Synthesis of pyrido[3′,2′:4,5]thieno[2,3-e][1,2,4]triazolo[4,3- a]pyrimidin-5(4H)-one derivatives

Article abstract of DOI:10.1007/s00706-007-0844-6

Some new pyrido[3′,2′:4,5]thieno[2,3-e]-[1,2,4]triazolo[4,3-a] pyrimidin-5(4H)-ones were prepared through heterocyclization of ethyl 3-aminothieno[2,3-b]pyridine-2-carboxylate with phenyl or ethyl isothiocyanate followed by nucleophilic displacement with hydrazine, and finally cyclocondensation with orthoesters.

Full text of DOI:10.1007/s00706-007-0844-6

Monatsh Chem 139, 963–965 (2008)
DOI 10.1007/s00706-007-0844-6
Printed in The Netherlands
Synthesis of pyrido[30,20:4,5]thieno[2,3-e][1,2,4]triazolo[4,3-a]pyrimidin-
5(4H)-one derivatives
Abolghasem Davoodnia, Mehdi Bakavoli, Sharare Mohseni, Niloofar Tavakoli-Hoseini
Department of Chemistry, School of Sciences, Islamic Azad University, Mashhad Branch, Mashhad, Iran
Received 20 September 2007; Accepted 31 October 2007; Published online 19 June 2008
# Springer-Verlag 2008
Abstract Some new pyrido[30,20:4,5]thieno[2,3-e]-
[1,2,4]triazolo[4,3-a] pyrimidin-5(4H)-ones were
prepared through heterocyclization of ethyl 3-amino-
thieno[2,3-b]pyridine-2-carboxylate with phenyl or
ethyl isothiocyanate followed by nucleophilic dis-
placement with hydrazine, and finally cyclocondensa-
tion with orthoesters.
to 2-thioxo-2,3-dihydropyrido[30,20:4,5]thieno[3,2-d]-
pyrimidin-4(1H)-ones 2a and 2b when heated at reflux
temperature with phenyl or ethyl isothiocyanate in
the presence of potassium tert-butoxide in a mixture
of tert-butanol and N,N-dimethylformamide. The
construction of pyrimidine-2-thione through hetero-
cyclization of properly functionalized precursors
with isothiocyanates or carbon disulfide has already
been reported in the Refs. [15–19]. The thione deri-
vatives 2a and 2b were then refluxed with hydrazine
hydrate in pyridine to give the hydrazino derivatives
3a and 3b. The latter compounds subsequently un-
derwent cyclocondensation with triethyl orthoesters
in ethanol on heating under reflux to give the de-
sired tetracyclic products, pyrido[30,20:4,5]thieno[2,3-
e][1,2,4]triazolo[4,3-a]pyrimidin-5(4H)-ones 4a–4e
(Scheme 1).
Keywords Pyridothienotriazolopyrimidine; Isothiocyanates;
Hydrazine hydrate; Triethylorthoesters; Cyclocondensation.
Introduction
Among the various pyridothienotriazolopyrimidine
ring systems [1–6], pyrido[30,20:4,5]thieno[2,3-e]-
[1,2,4]triazolo[4,3-a]pyrimidines have found little
attention so far and there is only one reference deal-
ing with the synthesis and biological activities of this
heterocyclic ring system [7]. In connection with our
interest in the synthesis of new fused heterocyclic
compounds with potential biological activities [8–14]
we report herein the synthesis of some new pyrido-
[30,20:4,5]thieno[2,3-e][1,2,4]triazolo[4,3-a]pyrimi-
din-5(4H)-ones 4a–4e that might be of pharmaco-
logical interest.
The structural assignment of 2–4 was based upon
spectral and microanalytical data. For example, the
1H NMR spectrum of 4a did not show the NH2 and
NH signals of the precursor 3a at ꢀ ¼ 4.63 and
1
8.77 ppm, but instead showed a sharp H signal at
ꢀ ¼ 9.85 ppm belonging to the triazole ring indicat-
ing the formation of the tetracyclic 4a. The IR spec-
trum was devoid of the NH2 and NH absorption
bands at ꢁꢀ¼ 3390, 3320, and 3246 cmꢀ1 of the pre-
cursor. The MS of 4a showed a molecular ion peak
at m=z ¼ 319 (Mþ) corresponding to the molecular
formula C16H9N5OS.
