Synthesis of some new polyfused thienothiophenes part 4: Synthesis of thienopyrimidine, thienotriazine, thienoimidazotriazine, thienotriazolotriazine, and thienotetrazolotriazine derivatives

Article abstract of DOI:10.1080/10426500307907

3,4-Diamino-2,5-dicarboxamidothieno(2,3-b)thiophene 1 was allowed to react with CS₂, carbonyl compounds, ethyl chloroformate, S,S-acetals, and oxallyl chloride to give thienopyrimidines 2-6 and thieno1,4-diazepine 7. Treatment of compound 1 with nitrous acid afforded compound 8, which converted into the corresponding chloro derivative 9 by using PCl₅. Compound 9 was reacted with amino reagents to afford the corresponding thienoimidazotriazines 10 and 11, thienotriazolotriazines 12 and 13 and 4-hydrazinothienotriazine 14. Treatment of compound 14 with aldehydes, triethyl orthoformate, CS₂, nitrous acid and ylidenemalononitriles, afforded thienotriazolotriazine 16-18, thienotetrazolotriazine 19, and 4-pyrazolyl-thienotriazine 20-22 derivatives respectively.

Full text of DOI:10.1080/10426500307907

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Phosphorus, Sulfur, and Silicon and the Related
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Synthesis of Some New Polyfused Thienothiophenes
Part 4: Synthesis of Thienopyrimidine, Thienotriazine,
Thienoimidazotriazine, Thienotriazolotriazine, and
Thienotetrazolotriazine Derivatives
H. M. Moustafa a , A. Khodairy a & A. M. M. El-Saghier a
a Sohag, Egypt
Published online: 27 Oct 2010.
To cite this article: H. M. Moustafa , A. Khodairy & A. M. M. El-Saghier (2003) Synthesis of Some New Polyfused
Thienothiophenes Part 4: Synthesis of Thienopyrimidine, Thienotriazine, Thienoimidazotriazine, Thienotriazolotriazine,
and Thienotetrazolotriazine Derivatives, Phosphorus, Sulfur, and Silicon and the Related Elements, 178:6, 1211-1224, DOI:
10.1080/10426500307907
To link to this article: http://dx.doi.org/10.1080/10426500307907
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Phosphorus, Sulfur, and Silicon, 178:1211–1224, 2003
C
Copyright Taylor & Francis Inc.
ISSN: 1042-6507 print
DOI: 10.1080/10426500390200486
SYNTHESIS OF SOME NEW POLYFUSED
THIENOTHIOPHENES PART 4: SYNTHESIS
OF THIENOPYRIMIDINE, THIENOTRIAZINE,
THIENOIMIDAZOTRIAZINE,
THIENOTRIAZOLOTRIAZINE, AND
THIENOTETRAZOLOTRIAZINE DERIVATIVES
H. M. Moustafa, A. Khodairy, and A. M. M. El-Saghier
Sohag, Egypt
(Received September 10, 2002; accepted November 5, 2002)
3,4-Diamino-2,5-dicarboxamidothieno(2,3-b)thiophene 1 was allowed
to react with CS2, carbonyl compounds, ethyl chloroformate, S,S-
acetals, and oxallyl chloride to give thienopyrimidines 2–6 and thieno-
1,4-diazepine 7. Treatment of compound 1 with nitrous acid afforded
compound 8, which converted into the corresponding chloro derivative
9 by using PCl5. Compound 9 was reacted with amino reagents to afford
the corresponding thienoimidazotriazines 10 and 11, thienotriazolotri-
azines 12 and 13 and 4-hydrazinothienotriazine 14. Treatment of com-
pound 14 with aldehydes, triethyl orthoformate, CS2, nitrous acid and
ylidenemalononitriles, afforded thienotriazolotriazine 16–18, thienote-
trazolotriazine 19, and 4-pyrazolyl-thienotriazine 20–22 derivatives
respectively.
Keywords: 3,4-Diamino-2,5-dicarboxamidothieno(2,3-b)thiophene; 4-
pyrazolylthienotriazines; thienoimidazotriazines; thienopyrimidines;
thienotetrazolotriazines; thienotriazolotriazines
In our previous work1,2 we reported the synthesis of some new func-
tionally substituted thieno(2,3-b)thiophenes in a one-pot reaction us-
ing phase-transfer catalysis technique. The biological and pharmaceu-
6
10
tical activities of condensed pyrimidines,3 thienopyrimidines,4,6
triazolothienopyrimidines,11,12 and thienotriazines6,13
motivated us
15
to continue our work1,2,16
which deals with synthesis of poly-
18
fused thienothiophenes. So, we reported herein the synthesis of new
polyfused thienopyrimidine, thienotriazine, thienoimidazotriazine,
Address correspondence to H. M. Moustafa, Chemistry Department, Faculty of Sci-
ence, Sohag, Egypt. E-mail: hassa20002000@yahoo.com
1211

