A facile one-pot synthesis of 6,7,8,9-tetrahydrobenzo[4,5]thieno[2,3-d]-1, 2,4-triazolo[4,5-a]pyrimidin-5-ones

Article abstract of DOI:10.1007/s00706-008-0060-z

The reaction of 2-mercapto-6,7,8,9-tetrahydro-3H-benzo[4,5]thieno[2,3-d] pyrimidin-4-one or its 2-methylthio derivative with hydrazonoyl halides, in the presence of triethylamine, yielded 6,7,8,9-tetrahydrobenzo[4,5]thieno[2,3-d]-1, 2,4-triazolo[4,5-a]pyr

Full text of DOI:10.1007/s00706-008-0060-z

Monatsh Chem (2009) 140:213–220
DOI 10.1007/s00706-008-0060-z
ORIGINAL PAPER
A facile one-pot synthesis of 6,7,8,9-tetrahydrobenzo[4,5]
thieno[2,3-d]-1,2,4-triazolo[4,5-a]pyrimidin-5-ones
Sobhi M. Gomha
Received: 26 May 2008 / Accepted: 8 August 2008 / Published online: 30 September 2008
Ó Springer-Verlag 2008
Abstract The reaction of 2-mercapto-6,7,8,9-tetrahydro-
3H-benzo[4,5]thieno[2,3-d]pyrimidin-4-one or its 2-meth-
ylthio derivative with hydrazonoyl halides, in the presence
of triethylamine, yielded 6,7,8,9-tetrahydrobenzo[4,5]thieno
[2,3-d]-1,2,4-triazolo[4,5-a]pyrimidin-5-ones. The structure
of the latter compounds was further confirmed by reaction
of 2-mercapto-6,7,8,9-tetrahydro-3H-benzo[4,5]thieno[2,3-d]
pyrimidin-4-one with the appropriate active chlorom-
ethylenes followed by coupling of the products with
benzenediazonium chloride to afford the non-isolable azo-
coupling products which converted, in situ, to 6,7,8,
9-tetrahydrobenzo[4,5]thieno[2,3-d]-1,2,4-triazolo[4,5-a]
pyrimidin-5-ones. The reaction mechanism was proposed
and the products were screened for their biological activity.
Some of the newly synthesized compounds had a moderate
effect against some bacterial and fungal species.
synthesis of triazoles fused to another heterocyclic ring
has attracted widespread attention because of diverse
applications as antibacterial, antidepressant, antiviral, and
antitumor agents [8, 9]. This prompted us to synthesize a
new heterocyclic system, namely 6,7,8,9-tetrahydrobenzo
[4,5]thieno[2,3-d]-1,2,4-triazolo[4,5-a]pyrimidin-5-one 8,
which has not been reported. These compounds were
studied in continuation of our previous work on the syn-
thesis of bridgehead nitrogen poly-heterocycles [10–14].
Results and discussion
The starting compound 2-mercapto-6,7,8,9-tetrahydro-3H-
benzo[4,5]thieno[2,3-d]pyrimidin-4-one (3) [18, 19] was
prepared by adopting a procedure reported previously [15]
as depicted in Scheme 1. Thus, reaction of ethyl 2-amino-
4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate (1) [16,
17] with ethoxycarbonyl isothiocyanate in acetone under
reflux afforded compound 2. Treatment of the latter com-
pound with an ethanolic solution of sodium ethoxide
followed by acidification led to the formation of the start-
ing material 3. The physical constants and the spectral data
of compound 3 were found to be identical with those
reported in the literature [18, 19]. Methylation of com-
pound 3 with methyl iodide in DMF in the presence of
anhydrous K2CO3 afforded the corresponding 2-mercapto
Keywords Heterocycles ꢀ Cyclizations ꢀ
Hydrazonyl chlorides
Introduction
The synthesis of condensed heterocycles containing thie-
nopyrimidines has acquired conspicuous popularity in
recent years because of their wide spectrum of biological
activity, including as analgesic, anti-inflammatory, anti-
convulsant, antimicrobial, and anticancer agents [1–5].
