Synthesis of 3,4-biheterylthieno[2,3-b]-thiophenes. Part I: Synthesis of 3,4-Bi(1′,3′,4′-thiadiazolyl-, s-triazolyl-,1′,3′ ,4′-thiadiazinyl-, 1′,3′,4′-triazinyl-, thiazolyl-,1′,3′-thiazinyl- and primidinyl)- thieno[2,3-b]thiophenes

Article abstract of DOI:10.1080/10426500307830

3,4-Diamino-2,5-dicarbethoxythieno[2,3-b]thiophene (1) was allowed to react with NANO₂ and active methylenes to afford the corresponding azo compounds 2a-c. Hydrazonyl chloride 2a was treated with carbon disulfide, phenyl isothiocyanate, benzonitrile, benzyl cyanide, malononitrile, benzalaniline, ethyl mercaptoacetate, and ethyl glycinate to give 1,3,4-thiadiazolyl-, s-triazolyl-, 1,3,4-thiadiazinyl-, 1,3,4-triazinylthieno[2,3-b]thiophenes 3-6 respectively. The reaction of 2b,c with urea, thiourea, and guanidine afforded pyrimidinyl- and thiazinylazothieno [2,3-b]thiophenes 7-10 respectively. Bithiazolylthieno[2,3-b]thiophenes 11 and 13 were synthesized by treating compound 1 with CS₂ along with halo compounds. The addition of S,S-, N,S-, and N,O-acetals to the Schiff base 14 afforded compounds 15-17 respectively.

Full text of DOI:10.1080/10426500307830

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Synthesis of 3,4-Biheterylthieno[2,3-b]-thiophenes.
Part I: Synthesis of 3,4-Bi(1′,3′,4′-thiadiazolyl-, s-
triazolyl-,1′,3′,4′-thiadiazinyl-, 1′,3′,4′-triazinyl-,
thiazolyl-, 1′,3′-thiazinyl- and primidinyl)-thieno[2,3-
b]thiophenes
H. M. Moustafa a , A. Khodairy a & H. Abdel-Ghany a
a Chemistry Department, Faculty of Science, Sohag University, Sohag, Egypt
Available online: 27 Oct 2010
To cite this article: H. M. Moustafa, A. Khodairy & H. Abdel-Ghany (2003): Synthesis of 3,4-Biheterylthieno[2,3-b]-thiophenes.
Part I: Synthesis of 3,4-Bi(1′,3′,4′-thiadiazolyl-, s-triazolyl-,1′,3′,4′-thiadiazinyl-, 1′,3′,4′-triazinyl-, thiazolyl-, 1′,3′-
thiazinyl- and primidinyl)-thieno[2,3-b]thiophenes, Phosphorus, Sulfur, and Silicon and the Related Elements, 178:8,
1689-1701
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Phosphorus, Sulfur, and Silicon, 178:1689–1701, 2003
ꢀC
Copyright Taylor & Francis Inc.
ISSN: 1042-6507 print
DOI: 10.1080/10426500390200738
SYNTHESIS OF 3,4-BIHETERYLTHIENO[2,3-b]-
THIOPHENES. PART I: SYNTHESIS OF
3,4-Bi(1ꢀ,3ꢀ,4ꢀ-THIADIAZOLYL-, s-TRIAZOLYL-,1ꢀ,3ꢀ,4ꢀ-
THIADIAZINYL-, 1ꢀ,3ꢀ,4ꢀ-TRIAZINYL-, THIAZOLYL-,
1ꢀ,3ꢀ-THIAZINYL- AND PRIMIDINYL)-
THIENO[2,3-b]THIOPHENES
H. M. Moustafa, A. Khodairy, and H. Abdel-Ghany
Chemistry Department, Faculty of Science, Sohag University,
Sohag, Egypt
(Received August 27, 2002; accepted December 2, 2002)
3,4-Diamino-2,5-dicarbethoxythieno[2,3-b]thiophene (1) was allowed
to react with NaNO2 and active methylenes to afford the corresponding
azo compounds 2a–c. Hydrazonyl chloride 2a was treated with car-
bon disulfide, phenyl isothiocyanate, benzonitrile, benzyl cyanide, mal-
ononitrile, benzalaniline, ethyl mercaptoacetate, and ethyl glycinate to
give 1,3,4-thiadiazolyl-, s-triazolyl-, 1,3,4-thiadiazinyl-, 1,3,4-triaz-
inylthieno[2,3-b]thiophenes 3–6 respectively. The reaction of 2b,c with
urea, thiourea, and guanidine afforded pyrimidinyl- and thiaziny-
lazothieno [2,3-b]thiophenes 7–10 respectively. Bithiazolylthieno[2,3-
b]thiophenes 11 and 13 were synthesized by treating compound 1
with CS2 along with halo compounds. The addition of S,S-, N,S-
, and N,O-acetals to the Schiff base 14 afforded compounds 15–17
respectively.
Keywords: 3,4-Bi[(carbethoxychloromethyl-, carbethoxycyanomethyl-,
dicyanomethyl-) azo]-2,5-dicarbethoxythieno[2,3-b]thiophene; 3,4-
Diamino-2,5-dicabethoxythieno[2,3-b]thiophene; PTC
The chemistry of 1,3-dipolar cycloadditionreaction is of great impor-
tance to organic chemists and considerable attention has been paid
toward indepth studies of their synthetic potentials.1,2 In addition
to thiophenes3−6 thiazoles7−9 and s-triazoles10−13 exhibit various bi-
ological activities. These observations motivated us to continue our
previous work14,15 on the synthesis of polyfused thienothiophenes.
Address correspondence to A. Khodairy, Department of Chemistry, Faculty of Science,
Sohag University, Sohag, 82524 Egypt. E-mail: khodairy@yahoo.com
1689