1212
H. M. Moustafa et al.
thienotriazolotriazine, and thienotetrazolotriazine derivatives starting
with 3,4-diamino-2,5-dicarboxamidothieno(2,3-b)thiophene.1
RESULTS AND DISCUSSION
3,4-Diamino-2,5-dicarboxamidothieno(2,3-b)thiophene 1 was allowed
to react with carbon disulphide to give 2,9-dithioxo-1,2,3,4,7,8,9,10-
octahydro-pyrimido[400,500:40,50]thieno[30,20:4,5]thieno[3,2-d]pyrimidine-
4,7-dione 2. The condensation of 1 with piperonal or cyclopentanone
did not afford the expected Schiff bases as reported for a similar
function but afforded 2,9-dibenzo[d][1,3]-dioxol-5-yl-1,2,3,4,7,8,9,10-
octahydropyrimido[400,500:40,50]thieno[30,20:4,5]thieno[3,2-d]pyrimidine-
4,7-dione 3 or dispiro[cyclopentane-1,20-(30,40,70,100-tetra-hydro-10H,
80H-pyrimido[400,500:40,50 ]thieno[30,20:4,5]thieno[3,2-d]pyrimidine-90,100-
cyclopentane]-40,70-dione 4. While the cyclocondensation of compound 1
with ethyl chloroformate, 2-[di(methylthio)methylene]malononitrile or
3-[di-(methylthio)methylene]pentan-2,4-dione yielded 1,2,3,4,7,8,9,10-
octahydropyri-mido[400,500:40,50]thieno[30,20:4,5]thieno[3,2-d]pyrimidine-
2,4,7,9-tetrone 5, 2,9-di(1,1-dicyanomethylidene)-1,2,3,4,7,8,9,10-octa-
hydropyrimido[400,500:40,50]thieno[30,20:4,5]thieno[3,2-d]pyrimidine-4,7-
dione 6a or 2,9-di(1-acetyl-2-oxopropyl-idene)-1,2,3,4,7,8,9,10-octa-
hydropyrimido[400,500:40,50]thieno[30,20:4,5]thieno[3,2-d]pyrimidine-4,7-
dione 6b respectively (cf. Scheme 1). The formation of compounds
6a,b was suggested to be a nucleophilic attack of the amino group
to the ethylenic bond with elimination of MeSH molecule followed
by intramolecular cyclization through the elimination of another
MeSH molecule. Also, treatment of compound 1 with oxallyl chloride
in presence of triethyl amine as a base catalyst, afforded 2,3,4,5,9,
10,11,12-octahydro-H,8H-[1,4]diazepino[500,600:40,50 ]thieno[30,20:4,5]-
thieno[3,2-e][1,4]diazepine-2,3,5,8,10,11-hexaone 7 (cf. Scheme 1).
On treating a solution of o-aminoamide 1 in AcOH-HCl mixture
with sodium nitrite solution resulted in diazotization followed by self
coupling6 to furnish (1,2,3)triazino[400,500:40,50]thieno[30,20:4,5]thieno
[3,2-d][1,2,3]triazine-4,7-diol 8. Chlorination of compound 8 with an
excess amount of phosphorus pentachloride gave 4,7-dichloro(1,2,3)-
triazino[400,500:40,50]thieno[30,20:4,5]thieno[3,2-d][1,2,3]triazine 9 in good
yield (cf. Scheme 1).
Chlorotriazine derivative 9 was allowed to react with ethyl glycinate,
aminoacetonitrile or semicarbazide in refluxing dimethyl formamide
in presence of anhydrous potassium carbonate to give the promising
imidazo[1,2-c]imidazo[2000,1000:600,100](1,2,3)triazino[400,500:40,50]thieno[30,
20: 4,5]thieno[3,2-d](1,2,3)triazine-4,11-diol 10, 4,11-diaminoimidazo-