Moreover, some derivatives of thienopyrimidines are
active against many organisms [6, 7]. On the other hand,
1
derivative 4. The H NMR spectrum of compound 4 con-
tained the signals of S-CH3 and NH at d = 3.19 and
11.18 ppm.
The reaction of 3 with hydrazonoyl halides 5a–5u in
dioxane, in the presence of triethylamine, under reflux,
afforded one isolable product that was identified as
6,7,8,9-tetrahydrobenzo[4,5]thieno[2,3-d]-1,2,4-triazolo
[4,5-a]pyrimidin-5-one 8a–8u rather than its isomeric
S. M. Gomha (&)
Department of Chemistry, Faculty of Science,
Cairo University, Giza 12613, Egypt
e-mail: s.m.gomha@hotmail.com
123

214
S. M. Gomha
Scheme 1
COOEt
COOEt
SCNCOOEt
NaOEt
NH COOEt
NH
NH2
S
S
1
S
2
O
O
NH
N
NH
SH
SMe
MeI / K2CO3
N
S
S
3
4
Scheme 2
O
S
NH
X
8
a
b
c
d
e
f
g
h
i
j
k
l
m
n
o
p
q
r
R' / Z (Ar= ZC6H4)
Ph / H
COMe / H
COMe / 4-CH3
COMe / 4-Cl
COMe / 4-OCH3
COMe / 4-NO2
COOEt / H
COOEt / 4-CH3
COOEt / 3-Cl
COOEt / 4-Cl
COOEt / 4-NO2
CONHPh / H
CONHPh / 4-CH3
CONHPh / 4-Cl
CONHPh / 4-NO2
COPh / H
SR
R'
NNHAr
+
N
5a-5o, X= Cl
5I-5u, X=Br
3,R=H; 4, R=Me
R=H
R=Me
R'
N
N
NNHAr
SMe
R'
O
O
NH
N
NNHAr
S
6
S
7
S
O
R'
N
S
Ar
COPh / 4-CH3
COPh / 3-Cl
COPh / 4-Cl
COPh / 4-OCH3
COPh / 4-NO2
NH
O
N
N
R'
NH
s
t
u
N
N
Ar
6A
S
SMe
N
H
S
7A
- MeSH
R'
O
R'
SH
N
Ar
O
NH
N
N
N
O
N
N
N
N
Ar
N
-H2S
S
N
Ar
R'
6B
N
8a-8u
S
9
S
structure 6,7,8,9-tetrahydrobenzo[4,5]thieno[2,3-d]-1,2,4-
triazolo[5,4-a]pyrimidin-5-one 9 (Scheme 2).
series prepared, contained the signal of the carbonyl carbon
of the pyrimidinone ring residue at d = 166. Such chemi-
cal shift values are similar to those of annulated
pyrimidinones of type A rather than those of type B
(Fig. 1). On the basis of this similarity, the isolated prod-
ucts were assigned structure 8 and structure 9 was therefore
discarded. Furthermore, assignment of structure 8 to the
products isolated from the studied reactions is also sub-
stantiated by the similarity of their carbonyl stretching
An immediate distinction between these two structures
was reached by comparison of the 13C NMR and IR spectra
with those of similar annelated pyrimidinones. Literature
reports [20–23] have shown that the chemical shift for the
carbonyl carbon in 4-pyrimidinone derivatives is markedly
affected by the nature of the adjacent nitrogen (N3) (as in
our structure 8 and the other structure 9). For example, the
13C NMR spectrum of 8a, taken as typical example of the
frequencies ðm = 1,680–1,710 cm-1) with those reported
ꢀ
123

A facile one-pot synthesis
215
Fig. 1 13C NMR shifts (ppm)
of strategic carbon atoms
170-175
166
R
161-164
O
N
O
O
N
R
R
N
N
R
N
N
R
R
N
Ar
X
N
X
S
R
8
A
B
for pyrimidinones A. For example, pyrimidinones A
exhibit their CO bands in the region 1,680–1,690 cm-1
whereas pyrimidinones B exhibit their CO bands in the
region 1,640–1,660 cm-1 [22].
(Scheme 3) is analogous to S-alkylation reactions was
reported for 2-thioxopyrimidines [27].