Results and discussion
Our synthesis started from ethyl 3-aminothieno[2,3-
b]pyridine-2-carboxylate 1 [1] which was converted
In conclusion, we described the synthesis of new
pyrido[30,20:4,5]thieno[2,3-e][1,2,4]triazolo[4,3-a]-
pyrimidin-5(4H)-ones 4a–4e through heterocy-
clization of hydrazino derivatives 3a and 3b with
Correspondence: Abolghasem Davoodnia, Department of
Chemistry, School of Sciences, Islamic Azad University,
Mashhad Branch, Mashhad 91735-413, Iran. E-mail:
adavoodnia@yahoo.com

964
A. Davoodnia et al.
12.80 (br, s, 1H, NH) ppm; IR (KBr): ꢁꢀ¼ 3230 (NH), 1672
(C¼O) cmꢀ1; MS: m=z (%) ¼ 311 [Mþ] (2), 310 (4), 309 (26),
308 (76), 307 (96), 306 (100), 289 (26), 274 (90), 243 (98),
229 (90), 212 (40), 198 (94), 172 (92), 144 (94), 119 (52), 101
(93), 90 (88), 76 (92).
3-Ethyl-2-thioxo-2,3-dihydropyrido[30,20:4,5]thieno[3,2-d]-
pyrimidin-4(1H)-one (2b, C11H9N3OS2)
1
Mp 340–342ꢁC; H NMR (100MHz, DMSO-d6): ꢀ ¼ 1.18 (t,
3H, J ¼ 6.8 Hz, CH3), 3.90 (q, 2H, J ¼ 6.8 Hz, CH2), 7.50–
8.90 (m, 3H, C7H, C8H, C9H), 12.63 (br, s, 1H, NH) ppm; IR
(KBr): ꢁꢀ¼ 3242 (NH), 1667 (C¼O) cmꢀ1; MS: m=z (%) ¼
263 [Mþ] (2), 261 (4), 260 (18), 259 (24), 243 (84), 215 (41),
199 (13), 172 (100), 145 (42), 119 (10), 102 (37), 76 (17).
General procedure for the synthesis of 2-hydrazinopyrido-
[30,20:4,5]thieno[3,2-d]pyrimidin-4(3H)-ones 3a, 3b
A mixture of 2-thioxo-2,3-dihydropyrido[30,20:4,5]thieno[3,2-
d]pyrimidin-4(1H)-ones 2a and 2b (3mmol) and hydrazine
hydrate (1cm3) in pyridine (15 cm3) was heated under reflux
for 8.0 h. After the completion of the reaction (monitored by
TLC, CHCl3:MeOH, 95:5), the mixture was cooled to room
temperature and the precipitate was filtered off and recrystal-
lized from ethanol to give compounds 3a and 3b as white
crystals in 75 and 70% yields, respectively.
Scheme 1
2-Hydrazino-3-phenylpyrido[30,20:4,5]thieno[3,2-d]-
pyrimidin-4(3H)-one (3a, C15H11N5OS)
triethylorthoesters in boiling ethanol in the presence
of catalytic amounts of acetic acid.
Mp 274–276ꢁC; 1H NMR (100MHz, DMSO-d6): ꢀ ¼ 4.63 (br,
2H, NH2), 7.28–7.73 (m, 6H, Phenyl, C8H), 8.40–8.72 (m,
2H, C7H, C9H), 8.77 (br, s, 1H, NH) ppm; IR (KBr): ꢁꢀ¼
3390, 3320, 3246 (NH2 and NH), 1660 (C¼O Stretching and
NH2 Bending) cmꢀ1; MS: m=z (%) ¼ 309 [Mþ] (7), 308 (27),
307 (97), 306 (100), 289 (8), 275 (47), 246 (8), 213 (6), 185
(6), 173 (15), 144 (28), 130 (14), 101 (33), 90 (20), 76 (47).
Experimental
Melting points were recorded on an Electrothermal type 9100
melting point apparatus. The IR spectra were obtained on a
4300 Shimadzu spectrophotometer as KBr disks. The 1H
NMR (100 MHz) spectra were recorded on a Bruker AC 100
spectrometer. The mass spectra were scanned on a Varian Mat
CH-7 instrument at 70 eV. Elemental analyses were performed
on a Thermo Finnigan Flash EA microanalyzer and the results
were found to agree satisfactorily with the calculated values.
3-Ethyl-2-hydrazinopyrido[30,20:4,5]thieno[3,2-d]pyrimidin-
4(3H)-one (3b, C11H11N5OS)
1
Mp 264–267ꢁC; H NMR (100MHz, DMSO-d6): ꢀ ¼ 1.21 (t,
3H, J ¼ 6.8 Hz, CH3), 4.12 (q, 2H, J ¼ 6.8 Hz, CH2), 4.55 (br,
2H, NH2), 7.50–8.85 (m, 3H, C7H, C8H, C9H), 8.95 (br, s,
1H, NH) ppm; IR (KBr): ꢁꢀ¼ 3378, 3324, 3252 (NH2 and NH),
1662 (C¼O Stretching and NH2 Bending) cmꢀ1; MS: m=z
(%) ¼ 261 [Mþ] (2), 260 (8), 259 (26), 258 (98), 257 (100),
241 (24), 228 (77), 225 (34), 214 (17), 198 (88), 185 (7), 172
(45), 158 (8), 144 (49), 128 (20), 120 (8), 101 (84), 76 (13).