Synthesis of Some New Polyfused Thienothiophenes
1213
SCHEME 1

1214
H. M. Moustafa et al.
[1,2-c]imidazo[2000,1000:600,100](1,2,3)triazino[400,500 :40,50]thieno[30,20 :4,5]-
thieno[3,2-d](1,2,3)triazine 11 or 4,11-diamino(1,2,4)triazolo[4,3-c][1,2,
4]triazolo[3000,4000:600,100](1,2,3)triazino[400,500:40,50]thieno[30,20:4,5]thieno-
[2,3-e](1,2,3)triazine 12 respectively. Moreover, the interaction of
compound 9 with benzoic acid hydrazide or nicotinic acid hydrazide
in refluxing dimethyl formamide, afforded 4,11-diphenyl(3-pyridinyl)-
[1,2,4]triazolo[4,3-c][1,2,4]triazolo[3000,4000:600,100][1,2,3]triazino[400,500:
40,50]thieno[30,20:4,5]thieno[2,3-e][1,2,3]triazine 13a,b respectively (cf.
Scheme 2). The reaction mechanism for the formation of compounds
10–13a,b was postulated to proceed via a nucleophilic substitution
reaction followed by intramolecular cyclization through the elimination
SCHEME 2

Synthesis of Some New Polyfused Thienothiophenes
1215
of either ethanol molecule in case of compound 10 or water molecule to
give compounds 12 and 13a,b. In case of compound 11 the intramolec-
ular cyclization was carried out via the addition of the NH group to the
cyano group.
On treating compound 9 with hydrazine, nucleophilic displace-
ment took place and the 4,7-dihydrazino(1,2,3)triazino[400,500:40,50]-
thieno[30,20:4,5]thieno[3,2-d][1,2,3]triazine 14 was obtained in good
yield (cf. Scheme 2).
Condensation of compound 14 with p-chlorobenzaldehde or p-nitro-
benzaldehyde afforded the corresponding Sciff bases 15a,b. Oxidative
cyclisation of compounds 15a,b with thionyl chloride afforded 4,11-
di(4-chlorophenyl or 4-nitropheny)[1,2,4]triazolo[4,3-c][1,2,4]triazolo-
[3000,4000:600,100][1,2,3]triazino[400,500:40,50]thieno[30,20:4,5]thieno[2,3-e][1,2,
3]triazine 16a,b respectively (cf. Scheme 3).
Also, compound 14 easily underwent ring closure with triethyl ortho-
formate and gave [1,2,4]triazolo[4,3-c][1,2,4]triazolo[3000,4000:600,100][1,2,3]-
triazino[400,500:40,50]thieno[30,20:4,5]thieno[2,3-e][1,2,3]triazine 17. While
refluxing of compound 14 in formic acid yielded product which is
identical in all respects with authentic sample of compound 17 (cf.
Scheme 3).
4,5,10,11-Tetrahydro[1,2,4]triazolo[4,3-c][1,2,4]triazolo[3000,4000:600,100]-
[1,2,3]triazino[400,500:40,50]thieno[30,20:4,5]thieno[2,3-e][1,2,3]triazine-4,
11-dithione 18 could be synthesized by refluxing hydrazino compound
14 with carbon disulfide in pyridine (cf. Scheme 3).
Also, [1,2,3,4]tetrazolo[1,5-c][1,2,3,4]tetrazolo[5000,1000:600,100 ][1,2,3]-
triazino[400,500:40,50]thieno[30,20:4,5]thieno[2,3-e][1,2,3]triazine 19 was
obtained upon treatment of compound 14 with nitrous acid. On the
other hand, compound 14 was allowed to react with a variety of
ylidenemalononitriles namely, ethoxymethylenemalononitrile, benzyli-
denemalononitrile, p-chlorobenzylidene-malononitrile, or cyclopentyli-
denemalononitrile to give 4,7-di(5-amino-4-cyano-1H-pyrazol-1-yl)-
[1,2,3]triazino[400,500:40,50]thieno[30,20:4,5]thieno[3,2-d][1,2,3]triazine 20,
4,7-di(5-amino-3-phenyl(4-chlorophenyl)-4-cyano-1H-pyrazol-1-yl)-[1,2,
3]triazino[400,500:40,50]thieno[30,20:4,5]thieno[2,3-e][1,2,3]triazine 21a,b
or 4,7-di(50-amino-40-cyano-spiro[cyclopentane-1-30-(10,20-dihydropyra-
zole)]-1-yl)-[1,2,3]triazino[400,500:40,50]thieno[30,20:4,5]thieno[3,2-d][1,2,
3]triazine 22 respectively (cf. Scheme 3). The reaction pathway was
assumed to proceed via the nucleophilic addition of the amino group
to the ethylenic bond followed by intramolecular cyclization through
the addition of the imino group to the cyano group. In case of com-
pounds 21a,b, aromatization was gained by elimination of hydrogen
molecule and absorbed by another molecule of arylidenemalono-
nitrile.19,20