1690
H. M. Moustafa et al.
Thus, we report herein the synthesis of heterocyclic compounds con-
taining these rings via the available starting material of 3,4-diamino-
2,5-dicarbethoxythieno[2,3-b]thiophene16 in our laboratory.
RESULTS AND DISCUSSION
3,4-Diamino-2,5-dicarbethoxythieno[2,3-b]thiophene 1 was dissolved in
H2SO4 and treated with NaNO2 at 0◦C to afford the corresponding di-
azonium sulphate, which then was coupled with ethyl chloroacetate,
ethyl cyanoacetate, or malononitrile to give 3,4-bi(carbethoxychloro-
methylazo)-2,5-dicarbethoxythieno[2,3-b]thiophene 2a, 3,4-bi(carbet-
hoxycyanomethylazo)-2,5-dicarbethoxythieno[2,3-b]thiophene 2b, or
3,4-bi(dicyanomethylazo)-2,5-dicarbethoxythieno[2,3-b]thiophene 2c.
These compounds were proved to be good starting materials for the syn-
thesis of 3,4-diheterylthieno[2,3-b]thiophene derivatives (cf. Scheme 1,
Table I).
SCHEME 1
It has been found that hydrazonyl chloride 2a reacts with car-
bon disulfide and phenyl isothiocyanate as polarophiles in pyridine to
yield 3,4-bi[5ꢁ-ethoxycarbonyl-1ꢁ,3ꢁ,4ꢁ-thiadiazol-3ꢁ-yl-2ꢁ-thione(phenyl-
imine)azo]-2,5-dicarbethoxythieno-[2,3-b]thiophene 3a,b respectively.
The reaction pathway is assumed to proceed via the cycloaddition of
the polarophiles with the nitrilimine, which is generated from the hy-
drazonyl chloride in basic medium. The regioselectivity of this reaction
on C S or C N has been reported,17 and cycloaddition reaction occurs

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1692

1693

1694
H. M. Moustafa et al.
on C S to yield the thiadiazole structure and not the isothermic struc-
ture 1,2,4-triazole (cf. Scheme 2, Table I).
SCHEME 2
The reaction of hydrazonyl chloride 2a with active nitriles, namely
benzonitrile, benzyl cyanide, and malononitrile, using pyridine as a
solvent affords 3,4-bi[(3ꢁ-carbethoxy-5ꢁ-phenyl(benzyl, cyanomethyl)-
1ꢁ,2ꢁ,4ꢁ-triazol-1ꢁ-yl)azo]-2,5-dicarbethoxythieno[2,3-b]thiophene 4a–c
respectively. The formation of these compounds is assumed to proceed
via the dipolar cycloaddition of the nitrileimine to the cyano group.
Similarly, treatment of compound 2a with benzalaniline in
presence of triethylamine gives 3,4-bi[(3ꢁ-carbethoxy-4ꢁ,5ꢁ-diphenyl-
1ꢁ,2ꢁ,4ꢁ-triazol-1ꢁ-yl)azo]-2,5-dicarbethoxythieno[2,3-b]thiophene 5. The

