Synthesis of polyfused thieno(2,3-b)thiophenes part 3: Synthesis of thienopyrimidinotetrazole, thienopyrimidinotriazepine, thienopyrimidinotriazine, thienopyrimidinotriazole and pyrazolylthienopyrimidine derivatives

Article abstract of DOI:10.1080/10426500307790

2,9-Dihydrazinobipyrimidino(2,3-b)thienothiophene (2) was reacted with nitrous acid, ethoxymethylenemalononitrile, bromomalononitrile, triethyl formate, CS₂ or isatine to afford the corresponding tetrazole, triazepine, triazine, and triazole derivatives 3-8 respectively. Treatment of compound 2 with cyclohexylidenenitriles, acetylacetone, ethyl acetoacetate, 2-hydroxyacetophenone, or S,S-acetals afforded the corresponding pyrazole derivatives 9-15 respectively.

Full text of DOI:10.1080/10426500307790

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Synthesis of Polyfused Thieno(2,3- b )thiophenes
Part 3: Synthesis of Thienopyrimidinotetrazole,
Thienopyrimidinotriazepine, Thienopyrimidinotriazine,
Thienopyrimidinotriazole and
Pyrazolylthienopyrimidine Derivatives
A. Khodairy a
a Chemistry Department, Faculty of Science, South Valley University, Sohag, Egypt
Available online: 27 Oct 2010
To cite this article: A. Khodairy (2003): Synthesis of Polyfused Thieno(2,3- b )thiophenes Part 3: Synthesis of
Thienopyrimidinotetrazole, Thienopyrimidinotriazepine, Thienopyrimidinotriazine, Thienopyrimidinotriazole and
Pyrazolylthienopyrimidine Derivatives, Phosphorus, Sulfur, and Silicon and the Related Elements, 178:4, 893-901
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Phosphorus, Sulfur and Silicon, 2003, Vol. 178:893–901
C
Copyright 2003 Taylor & Francis
1042-6507/03 $12.00 + .00
DOI: 10.1080/10426500390198066
SYNTHESIS OF POLYFUSED
THIENO(2,3-b)THIOPHENES PART 3: SYNTHESIS
OF THIENOPYRIMIDINOTETRAZOLE,
THIENOPYRIMIDINOTRIAZEPINE,
THIENOPYRIMIDINOTRIAZINE,
THIENOPYRIMIDINOTRIAZOLE AND
PYRAZOLYLTHIENOPYRIMIDINE DERIVATIVES
A. Khodairy
Chemistry Department, Faculty of Science, South Valley
University, Sohag, Egypt
(Accepted October 2, 2002)
2,9-Dihydrazinobipyrimidino(2,3-b)thienothiophene (2) was reacted
with nitrous acid, ethoxymethylenemalononitrile, bromomalononitrile,
triethyl formate, CS2 or isatine to afford the corresponding tetrazole, tri-
azepine, triazine, and triazole derivatives 3–8 respectively. Treatment of
compound 2 with cyclohexylidenenitriles, acetylacetone, ethyl acetoac-
etate, 2-hydroxyacetophenone, or S,S-acetals afforded the correspond-
ing pyrazole derivatives 9–15 respectively.
Keywords: Pyrazol-2-ylpyrimidinothienothiophene; tetrazolopyrimi-
dinothienothiophene; thienopyrimidine; triazepinopyrimidinothieno-
thiophene; triazinopyrimidinothienothiophene derivatives
Thieno(2,3-b)thiophenes have been studied1 and developed for different
purposes in the pharmaceutical field and have been tested as, depend-
ing on the nature of the substituents, potential antiviral,2 antibiotic,3
antiglaucoma,4 analgesic, and antipyretic5 drugs.
8
In our previous work,6 we reported the synthesis of thieno(3,2-
d)pyrimidine, thieno(3,2-d)thiazine, thienopyrrolopiprazine, and thie-
nothiazaphospholine; here we undertook the synthesis of some new het-
erocyclic compounds containing thieno(3,2-d)pyrimidine moiety fused
See Refs. 6 and 7 for Parts 1 and 2.
Address correspondence to A. Khodairy, Chemistry Department, Faculty of Science,
Sohag 82524, Egypt. E-mail: Khodairy@yahoo.com
893