Treatment of 11a–11c with benzenediazonium chloride
in ethanol, in the presence of sodium acetate, at 0–5 °C
yielded the corresponding non-isolable thiohydrazonate
esters 6b, 6g, and 6l which undergo in-situ Smiles rear-
rangement [25, 26] to give the intermediate 6A (b, g, l);
cyclization of the latter gave products identical in all
respects (mp., mixed mp., IR) with that obtained from
reaction of each of compounds 3 and 4 with hydrazonoyl
halides 5b, 5g, and 5l.
The direct formation of the products 8 from reaction of
each of compounds 3 and 4 with hydrazonoyl halides 5
indicates that the intermediate amidrazone 6 underwent in-
situ cyclization as soon as they were formed (Scheme 2).
To account for this transformation, we thought of an
alternate synthesis of the products 8. The synthesis used in
this work for preparation of the latter compounds is based
on application of the Japp–Klingemann reaction [24] and
the Smiles rearrangement [25, 26]. Thus, treatment of 3
with each of active chloromethylene compounds 10a–10c
in KOH/DMF at room temperature yielded the substitution
products 11a–11c, respectively. The structure of the latter
products was evident from microanalysis and spectral data
Antimicrobial activity
The products 8b–8h and 8k–8m were tested for their anti-
microbial activity using four species of fungi—Aspergillus
fumigatus (AF), Penicillium italicum (PI), Syncephalastrum
racemosum (SR), and Candida albicans (CA)—and four
species of bacteria—Staphylococcus aureus (SA), Pseudo-
monas aeruginosa (PA), Bacillus subtilis (BS), and
Escherichia coli (EC). The microorganisms were tested
against the activity of each compound at a concentration of
5 mg/cm3 and using inhibition zone diameter in cm (IZD) as
1
1
(mass, IR, H NMR). The H NMR data showed singlet
signals near d = 2.13 and 4.48 ppm assignable to the
COMe and methine protons, respectively, in addition to the
characteristic signals of COMe, COOEt, and CONHPh
groups in the compounds 11a–11c, respectively. The for-
mation of 11a–11c by reaction of 3 with 10a–10c
Scheme 3
Cl
O
R'
O
NH
N
NH
N
R'
COMe
10a-10c
SH
COMe PhN2Cl
S
KOH / DMF / r.t.
S
S
11a-11c
3
R'
O
R'
HS
O
NH
N
S
Ph
N
O
NH
N
NH
N
NNHPh
S
N
R'
N
Ph
H
S
N
S
6 (b, g, l)
S
6A (b, g, l)
6B (b, g, l)
R'
N
N
-H2S
O
N
N
10a,11a, 8b, R'=COMe
10b,11b, 8g, R'=COOEt
10c,11c, 8l, R'=CONHPh
Ph
S
8 (b, g, l)
123

216
S. M. Gomha
2-Mercapto-5,6,7,8-tetrahydro-3H-benzo[4,5]
thieno[2,3-d]pyrimidin-4-one (3)
Table 1 Antimicrobial activity of compound 8
Compd.a
AF
PI
SR
CA
SA
PA
BS
EC
M.p. 241 °C [Lit. mp = 231–233 °C] [18, 19]; IR, mass,
and H NMR spectra of compound 3 were found to be
identical with those described in [18, 19].