3,4-Biheterylthieno[2,3-b]thiophenes
1695
reaction mechanism is suggested to proceed via the dipolar cycloaddi-
tion of the formed nitrileimine to the C N (cf. Scheme 2, Table I).
Moreover, on treating compound 2a with ethyl mercaptoacetate and
ethyl glycinate in presence of triethylamine, 3,4-bi[(2ꢁ-ethoxycarbonyl-
5ꢁ,6ꢁ-dihydro-1ꢁ,3ꢁ,4ꢁ-thiadiazin-4ꢁ-yl-5ꢁ-one)azo]-2,5-diethoxycarbonyl-
thieno[2,3-b]thiophene 6a and 3,4-bi[(2ꢁ-ethoxycarbonyl-1ꢁ,5ꢁ,6ꢁ-
trihydro-1ꢁ,3ꢁ,4ꢁ-triazin-4ꢁ-yl-6ꢁ-one)azo]-2,5-diethoxycarbonylthieno-
[2,3-b] thiophene 6b, respectively, are obtained. The reaction pathway
is assumed to proceed via the addition of the SH or NH2 group to the
nitrileimine followed by intramolecular cyclization with elimination of
ethanol molecule.
Also, the reacion of compounds 2b,c with urea, thiourea, and guani-
dine was investigated. Treatment of compound 2b with these reagents
affords 3,4-bi[(6ꢁ-amino-1ꢁ,2ꢁ,3ꢁ,4ꢁ-tetrahydroprimidin-5ꢁ-yl-2ꢁ,4ꢁ-dione)
azo]-2,5-diethoxycarbonylthieno[2,3-b]thiophene 7, 3,4-bi[(2ꢁ,6ꢁ-diamino-
1ꢁ,3ꢁ,4ꢁ-thiazin-5ꢁ-yl-4ꢁ-one)azo]-2,5-diethoxycarbonylthieno[2,3-b]thio-
phene 8a, and 3,4-bi[(2ꢁ,6ꢁ-diamino-1ꢁ (H)-primidin-5ꢁ-yl-4ꢁ-one)azo]-
2,5-diethoxycarbonylthieno[2,3-b]thiophene 8b respectively. The
formation of these compounds is assumed to be via the addition of the
NH2 group or SH group to the cyano group followed by cyclization with
elimination of ethanol molecule.
On the other hand, the reaction of compound 2c with urea, thiourea,
and guanidine yields 3,4-bi[(4ꢁ,6ꢁ-diamino-1ꢁ-3ꢁ-oxazin-5ꢁ-yl-2ꢁ-one)azo]-
2,5-diethoxycarbonylthieno[2,3-b]thiophene 9a, 3,4-bi[(4ꢁ,6ꢁ-diamino-
2ꢁ-imino-1ꢁ,3ꢁ-thiazin-5ꢁ-yl)azo]-2,5-diethoxycarbonylthieno[2,3-b]thio-
pophene 9b, and 3,4-bi[(2ꢁ,4ꢁ,6ꢁ-triaminoprimidin-5ꢁ-yl)azo]-2,5-dieth-
oxycarbonylthieno[2,3-b]thiophene 10 respectively. The formation
mechanism is assumed to proceed through the addition of the NH2
group or SH group to the cyano group followed by cyclization via
the addition of the second NH2 group to the other cyano group (cf.
Scheme 3, Table I).
Bithiazolylthieno[2,3-b]thiophene derivatives 11a–c and 13a–c are
obtained from the reaction of compound 1 with CS2 along with halo com-
pounds namely chloroacetonitrile, bromomalononitrile, phenacyl bro-
mide, ethyl chloroacetate, and diethyl bromomalonate in presence of
KOH using DMF as a solvent. The reaction pathway is suggested to
proceed via the addition of the NH2 of compound 1 to CS2, forming
the corresponding potassium dithiocarbamate which reacts with the
halo compound to afford the corresponding dithioester. This dithioester
undergoes intramolecular cyclization through the addition of the NH
group to the cyano group to give compounds 11a,b or elimination of
either water molecule to yield compound 11c or ethanol molecule to
afford compounds 13a,b.