894

895

896
A. Khodairy
with tetrazol, triazepine, triazine, triazole, and attached to a pyrazole
nucleus.
2,9-Dihydrazino-3,8-diphenyl-4,7-dioxo-bipyrimidino(50,60-b)thieno
(2,3-b)thiophene 2 was synthesized in 90% yield from the reaction
of bisthieno(3,2-d)pyrimidine-2-thione derivative 16 with hydrazine
hydrate in pyridine. IR spectrum showed an absorption bands at 3400,
1
1
1
3340, 3100 Cm (NH,NH2) and 1689 Cm (CO). H-NMR ( , ppm)
showed signals at 8.0–7.2 (m, 10H, aromatic), 6.4 (s, 2H, 2NH) and
5.5–5.2 (br, 4H, 2NH2) respectively (cf. Table I).
Compound 2 was investigated as starting material for the synthe-
sis of many heterocyclic compounds fused to thieno(3,2-d)pyrimidine
moiety. Thus, compound 2 was treated with nitrous acid9 to afford
tetrazolopyrimidino(2,3-b)thienothiophene derivative 3 (cf. Scheme 1,
Table I).
Treatment of compound 2 with ethoxymethylenemalononitrile in
the presence of triethylamine, afforded the corresponding triazepino-
pyrimidino(2,3-b)thienothiophene derivative 4 (cf. Scheme 1, Table I).
Cyclization of compound 2 with bromomalononitrile gave the cor-
responding triazinopyrimidino(2,3-b)thienothiophene derivative 5. IR
1
spectrum showed an absorption bands at 3400, 3340, 3100 Cm
(NH,NH2) and 2100 Cm (CN) (cf. Scheme 1, Table I).
1
The reaction of compound 2 with triethylorthoformate10 in the
presence of triethylamine or carbon disulphide9 in the presence of
potassium hydroxide gave the corresponding triazolopyrimidino(2,3-
b)thienothiophene derivatives 6 and 7 respectively (cf. Scheme 1,
Table I).
Treatment of compound 2 with isatine in the presence of POCl3
afforded the corresponding indolotriazinopyrimidino(2,3-b)thienothio-
phene derivative 8 (cf. Scheme 1, Table I).
Compound 2 was allowed to react with cyclohexylidenemalononitrile,
cyclohexylidenecyanoacetamide, cyclohexylidenecyanothioacetamide,
or ethyl cyclohexylidenecyanoacetate in refluxing DMF and triethy-
lamine to give 2-pyrazolylpyrimidino(2,3-b)thienothiophene deriva-
tives 9 and 10 respectively. The reaction pathway11 was assumed
to proceed via a nucleophilic addition of the NH2 group to the
ethylenic bond, followed by a nucleophilic attack of the NH group
to the CN, CO(amide), CS, or CO(ester) groups with elimination of

Synthesis of Polyfused Thieno(2,3-b)thiophenes Part 3
897
SCHEME 1
H2O, H2S, or EtOH molecules, respectively (cf. Schemes 1 and 2,
Table I).
Condensation of compound 2 with acetylacetone or ethyl acetoac-
etate in the presence of triethylamine afforded the corresponding (3,5-
dimethylpyrazol-2-yl)- and (3-methyl-5-oxopyrazolin-2-yl)pyrimidino-
(2,3-b)thienothiophene 11 and 12 respectively (cf. Scheme 2, Table I).

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A. Khodairy
SCHEME 2
Treatment of compound 2 with 2-hydroxyacetophenone and POCl3
gave the corresponding 2-pyrazolylpyrimidinothienothiophene 13 (cf.
Scheme 2, Table I).
Finally, compound 2 was reacted with CS2 and malononitrile
or ethyl cyanoacetate in 1:1:1 molar ratio under PTC conditions