General procedure for the synthesis of 2-thioxo-2,3-dihydro-
pyrido[30,20:4,5]thieno[3,2-d]pyrimidin-4(1H)-ones 2a, 2b
A mixture of ethyl 3-aminothieno[2,3-b]pyridine-2-carboxyl-
ate (1) (3mmol), the appropriate isothiocyanate (3.5mmol) in
25cm3 DMF and 5 mmol potassium tert-butoxide in 7 cm3
tert-butanol was heated under reflux for 4.0 h. After the com-
pletion of the reaction (monitored by TLC, CHCl3:MeOH,
95:5), the solvent was evaporated in vacuo, the residue was
dissolved in 10 cm3 water and subsequently neutralized with
1 N HCl. The crude product was collected and recrystallized
from ethanol to give 2a and 2b as white crystals in 83 and
81% yields.
General procedure for the synthesis of pyrido[30,20:4,5]-
thieno[2,3-e][1,2,4]triazolo[4,3-a]pyrimidin-5(4H)-ones
4a–4e
To a solution of the 2-hydrazinopyrido[30,20:4,5]thieno[3,2-
d]pyrimidin-4(3H)-ones 3a, 3b (3mmol) in 20 cm3 ethanol
in the presence of 5 drops acetic acid as catalyst, the respec-
tive triethyl orthoester (5mmol) was added. The reaction mix-
ture was heated under reflux for 7.0 h. After the completion of
the reaction (monitored by TLC, CHCl3:MeOH, 93:7), the
mixture was cooled to room temperature. The crude product
3-Phenyl-2-thioxo-2,3-dihydropyrido[30,20:4,5]thieno[3,2-d]-
pyrimidin-4(1H)-one (2a, C15H9N3OS2)
1
Mp 314–315ꢁC; H NMR (100 MHz, DMSO-d6): ꢀ ¼ 6.90–
7.85 (m, 6H, Phenyl, C8H), 8.60–8.90 (m, 2H, C7H, C9H),

Pyrido[30,20:4,5]thieno[2,3-e][1,2,4]triazolo[4,3-a]pyrimidin-5(4H)-one derivatives
965
3
3
was collected and recrystallized from 1,4-dioxane to give
4a–4e as white crystals.
CH2), 7.68 (dd, 1H, J1 ¼ 8.7, J2 ¼ 4.5 Hz, C9H), 8.81 (dd,
3
4
3
1H, J1 ¼ 4.5, J2 ¼ 1.3 Hz, C10H), 9.05 (dd, 1H, J1 ¼ 8.7,
4J2 ¼ 1.3 Hz, C8H) ppm; IR (KBr): ꢁꢀ¼ 1662 (C¼O) cmꢀ1
;
MS: m=z (%) ¼ 285 [Mþ] (2), 284 (6), 283 (30), 282 (39),
253 (87), 243 (100), 215 (86), 199 (63), 172 (98), 145 (87),
131 (13), 119 (40), 103 (87), 102 (88), 101 (84), 93 (18),
76 (65).
4-Phenylpyrido[30,20:4,5]thieno[2,3-e][1,2,4]triazolo[4,3-a]-
pyrimidin-5(4H)-one (4a, C16H9N5OS)
1
Yield 83%; mp 308–309ꢁC; H NMR (100 MHz, DMSO-d6):
3
ꢀ ¼ 7.55–7.68 (m, 5H, Phenyl), 7.85 (dd, 1H, J1 ¼ 8.7 Hz,
3
4
3J2 ¼ 4.5 Hz, C9H), 8.87 (dd, 1H, J1 ¼ 4.5 Hz, J2 ¼ 1.3 Hz,
3
4
C10H), 9.23 (dd, 1H, J1 ¼ 8.7 Hz, J2 ¼ 1.3 Hz, C8H), 9.85
(s, 1H, C1H) ppm; IR (KBr): ꢁꢀ¼ 1668 (C¼O) cmꢀ1; MS:
m=z (%) ¼ 319 [Mþ] (16), 318 (60), 317 (98), 316 (100), 289
(97), 275 (7), 254 (20), 198 (13), 184 (22), 170 (39), 158 (60),
144 (66), 131 (90), 101 (73), 76 (63).