1216
H. M. Moustafa et al.
SCHEME 3

Synthesis of Some New Polyfused Thienothiophenes
1217
All the new synthesized products are proved by their analytical and
spectral (IR and 1H-NMR) data (cf. Table I).
EXPERIMENTAL
Synthesis of Compound 2
A mixture of compound 1 (0.05 mmol), carbon disulfide (0.1 mmol) and
dry pyridine (20 ml) was refluxed until the evolution of H2S ceased
(20 h). The reaction mixture was allowed to cool, the solid product
formed upon pouring onto ice containing few drops of hydrochoric acid
(pH = 6) was collected and crystallized from the suitable solvent (cf.
Scheme 1, Table I).
Synthesis of Compounds 3 and 4: General Procedure
To a solution of compound 1 (0.01 mmol) in glacial acetic acid (20 ml),
piperonal (0.02 mmol) or cyclopentanone (0.02 mmol) was added. The
reaction mixture was treated with sodium acetate (3 g), refluxed for
5 h, evaporated in vacuo and the residual solid was washed with water,
dried and crystallized from the suitable solvent (cf. Scheme 1, Table I).
Synthesis of Compound 5
A mixture of compound 1 (0.05 mmol), ethyl chloroformate (0.1 mmol),
and pyridine (10 ml) was refluxed for 4 h and then allowed to cool. The
solid product formed upon pouring onto ice/HCl was collected by filtra-
tion and crystallized from the suitable solvent (cf. Scheme 1, Table I).
Synthesis of Compounds 6a,b: General Procedure
To a solution of compound 1 (0.005 mmol) in ethanol (30 ml), (0.01 mmol)
of 2-[di(methylthio)methylene]malononitrile or 3-[di(methylthio)meth-
ylene]pentane-2,4-dione and TEA (0.012 mmol) were added. The reac-
tion mixture was refluxed for 12 h, till the MeSH had ceased, evapo-
rated in vacuo and the remaining product was triturated with pet. ether
(40/60 C). The residual solid was collected by filtration and crystallized
from the suitable solvent (cf. Scheme 1, Table I).
Synthesis of Compound 7
To a solution of compound 1 (0.01 mmol) in dry pyridine (20 ml), oxallyl
chloride (0.02 mmol) was added. The reaction mixture was refluxed for