1
8b
8c
0.2
–
0.3
–
0.9
–
0.1
–
0.3
0.5
–
–
–
0.3
0.4
0.2
0.4
0.3
–
–
–
8d
8e
0.2
0.5
–
0.3
0.4
0.3
–
–
–
–
–
2-Methylthio-5,6,7,8-tetrahydro-3H-benzo[4,5]
0.2
–
–
–
–
0.1
–
thieno[2,3-d]pyrimidin-4-one (4, C11H12N2OS2)
8f
–
0.4
0.3
0.5
0.8
–
–
To 2.38 g compound 3 (10 mmol) in 20 cm3 DMF was
added 2.07 g anhydrous K2CO3 (15 mmol) and 1.42 g
methyl iodide (10 mmol). The reaction mixture was stirred
at room temperature for 1 h then poured into an ice–water
mixture. The solid formed was filtered, washed with water,
dried, and crystallized from DMF to give compound 4 as
white crystals in 86% yield, mp = 260 °C [Lit. mp = 259
8g
0.3
–
0.4
0.3
0.9
0.4
0.5
0.1
0.3
–
–
–
8h
8k
8l
–
–
–
0.2
1.0
0.2
0.7
1.0
0.4
0.3
0.3
0.2
0.4
–
0.2
0.2
–
–
–
0.1
0.2
2.6
8m
CAb
TEc
–
–
1.0
2.8
°C] [18]; IR (KBr): m ¼ 3; 332 (NH), 1,666 (CO) cm-1; 1H
3.0
3.6
3.6
3.0
ꢀ
Micro-organism, IZD/cm
a
NMR (300 MHz, DMSO-d6): d = 1.17-1.22 (m, 4H, 2CH2),
2.99-3.07 (m, 4H, 2CH2), 3.19 (s, 3H, S-CH3), 11.18 (s, 1H,
NH, D2O-exchangeable); MS (70 eV): m/z = 253 (M??1,
14.4), 252 (M?, 100), 178 (82), 151 (27).
A 1 cm3 solution with a concentration of 5.0 mg/cm3 was used in
the assay
b
Chloramphenicol
c
Terbinafin
Synthesis of 1,3-disubstituted 6,7,8,9-tetrahydrobenzo[4,5]
thieno[2,3-d]-1,2,4-triazolo[4,5-a]pyrimidin-5-ones 8a–8u
criterion for antimicrobial activity. The results indicate that
compounds 8b, 8k are active against the species SR, whereas
the other compounds have moderate activity against all
species of fungi. Furthermore, while the compounds tested
exhibit little or no inhibition of the species of bacteria,
compound 8k was found to be active against the two species
SA and EC. Also, compound 8m was found to be active
against the species EC. The results are listed in Table 1.
Method A: To 2.38 g 3 (10 mmol) and the appropriate
hydrazonoyl halides 5a–5u (10 mmol) in 50 cm3 dioxane
was added 1.4 cm3 triethylamine (10 mmol) at room tem-
perature. The reaction mixture was heated under reflux
until all the starting material was consumed and hydrogen
sulfide gas ceased to evolve (6–10 h, monitored by TLC).
The solvent was evaporated and the residue was triturated
with methanol. The solid that formed was filtered and
recrystallized from DMF to give compounds 8a–8u.
Method B: Treatment of the methylthio derivative 4
with hydrazonoyl halides 5a–5u following the same pro-
cedure as in method A led to the formation of products
which were found to be identical in all respects (mp. mixed
mp. and IR) with products 8a–8u.
Experimental
Melting points were recorded on Gallenkamp electrother-
mal apparatus. Infrared spectra (KBr) were determined on a
Pye–Unicam SP-3000 infrared spectrophotometer. 1H
NMR spectra were determined on a Varian Gemini 300
spectrometer (300 MHz) in DMSO-d6 with TMS as inter-
nal standard. Mass spectra were recorded on a GCMS-QP
1000 EX Shimadzu spectrometer. Elemental analyses were
carried out at the Microanalytical Center, University of
Cairo, Giza, Egypt, and their results were found to be in
good agreement ( 0.2%) with the calculated values.
Hydrazonoyl halides 5 [28–36] were prepared by literature
methods. The biological evaluation of the products was
carried out at the Regional Center for Mycology and Bio-
technology at Al-Azhar University, Cairo, Egypt.
1,3-Diphenyl-6,7,8,9-tetrahydrobenzo[4,5]thieno[2,3-d]-
1,2,4triazolo[4,5-a]pyrimidin-5-one (8a, C23H18N4OS)
M.p. 270–272 °C; yield: 3.14 g (79%) starting from 2.31 g
1
(10 mmol) 5a; IR (KBr): m ¼ 1; 701 (CO) cm-1; H NMR
ꢀ
(300 MHz, DMSO-d6): d = 1.18–1.22 (m, 4H, 2CH2), 3.0–
3.07 (m, 4H, 2CH2), 7.43–8.28 (m, 10H, Ar–H); 13C NMR
(75 MHz, DMSO-d6): d = 20.7, 21.1, 24.6, 26.4, 124.9,
125.7, 127.1, 127.8, 130.8, 131.0, 132.1, 132.4, 138.3,
138.7, 139.7, 149.3, 156.7, 158.5, 166.1 ppm; MS (70 eV):
m/z = 424 (M??1, 34), 423 (M?, 100), 91 (15), 77(21).
