hz), 5.7 (s, 4H, OCH2), 6.89 (s, 2H, thiazole-5-CH), 6.91–7.45
(m, 10H, ArH, NH); MS: m/z 721 (M+, 79.31%); C34H32N4O6S4: Anal. Calcd C, 56.65; H, 4.47;
N, 7.77; S, 17.79.Found C, 56.60%; H, 4.50%; N, 7.70%; S, 17.82%.
4.5.1.4. Diethyl 3,4-bis((2-(2-methylthiazol-4-yl)phenoxy)methyl)thieno[2,3-b]thiophene-2,5-
1
dicarboxylate (22) Yield (67%), mp. 148–150°C; IR (cm−1): 1712 (CO), 1596 (C N); H
=
NMR (DMSO-d6): δ 1.18 (t, 6H, CH2CH3, J = 6.3 Hz), 2.60 (s, 6H, CH3), 4.24 (q, 4H,
CH2CH3, J = 6.3 Hz), 5.58 (s, 4H, OCH2), 6.82–7.99 (m, 10H, ArH, thiazole-5-CH); MS: m/z
691 (M+, 5.21%); C34H30N2O6S4: Anal. Calcd C, 59.11; H, 4.38; N, 4.05; S, 18.56. Found C,
59.15%; H, 4.40%; N, 4.06%; S, 18.52%.

8
O.M. Sayed et al.
4.6. Synthesis of bis(hydrazinylthiazol) derivatives 24 and 25
4.6.1. General procedure
To a solution of the appropriate bis(α-bromoacetophenones) compound 14 or 15 (10 mmol)
in ethanol (20 mL) containing few drops of TEA, p-chlorobenzaldehyde thiosemicarbazone
23 (20 mmol) was added. The reaction mixture was heated under reflux for 3 h. The solid
obtained upon cooling was filtered, collected and recrystallized from n-butanol to give the
corresponding bis(hydrazinylthiazol) products 24 and 25 as yellow crystals.
4.6.1.1. Diethyl-3,4-bis((2-(2-((E)-2-(4-chlorobenzylidene)hydrazinyl)thiazol-4-yl)phenoxy)
methyl)thieno[2,3-b]thiophene-2,5-dicarboxylate (24) Yield (83%), mp. 207–210°C; IR
1
(cm−1): 3167 (NH), 1706 (CO), 1567 (C N); H NMR (DMSO-d6): δ 1.16 (t, 6H, CH2CH3,
=
J = 7.2 Hz), 4.20 (q, 4H, CH2CH3, J = 7.2 Hz), 4.85 (s, 2H, NH), 5.60 (s, 4H, OCH2), 6.80–
+
=
7.92 (m, 18H, ArH, thiazole-5-CH), 7.98 (s, 2H, CH N); MS: m/z 966 (M , 21.04%), 968
(M+ 2, 25.00%); C46H36Cl2N6O6S4: Anal. Calcd C, 57.08; H, 3.75; N, 8.68; S, 13.25. Found C,
57.10%; H, 3.72%; N, 8.65%; S, 13.22%.
4.6.1.2. Diethyl-3,4-bis((4-(2-((E)-2-(4-chlorobenzylidene)hydrazinyl)thiazol-4-yl)phenoxy)
methyl)thieno[2,3-b]thiophene-2,5-dicarboxylate (25) Yield (82%), mp. 220–224°C; IR
1
(cm−1): 3116 (NH), 1712 (CO), 1565 (C N); H NMR (DMSO-d6): δ 1.28 (t, 6H, CH2CH3,
=
J = 7.2 Hz), 4.33 (q, 4H, CH2CH3, J = 7.2 Hz), 4.98 (s, 2H, NH), 5.64 (s, 4H, OCH2), 6.86–
+
=
770 (m, 18H, ArH, thiazole-5-CH), 8.06 (s, 2H, CH N); MS: m/z 966 (M , 8.06%), 968 (M + 2,
10.17%); C46H36Cl2N6O6S4: Anal. Calcd C, 57.08; H, 3.75; N, 8.68; S, 13.25. Found C, 57.10%;
H, 3.72%; N, 8.65%; S, 13.22%.
4.7. Synthesis of the bis(thiocarbazone) derivatives 27 and 28
4.7.1. General procedures
A solution of the appropriate bis(aldehydes) 13 or 14 (10 mmol) and thiosemicarbazide 26
(20 mmol) in absolute ethanol (25 mL), in the presence of few drops of acetic acid as a cat-
alyst, was heated under reflux for 3 h. The reaction mixture was then cooled and the solid
formed was collected and recrystallized from the appropriate solvent to give the corresponding
bis(thiocarbazones) 27 and 28 as white crystals.