1696
H. M. Moustafa et al.
SCHEME 3
On treating compound 1 with p-nitrobenzaldehyde in a mixture
of acetic anhydride and acetic acid, the corresponding Schiff base
14 is obtained. The addition of S-,S-, N-,S-, and N-,O- acetals to
compound 14 was investigated. The reaction of compound 14 with S-,S-
acetal obtained by treating malononitrile with CS2 using solid-liquid
phase-transfer catalysis (PTC) technique [dioxan/K2CO3/tetrabutyl-
ammonium bromide (TBAB)] affords 3,4-bi(4ꢁ-amino-5ꢁ-cyano-2ꢁ,6ꢁ-
ꢁ
dihydro-2ꢁ-p-nitrophenyl-1,3ꢁ-thiazin-1ꢁ-yl-6ꢁ-thione)-2,5-dicarbethoxy-
thieno[2,3-b]thiophene 15. Treatment of compound 14 with N-,S-
acetal synthesized from the reaction of malononitrile with phenyl
isothiocyanate under the same experimental conditions yields 3,4-bi(4ꢁ-
amino-5ꢁ-cyano-6ꢁ-phenylimino-2ꢁ-p-nitrophenyl-1ꢁ,3ꢁ-thiazin-3ꢁ-yl)-2,5
-dicarbethoxythieno[2,3-b]thiophene 16a and 3,4-bi (4ꢁ-amino-5ꢁ-
cyano-2ꢁ-p-nitrophenyl-1ꢁ-phenylprimidin-3ꢁ-yl-6ꢁ-thione)-2,5-dicarbet-
hoxythieno[2,3-b]thiophene 17a. Also, the reaction of compound

3,4-Biheterylthieno[2,3-b]thiophenes
1697
14 with N-,O- acetal obtained by treating malononitrile with
phenyl isocyanate using the same PTC technique gives 3,4-bi(4ꢁ-
amino-5ꢁ-cyano-6ꢁ-phenylimino-2ꢁ-p-nitrophenyl-1ꢁ,3ꢁ-oxazin-3ꢁ-yl)-2,5-
dicarbethoxythieno[2,3-b]thiophene 16b and 3,4-bi(4ꢁ-amino-5ꢁ-cyano-
2ꢁ-p-nitrophenyl-1ꢁ-phenylprimidin-3ꢁ-yl-6ꢁ-thione)-2,5-dicarbethoxyt-
hieno[2,3-b]thiophene 17b. The reaction mechanism was postulated to
proceed through the nucleophilic attack of the SH, NH, or OH group of
the S,S-, N,S- or N,O-acetal at the active C N followed by cyclization
through the addition of the NH group to the CN group (cf. Scheme 4,
Table I).
EXPERIMENTAL
Synthesis of Compounds 2a–c: General Procedure
A solution of compound 1 (1.96 g, 0.01 mmol) in conc. H2SO4 (10 ml)
was cooled in an ice bath at 0–5◦C, whereupon a cold solution of sodium
nitrite (1.4 g, 0.02 mmol) in conc. H2SO4 (5 ml) was added dropwise dur-
ing stirring. The reaction mixture was set aside for 30 min at 5◦C, and
then treated with a stirred solution of (0.02 mmol) of ethyl chloroacetate
(2.36 ml), ethyl cyanoacetate (2.26 ml), or malononitrile (1.32 g) at the
same temperature in the presence of sodium acetate (3.5 g, 0.04 mmol).
The reaction mixture was stirred for 1 h at room temperature. The sep-
arated solid was collected by filtration and crystallized from a suitable
solvent (cf. Table I).
Synthesis of Compounds 3a,b and 4a–c:
General Procedure
A mixture of compound 2a (2.9 g, 0.005 mmol) and (0.01 mmol) of car-
bondisulfide (0.76 ml), phenyl isothiocyanate (1.19 ml), benzonitrile
(1.03 ml), benzyl cyanide (1.17 ml), or malononitrile (0.66 ml) was re-
fluxed in dry pyridine (50 ml) for 3 h. The reaction mixture was cooled
and poured into ice/HCl mixture. The resulting solid was collected by
filtration and crystallized from a suitable solvent (cf. Table I).
Synthesis of Compound 5
To a solution of compound 2a (2.9 g, 0.005 mmol) and benzalaniline
(1.81 g, 0.01 mmol) in dry benzene (80 ml) was added TEA (1 ml,
0.01 mmol). The reaction mixture was refluxed for 4 h and evaporated
in vacuo. The residual solid was washed with water and crystallized
from a proper solvent (cf. Table I).