N-[3-(Ethoxycarbonyl)-4,5,6,7-tetrahydrobenzothiophene-
2-yl]-N0-ethoxycarbonylthiourea (2)
M.p. 224 °C; IR, mass, and 1H NMR spectra of compound
2 were found to be identical with those described in
Ref. [16, 17].
3-Acetyl-1-phenyl-6,7,8,9-tetrahydrobenzo[4,5]thieno
[2,3-d]-1,2,4-triazolo[4,5-a]pyrimidin-5-one
(8b, C19H16N4O2S)
M.p. 258–260 °C; yield: 2.84 g (78%) starting from 1.97 g
-1
;
ꢀ
(10 mmol) 5b; IR (KBr): m ¼ 1; 722; 1,689 (2CO) cm
123

A facile one-pot synthesis
217
1H NMR (300 MHz, DMSO-d6): d = 1.18–1.23 (m, 4H,
2CH2), 2.51 (s, 3H, COCH3), 3.01–3.07 (m, 4H, 2CH2),
7.43–8.2 (m, 5H, Ar–H); 13C NMR (75 MHz, DMSO-d6):
d = 17.3, 20.7, 21.2, 24.5, 26.1, 124.3, 126.0, 129.4, 133.2,
142.8, 147.0, 153.2, 156.7, 157.0, 158.3, 166.3, 188.2 ppm;
MS (70 eV): m/z = 365 (M??1, 3.5), 364 (M?, 15.1), 101
(14.6), 86 (100), 77 (2.1).
Ethyl 5-oxo-1-phenyl-6,7,8,9-tetrahydrobenzo[4,5]
thieno[2,3-d]-1,2,4-triazolo[4,5-a]pyrimidin-3-carboxylate
(8g, C20H18N4O3S)
M.p. 252–254 °C; yield: 3.1 g (78%) starting from 2.27 g
-1
ꢀ
(10 mmol) 5g; IR (KBr): m ¼ 1; 751; 1,705 (2CO) cm
;
1H NMR (300 MHz, DMSO-d6): d = 1.16 (t, 3H,
J = 7.2 Hz, CH3), 1.18–1.22 (m, 4H, 2CH2), 2.99–3.07
(m, 4H, 2CH2), 4.35 (q, 2H, J = 7.2 Hz, CH2), 7.40–8.16
(m, 5H, Ar–H); 13C NMR (75 MHz, DMSO-d6): d = 15.0,
20.6, 21.3, 24.6, 26.4, 62.0, 123.9, 126.2, 129.5, 133.6,
145.0, 147.3, 152.7, 155.0, 157.3, 157.7, 164.1, 166.8 ppm;
MS (70 eV): m/z = 395 (M??1, 5.7), 394 (M?, 9.4), 347
(42), 86 (100), 56 (19).
3-Acetyl-1-(4-tolyl)-6,7,8,9-tetrahydrobenzo[4,5]thieno
[2,3-d]-1,2,4-triazolo[4,5-a]pyrimidin-5-one
(8c, C20H18N4O2S)
M.p. 276–268 °C; yield: 3.1 g (82%) starting from 2.11 g
-1
ꢀ
(10 mmol) 5c; IR (KBr): m ¼ 1; 701; 1,689 (2CO) cm
;
1H NMR (300 MHz, DMSO-d6): d = 1.13–1.23 (m, 4H,
2CH2), 1.26 (s, 3H, CH3), 2.50 (s, 3H, COCH3), 2.99–3.07
(m, 4H, 2CH2), 7.41 (d, 2H, J = 7.2 Hz, Ar–H), 8.01 (d,
2H, J = 7.2 Hz, Ar–H); 13C NMR (75 MHz, DMSO-d6):
d = 17.2, 20.6, 21.1, 21.3, 24.6, 26.3, 124, 126.3, 129.5,
133, 143, 148, 153.2, 156.3, 157, 158.3, 166.3, 188.2 ppm;
MS (70 eV): m/z = 378 (M?, 6.2) 86 (100), 58 (41.1).