Synthesis of Polyfused Thieno(2,3-b)thiophenes Part 3
899
[K2CO3/DMF/tetrabutylammonium bromide (TBAB)] to give the
corresponding (3-mercapto-4-cyano(carbethoxy)-5-aminopyrazol-2-
yl)thieno(3,2-d)pyrimidine derivative 14a,b. The reaction pathway12
was assumed to proceed via the addition of the NH2 group to the
ethylenic bond with elimination of H2S molecule, followed by a nucle-
ophilic attack of the NH group to the CN group or to the carbethoxy
group with elimination of ethanol molecule. Compounds 14a,b were
alkylated with methyl iodide in the presence of sodium hydroxide
to afford S-Me derivatives 15a,b. Another route for the synthesis of
compounds 15a,b is the reaction of compound 2 with cyanoketene S,S
acetals in refluxing ter butanol for 48 h (cf. Scheme 2, Table I).
EXPERIMENTAL
Synthesis of Compound 2
To a suspension of compound 1 (0.01 mmol) in pyridine (10 ml) hy-
drazine hydrate (0.02 mmol) was added. The reaction mixture was re-
fluxed for 10 h. After cooling, it was poured into a mixture of ice-water
(200 ml) and HCl (10 ml). The separated solid was collected by filtration,
washed with water, dried, and crystallized from dioxane (Table I).
Synthesis of Compound 3
A solution of compound 2 (0.01 mmol) in conc. HCl (4 ml) and water
(3 ml) was cooled in an ice bath at 0–5 C, whereupon a cold solution of
sodium nitrite (0.06 mmol) in water (5 ml) was added dropwise while
stirring. The reaction mixture was set aside for 3 h. The separated solid
was filtered, washed with water, dried, and crystallized from dioxane
(cf. Scheme 1, Table I).
Synthesis of Compounds 4, 9–12 (General Procedure)
Compound 2 (0.003 mmol) was added to a stirred solution of the appro-
priate reagent (0.006 mmol) namely, ethoxymethylenemalononitrile,
cyclohexylidenemalononitrile, cyclohexylidenecyanoacetamide, cyclo-
hexylidenecyanothioacetamide, ethyl cyclohexylidenecyanoacetate,
acetyacetone, and ethyl acetoacetate in presence of triethylamine
(0.006 mmol) in DMF (50 ml). The reaction mixture was refluxed for
3 h, after cooling it was poured into a mixture of ice-water (200 ml)
and HCl (10 ml). The separated solid was collected by filtration,
washed with water, dried, and crystallized from appropriate solvent
(cf. Schemes 1 and 2, Table I).

900
A. Khodairy
Synthesis of Compounds 5 and 7 (General Procedure)
A mixture of compound 2 (0.02 mmol), potassium hydroxide (0.04 mmol)
and bromomalononitrile (0.04 mmol) or carbon disulphide (0.04 mmol)
in DMF (20 ml) was refluxed for 4 h. On cooling, the precipitated solid
was filtered, dried, washed with ether, dissolved in water, and the prod-
uct was reprecipitated by addition of HCl (20 ml). The product was
filtered, washed with water, dried, and crystallized from n-butanol (cf.
Scheme 1, Table I).
Synthesis of Compound 6
To a stirred solution of compound 2 (0.01 mmol) in acetic anhydride
(20 ml), triethylorthoformate (0.02 mmol) was added. The reaction mix-
ture was refluxed for 12 h, evaporated in vacuo and the remaining prod-
uct was triturated with water and the residual solid was collected by
filtration and crystallized from dioxane (cf. Scheme 1, Table I).
Synthesis of Compounds 8 and 13 (General Procedure)
To a stirred solution of compound 2 (0.01 mmol) in POCl3 (30 ml), isatine
(0.02 mmol), or 2-hydroxyacetophenone (0.02 mmol) was added. The
reaction mixture was refluxed for 2 h, evaporated in vacuo and
the remaining product was triturated with pet. ether (60–80 C) and
the residual solid was collected by filtration and crystallized from DMF
(cf. Schemes 1 and 2, Table I).
Synthesis of Compounds 14a,b (General Procedure)
A mixture of a proper active methylene compound (0.04 mmol), CS2
(0.045 mmol), anhydrous potassium carbonate (3 gm), a catalytic
amount of TBAB, and dioxane (20 ml) was stirred for 40 min at 60 C.
To the dianionic ambident was added compound 2 (0.02 mmol). The re-
action mixture was stirred for 6 h at 40 C, filtered, and evaporated in
vacuo. The residual solid was washed with water, collected by filtration,
and crystallized from ethanol (cf. Schemes 1 and 2, Table I).
Synthesis of Compounds 15a,b
Method A
To a stirred solution of compounds 14a,b (0.01 mmol) in DMF (30 ml),
methyl iodide (0.02 mmol) and potassium hydroxide (0.02 gm) were
added. The reaction mixture was refluxed for 2 h, evaporated in vacuo

Synthesis of Polyfused Thieno(2,3-b)thiophenes Part 3
901
and the remaining product was triturated with water and the resid-
ual solid was collected by filtration and crystallized from the suitable
solvent (cf. Scheme 2, Table I).
Method B
An equimolar amount (0.02 mmol) of compound 2 and the proper
S,S-acetals (0.04 mmol) were dissolved in ter. butanol (30 ml). The re-
action mixture was refluxed until the evolution of MeSH ceased (48 h),
evaporated in vacuo and the remaining product was triturated with
pet. ether (40–60 C) and the residual solid was collected by filtration
and crystallized from dioxane (cf. Scheme 2, Table I).
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