References
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48:20
1-Methyl-4-phenylpyrido[30,20:4,5]thieno[2,3-e][1,2,4]tri-
azolo[4,3-a]pyrimidin-5(4H)-one (4b, C17H11N5OS)
1
Yield 75%; mp 288–290ꢁC; H NMR (100MHz, DMSO-d6):
ꢀ ¼ 3.11 (s, 3H, Me), 7.45–7.64 (m, 5H, Phenyl), 7.73 (dd, 1H,
3
3
4
3J1 ¼ 8.7, J2 ¼ 4.5 Hz, C9H), 8.88 (dd, 1H, J1 ¼ 4.5, J2 ¼
5. Abdel-Rahman AE, Bakhite EA, Mohamed OS, Thabet
EA (2000) Pharmazie 66:577
3
4
1.3 Hz, C10H), 9.12 (dd, 1H, J1 ¼ 8.7, J2 ¼ 1.3 Hz, C8H)
ppm; IR (KBr): ꢁꢀ¼ 1665 (C¼O) cmꢀ1; MS: m=z (%) ¼ 333
[Mþ] (8), 332 (33), 331 (100), 306 (63), 289 (36), 275 (33), 184
(7), 170 (11), 158 (7), 144 (21), 131 (9), 101 (23), 76 (28).
6. Bakhite EA, Abdel-Rahman AE, Mohamed OS, Thabet
EA (2003) J Chem Research Synopses 2:58
7. Bakhite EA, Abdel-Rahman AE, Mohamed OS, Thabet
EA (2002) Bull Korean Chem Soc 23:1709
8. Rahimizadeh M, Davoodnia A, Heravi MM, Bakavoli M
(2002) Phosphorus Sulfur Silicon 177:2923
9. Bakavoli M, Davoodnia A, Rahimizadeh M, Heravi MM,
Ghassemzadeh M (2002) J Chem Res (s) 1:178
10. Bakavoli M, Davoodnia A, Rahimizadeh M, Heravi MM
(2002) Phosphorus Sulfur Silicon 177:2303
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(2004) Phosphorus Sulfur Silicon 179:1153
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Bashash M (2007) Phosphorus Sulfur Silicon 182:1219
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M, Dehabadi L (2007) J Chem Res 5:257
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Tavakoli-Hoseini N (2007) Chin Chem Lett 18:1163
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34:937
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1-Ethyl-4-phenylpyrido[30,20:4,5]thieno[2,3-e][1,2,4]tri-
azolo[4,3-a]pyrimidin-5(4H)-one (4c, C18H13N5OS)
1
Yield 69%; mp 264–266ꢁC; H NMR (100 MHz, DMSO-d6):
ꢀ ¼ 1.20 (t, 3H, J ¼ 7.0 Hz, CH3), 2.72 (q, 2H, J ¼ 7.0 Hz,
CH2), 7.45–9.15 (m, 8H, Phenyl, C8H, C9H, C10H) ppm;
IR (KBr): ꢁꢀ¼ 1670 (C¼O) cmꢀ1; MS: m=z (%) ¼ 347 [Mþ]
(11), 346 (44), 345 (100), 330 (4), 289 (28), 260 (4), 183 (13),
158 (7), 144 (15), 131 (8), 101 (20), 76 (28).
4-Ethylpyrido[30,20:4,5]thieno[2,3-e][1,2,4]triazolo[4,3-a]-
pyrimidin-5(4H)-one (4d, C12H9N5OS)
1
Yield 70%; mp 343–345ꢁC; H NMR (100MHz, DMSO-d6):
ꢀ ¼ 1.30 (t, 3H, J ¼ 7.2 Hz, CH3), 4.28 (q, 2H, J ¼ 7.2 Hz, CH2),
7.76 (dd, 1H, 3J1 ¼ 8.7, 3J2 ¼ 4.5 Hz, C9H), 8.89 (dd, 1H,
4
3
4
3J1 ¼ 4.5, J2 ¼ 1.3 Hz, C10H), 9.13 (dd, 1H, J1 ¼ 8.7, J2 ¼
1.3 Hz, C8H), 9.78 (s, 1H, C1H) ppm; IR (KBr): ꢁꢀ¼ 1666
(C¼O) cmꢀ1; MS: m=z (%) ¼ 271 [Mþ] (2), 270 (5), 269
(14), 268 (73), 267 (76), 238 (100), 211 (11), 197 (9), 183
(10), 158 (14), 144 (25), 130 (29), 104 (10), 101 (30), 76 (7).
4-Ethyl-1-methylpyrido[30,20:4,5]thieno[2,3-e][1,2,4]tri-
azolo[4,3-a]pyrimidin-5(4H)-one (4e, C13H11N5OS)
1
Yield 80%; mp 327–330ꢁC; H NMR (100 MHz, DMSO-d6):
19. Hussein AM, Abu-Shanab FA, Ishak EA (2000) Phos-
phorus Sulfur Silicon 159:55
ꢀ ¼ 1.31 (t, 3H, J ¼ 7.2 Hz, CH3), 4.25 (q, 2H, J ¼ 7.2 Hz,