Ethyl 1-(4-tolyl)-5-oxo-6,7,8,9-tetrahydrobenzo[4,5]
thieno[2,3-d]-1,2,4-triazolo[4,5-a]pyrimidin-3-carboxylate
(8h, C21H20N4O3S)
M.p. 260–262 °C; yield: 3.1 g (76%) starting from 2.41 g
-1
ꢀ
(10 mmol) 5h; IR (KBr): m ¼ 1; 755; 1,705 (2CO) cm
;
1H NMR (300 MHz, DMSO-d6): d = 1.16 (t, 3H,
J = 7.3 Hz, CH3), 1.13–1.22 (m, 4H, 2CH2), 2.26 (s, 3H,
CH3), 2.99–3.07 (m, 4H, 2CH2), 4.33 (q, 2H, J = 7.3 Hz,
CH2), 7.46–8.18 (m, 4H, Ar–H); 13C NMR (75 MHz,
DMSO-d6): d = 15.0, 20.6, 21.2, 21.3, 24.1, 25.8, 62.0,
124.1, 126.3, 129.5, 133.6, 145.0, 146.3, 153.3, 154.7,
156.1, 158.2, 163.8, 166.8 ppm; MS (70 eV): m/z = 409
(M??1, 10.1), 408 (M?, 29.8), 149 (6.1), 100 (21.7), 86
(100) 52 (10.1).
3-Acetyl-1-(4-chlorophenyl)-6,7,8,9-tetrahydrobenzo[4,5]
thieno[2,3-d]-1,2,4-triazolo[4,5-a]pyrimidin-5-one
(8d, C19H15ClN4O2S)
M.p. 250–254 °C; yield: 3.4 g (86%) starting from 2.31 g
-1
ꢀ
(10 mmol) of 5d; IR (KBr): m ¼ 1; 705; 1,696 (2CO) cm
;
1H NMR (300 MHz, DMSO-d6): d = 1.17–1.22 (m, 4H,
2CH2), 2.50 (s, 3H, COCH3), 2.99–3.07 (m, 4H, 2CH2),
7.72 (d, 2H, J = 7.1 Hz, Ar–H), 8.23 (d, 2H, J = 7.1 Hz,
Ar–H); 13C NMR (75 MHz, DMSO-d6): d = 17.2, 20.6,
21.3, 24.6, 26.3, 124.0, 126.1, 129.0, 132.9, 143.2, 148.0,
153.6, 156.3, 157.1, 158.0, 166.3, 188.7 ppm; MS (70 eV):
m/z = 398 (M?, 7.3), 86 (100), 58 (45.5).
Ethyl 1-(3-chlorophenyl)-5-oxo-6,7,8,9-tetrahydrobenzo
[4,5]thieno[2,3-d]-1,2,4-triazolo[4,5-a]pyrimidin-
3-carboxylate (8i, C20H17ClN4O3S)
M.p. 241–243 °C; yield: 3.1 g (72%) starting from 2.61 g
(10 mmol) 5i; IR (KBr): m ¼ 1; 761; 1,705 (2CO) cm-1; 1H
ꢀ
3-Acetyl-1-(4-methoxyphenyl)-6,7,8,9-tetrahydrobenzo
[4,5]thieno[2,3-d]-1,2,4-triazolo[4,5-a]pyrimidin-5-one
(8e, C20H18N4O3S)
NMR (300 MHz, DMSO-d6): d = 1.18 (t, 3H, J = 7.2 Hz,
CH3), 1.13–1.22 (m, 4H, 2CH2), 2.99–3.07 (m, 4H, 2CH2),
4.37 (q, 2H, J = 7.1 Hz, CH2), 7.61–7.75 (m, 4H, Ar–H);
MS (70 eV): m/z = 428 (M?, 8), 175 (14), 101 (36), 86
(100), 77(24), 55 (10).