4.7.1.1. Diethyl-3,4-bis((2-((E)-(2-carbamothioylhydrazono)methyl)phenoxy)methyl) thieno
[2,3-b]thiophene-2,5-dicarboxylate (27) Yield (70%, AcOH), mp. 240–242°C; IR (cm−1):
1
=
3420, 3356, 3270 (NH2, NH), 1706 (CO), 1596 (C N); H NMR (DMSO-d6): δ 1.25 (t, 6H,
CH2CH3, J = 7.2 Hz), 4.32 (q, 4H, CH2CH3, J = 7.2 Hz), 5.59 (s, 4H, OCH2), 6.79–8.00
+
=
(m, 12H, ArH, NH2), 8.27 (s, 2H, CH N), 11.28 (s, 2H, NH); MS: m/z 699 (M , 9.66%);
C30H30N6O6S4: Anal. Calcd C, 51.56; H, 4.33; N, 12.03; S, 18.35. Found C, 51.56%; H, 4.31%;
N, 12.05%; S, 18.32%.
4.7.1.2. Diethyl-3,4-bis((4-((E)-(2-carbamothioylhydrazono)methyl)phenoxy)methyl) thieno
[2,3-b]thiophene-2,5-dicarboxylate (28) Yield (75%, AcOH), mp. 206–208°C; IR (cm−1):
1
=
3410, 3397, 3318 (NH2, NH), 1708 (CO), 1602 (C N); H NMR (DMSO-d6): δ 1.27 (t, 6H,
CH2CH3, J = 7.2 Hz), 4.33 (q, 4H, CH2CH3, J = 7.2 Hz), 5.68 (s, 4H, OCH2), 6.91–7.88
+
=
(m, 12H, ArH, NH2), 7.95 (s, 2H, CH N), 11.27 (s, 2H, NH); MS: m/z 699 (M , 2.42%);

Journal of Sulfur Chemistry
9
C30H30N6O6S4: Anal. Calcd C, 51.56; H, 4.33; N, 12.03; S, 18.35. Found C, 51.56%; H, 4.31%;
N, 12.05%; S, 18.32%.
4.8. Synthesis of bis(thiazolylhydrazones) 30 and 31
4.8.1. General procedures
A solution of the appropriate bis(benzaldehydthiosemicarbazide) compounds 27 or 28 (10 mmol)
and p-chlorophenacyl bromide 29 (20 mmol) in absolute ethanol (20 mL) containing few drops
of TEA was heated under reflux for 5 h. The reaction mixture was then cooled and the solid
formed was collected and recrystallized from the appropriate solvent to give the corresponding
bis(thiazolylhydrazones) 30 and 31 as white crystals.
4.8.1.1. Diethyl-3,4-bis((2-((E)-(2-(4-(4-chlorophenyl)thiazol-2-yl)hydrazono)methyl)
phenoxy)methyl)thieno[2,3-b]thiophene-2,5-dicarboxylate (30) Yield (78%, EtOH/DMF), mp.
1
186–188°C; IR (cm−1): 3120 (NH), 1704 (CO), 1559 (C N); H NMR (DMSO-d6): δ 1.24 (t,
=
6H, CH2CH3, J = 7.2 Hz), 4.31 (q, 4H, CH2CH3, J = 7.2 Hz), 5.64 (s, 4H, OCH2), 6.88–7.81
+
=
(m, 18H, ArH, thiazole-5-CH), 8.20 (s, 2H, CH N), 11.92 (s, 2H, NH); MS: m/z 966 (M ,
1.94%), 968 (M +2, 15.20%); C46H36Cl2N6O6S4: Anal. Calcd C, 57.08; H, 3.75; N, 8.68; S,
13.25. Found C, 57.10; H, 3.77; N, 8.65; S, 13.22%.
4.8.1.2. Diethyl-3,4-bis((4-((E)-(2-(4-(4-chlorophenyl)thiazol-2-yl)hydrazono)methyl)
phenoxy)methyl)thieno[2,3-b]thiophene-2,5-dicarboxylate (31) (81%, AcOH), mp. 208–
210°C; IR (cm−1): 3429 (NH), 1705 (CO);1H NMR (DMSO-d6): δ 1.29 (t, 6H, CH2CH3,
J = 6.9 Hz), 4.34 (q, 4H, CH2CH3, J = 6.9 Hz), 5.62 (s, 4H, OCH2), 6.72–7.77 (m, 18H, ArH,
+
=
thiazole-5-CH), 7.91 (s, 2H, CH N), 11.92 (s, 2H, NH); MS: m/z 966 (M , 1.94%), 968 (M + 2,
15.20%); C46H36Cl2N6O6S4: Anal. Calcd C, 57.08; H, 3.75; N, 8.68; S, 13.25. Found C, 57.10%;
H, 3.77%; N, 8.65%; S, 13.22%.
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