1218

1219

1220

Synthesis of Some New Polyfused Thienothiophenes
1221
2 h, cooled and poured into ice/HCl mixture. The formed precipitate
was filtered off, dried and crystallized from the suitable solvent (cf.
Scheme 1, Table I).
Synthesis of Compound 8
To a solution of compound 1 (0.01 mmol) in acetic acid (10 ml) and conc.
hydrochloric acid (10 ml), sodium nitrite solution (0.05 mmol) was added
dropwise at 0–5 C with stirring. The reaction mixture was stirred at
the same temperature for 1 h. The obtained solid product was filtered
off, washed with water, and crystallized from the proper solvent (cf.
Scheme 1 and Table I).
Synthesis of Compound 9
A mixture of compound 8 (0.01 mmol) and phosphorus pentachloride
(0.05 mmol) was fused at 160–170 C for 1 h. After cooling, the reaction
mixture was added gradually to ice/cold water mixture. The formed
precipitate was collected by filtration, dried and crystallized from the
suitable solvent (cf. Scheme 1, Table I).
Synthesis of Compounds 10–12: General Procedure
A mixture of compound 9 (0.005 mmol), K2CO3 (0.01 mmol), DMF
(30 ml) and ethyl glycinate hydrochoride, aminoacetonitrile sulphate
or semicarbazide hydrochoride (0.01 mmol) was refluxed for 8 h. The
reaction mixture was filtered while hot. The filtrate was concentrated
and cooled. The formed precipitate was collected by filtration, washed
with water and crystallized from the suitable solvent (cf. Scheme 2,
Table I).
Synthesis of Compounds 13a,b: General Procedure
A solution of compound 9 (0.005 mmol) in DMF (30 ml) was treated
with benzoic acid hydrazide or nicotinic acid hydrazide (0.01 mmol).
The reaction mixture was refluxed for 8 h. The obtained solid products
after cooling were filtered off and crystallized from the proper solvent
(cf. Scheme 2 and Table I).
Synthesis of Compound 14
Compound 9 (0.01 mmol) in hydrazine hydrate 99% (8 ml) was re-
fluxed for 3 h. The excess hydrazine hydrate was removed by distillation

1222
H. M. Moustafa et al.
under reduced pressure, the residue was triturated with petrolum ether
(60–80 C). The product was collected by filtration and crystallized from
the suitable solvent (cf. Scheme 2 and Table I).
Synthesis of Compounds 15a,b: General Procedure
A solution of compound 14 (0.005 mmol) in ethanol (40 ml) was treated
with the suitable aldehyde (0.01 mmol) and piperidine (0.01 mmol). The
reaction mixture was refluxed for 5 h. The obtained solid products after
cooling were filtered off and crystallized from the proper solvents (cf.
Scheme 3 and Table I).
Synthesis of Compounds 16a,b: General Procedure
A solution of compound 15a or 15b (0.005 mmol) in thionyl chloride
(20 ml) was refluxed for 2 h, cooled, and poured onto ice/cold water.
The obtained solid product was filtered off, washed with water, and
crystallized from the proper solvent (cf. Scheme 3 and Table I).
Synthesis of Compound 17
Method A
A mixture of compound 14 (0.01 mmol), triethyl orthoformate
(0.02 mmol) and acetic anhydride (10 ml) was refluxed for 4 h and al-
lowed to cool. The formed solid product upon pouring onto ice/water was
collected by filtration and crystallized from the suitable solvent.
Method B
Compound 14 (0.005 mmol) in formic acid (8 ml) was refluxed for
2 h and the unreacted formic acid was removed by distillation under
reduced pressure. The formed solid product was washed with water,
dried, and crystallized from the suitable solvent (cf. Scheme 3, Table I).
Synthesis of Compound 18
A mixture of compound 14 (0.01 mmol), carbon disulfide (0.02 mmol)
and dry pyridine (20 ml) was refluxed until the evolution of H2S ceased
(20 h). The reaction mixture was allowed to cool. The formed solid prod-
uct upon pouring onto ice containing few drops of hydrochoric acid (pH
= 6) was collected by filtration and crystallized from the suitable solvent
(cf. Scheme 3, Table I).

Synthesis of Some New Polyfused Thienothiophenes
1223
Synthesis of Compound 19
To a solution of compound 14 (0.01 mmol) in acetic acid (10 ml) and conc.
hydrochloric acid (10 ml) mixture, sodium nitrite solution (0.05 mmol)
was added dropwise at 0–5 C with stirring. The reaction mixture was
stirred at the same temperature for 1 h. The solid product obtained was
filtered off, washed with water, and crystallized from the proper solvent
(cf. Scheme 3 and Table I).
Synthesis of Compounds 20–22: General Procedure
A solution of compound 14 (0.005 mmol) in ethanol (30 ml) was treated
with the suitable ylidenemalononitrile (0.01 mmol) and piperidine
(0.01 ml). The reaction mixture was refluxed for 5 h. The obtained solid
prcoducts after cooling were filtered off and crystallized from the proper
solvents (cf. Scheme 3 and Table I). (Note: In case of arylidenemalonon-
itriles (0.02 mmol) was used.)
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