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H. M. Moustafa et al.
SCHEME 4

3,4-Biheterylthieno[2,3-b]thiophenes
1699
Synthesis of Compounds 6a,b: General Procedure
To a solution of compound 2a (2.9 g, 0.005 mmol) and (0.01 mmol) of
ethyl mercaptoacetate (1.1 ml) or ethyl glycinate (1.4 g) in dry dioxan
(70 ml) was added TEA (2 ml, 0.02 mmol), The reaction mixture was
refluxed for 5 h and evaporated in vacuo. The residual solid was washed
with water and crystallized from a suitable solvent (cf. Table I).
Synthesis of Compounds 7–10: General Procedure
To a mixture of (0.005 mmol) of compound 2b (2.8 g) or 2c (2.34 g), the
proper amino compound (0.01 mmol) (urea 0.06 g, thiourea 0.76 g, or
guanidine 0.96 g) and absolute ethanol (50 ml), sodium ethoxide (0.23 g
of Na in 8 ml ethanol) was added. The reaction mixture was refluxed
for 7 h, concentrated, and cooled. The separated solid was filtered off,
washed with water, and crystallized from a proper solvent (cf. Table I).
Synthesis of Compounds 11a–c and 12a,b:
General Procedure
To a solution of compound 1 (1.96 g, 0.01 mmol) in DMF (30 ml), a so-
lution of KOH (1.12 g, 0.02 mmol) in 10 ml H2O was added followed
by addition of CS2 (1.32 ml, 0.02 mmol). The reaction mixture was
refluxed in a water bath at 80◦C for 2 h and left to cool to 20◦C. To
the reaction mixture (0.02 mmol) of the appropriate halogen compound
chloroacetonitrile (1.26 ml), bromomalononitrile (2.9 g), phenacyl bro-
mide (3.98 g), ethyl chloroacetate (2.36 ml), and diethyl bromomalonate
(4.70 ml) was added. The reaction mixture was stirred at 20◦C for 1 h
and the solid product formed upon pouring onto ice containing few drops
of hydrochloric acid (pH = 6), was collected by filtration, and crystallized
from the suitable solvent (cf. Table I).
Synthesis of Compounds 13a,b: General Procedure
A solution of (0.005 mmol) of compound 12a (3.19 g) or 12b (3.91 g)
in ethanol (50 ml) contaning sodium ethoxide (0.23 g of Na in 10 ml
ethanol) was refluxed for 3 h, the separated product formed upon pour-
ing onto ice/water containing hydrochloric acid (pH = 6) was collected
by filtration and crystallized from a proper solvent (cf. Table I).
Synthesis of Compound 14
To a solution of compound 1 (1.96 g, 0.01 mmol) in glacial acetic acid
(20 ml), and acetic anhydride (10 ml), p-nitrobenzaldehyde (3.02 g,

1700
H. M. Moustafa et al.
0.02 mmol) was added. The reaction mixture was treated with sodium
acetate (3 g, 0.03 mmol), refluxed for 5 h, evaporated in vacuo and
the residual solid was washed with water, dried, and crystallized from
ethanol.
Synthesis of Compounds 15, 16a,b, and 17a,b:
General Procedure
To a suspension of anhydrous potassium carbonate (3 g) in dry dioxan
(20 ml), malononitrile (0.66 g, 0.01 mmol), and CS2 (0.76 ml, 0.01 mmol),
PhNCO (1.1 ml) or PhNCS (1.2 ml) was added. The reaction mixture
was treated with a catalytic amount of TBAB and vigorously stirred at
30◦C for 30 min. After the addition of compound 14 (2.9 g, 0.005 mmol),
the reaction mixture was stirred at 60◦C for 3 h (TLC). The reaction
mixture was filtered off and the filtrate was evaporated in vacuo. The
residual solid was washed with water and crystallized from the ap-
propriate solvent, where compounds 15 and 16a,b were obtained (cf.
Table I). The solid potassium carbonate was dissolved in distilled water
(50 ml). The separated solid was collected by filtration and crystallized
from the proper solvent, where compounds 17a,b were obtained. (cf.
Table I).
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