M.p. 247–249 °C; yield: 2.8 g (71%) starting from 2.27 g
-1
ꢀ
(10 mmol) 5e; IR (KBr): m ¼ 1; 742; 1,694 (2CO) cm
;
1H NMR (300 MHz, DMSO-d6): d = 1.17–1.22 (m, 4H,
2CH2), 2.51 (s, 3H, COCH3), 2.98–3.07 (m, 4H, 2CH2),
3.54 (s, 3H, OCH3), 7.44 (d, 2H, J = 7.0 Hz, Ar–H), 8.16
(d, 2H, J = 7.1 Hz, Ar–H); MS (70 eV): m/z = 394 (M?,
26), (14), 86 (100), 58 (37).
Ethyl 1-(4-chlorophenyl)-5-oxo-6,7,8,9-tetrahydrobenzo
[4,5]thieno[2,3-d]-1,2,4-triazolo[4,5-a]pyrimidin-
3-carboxylate (8j, C20H17ClN4O3S)
M.p. 256–258 °C; yield: 3.47 g (81%) starting from
ꢀ
2.61 g (10 mmol) 5j; IR (KBr): m ¼ 1; 753; 1,701 (2CO)
3-Acetyl-1-(4-nitrophenyl)-6,7,8,9-tetrahydrobenzo
[4,5]thieno[2,3-d]-1,2,4-triazolo[4,5-a]pyrimidin-5-one
(8f, C19H15N5O4S)
1
cm-1; H NMR (300 MHz, DMSO-d6): d = 1.14 (t, 3H,
J = 7.3 Hz, CH3), 1.13–1.22 (m, 4H, 2CH2), 2.99–3.07
(m, 4H, 2CH2), 4.36 (q, 2H, J = 7.2 Hz, CH2), 7.68 (d,
2H, J = 7.5 Hz, Ar–H), 7.71 (d, 2H, J = 7.5 Hz, Ar–H);
13C NMR (75 MHz, DMSO-d6): d = 15.2, 20.6, 21.3,
24.0, 26.2, 62.1, 123.9, 126.1, 129.2, 132.9, 145.4, 147.2,
153.0, 154.9, 157.0, 158.2, 164.2, 166.8 ppm; MS
(70 eV): m/z = 428 (M?, 6), 101 (15.2), 86 (100), 58
(45.2).
M.p. 258–260 °C; yield: 3.0 g (74%) starting from 2.42 g
(10 mmol) 5f; IR (KBr): m ¼ 1; 733; 1,636 (2CO) cm-1; 1H
ꢀ
NMR (300 MHz, DMSO-d6): d = 1.13–1.22 (m, 4H,
2CH2), 2.51 (s, 3H, COCH3), 2.99–3.07 (m, 4H, 2CH2),
7.72 (d, 2H, J = 7.2 Hz, Ar–H), 8.5 (d, 2H, J = 7.2 Hz,
Ar–H); MS (70 eV): m/z = 394 (M?, 20), 92 (51.4), 101
(31.4), 86 (100), 58 (40).
123

218
S. M. Gomha
Ethyl 1-(4-nitrophenyl)-5-oxo-6,7,8,9-tetrahydrobenzo
[4,5]thieno[2,3-d]-1,2,4-triazolo[4,5-a]pyrimidin-
3-carboxylate (8k, C20H17N5O5S)
24.4, 26.4, 118.0, 122.2, 125.1, 127.9, 129.3, 130.6, 131.1,
139.1, 148.0, 150.3, 152.8, 154.3, 157.0, 158.5, 162.1,
166.4 ppm; MS (70 eV): m/z = 477 (M??2, 18), 476
(M??, 28), 475 (M?, 48), 330 (32), 178 (24), 118 (59), 77
(67), 57 (100).
M.p. 266–268 °C; yield: 3.42 g (78%) starting from 2.72 g
-1
;
ꢀ
(10 mmol) 5k; IR (KBr): m ¼ 1; 756; 1,708 (2CO) cm
1H NMR (300 MHz, DMSO-d6): d = 1.17 (t,3H,
J = 7.1 Hz, CH3), 1.13–1.22 (m, 4H, 2CH2), 2.99–3.07
(m, 4H, 2CH2), 4.37 (q, 2H, J = 7.1 Hz, CH2), 7.66 (d, 2H,
J = 7.5 Hz, Ar–H), 7.76 (d, 2H, J = 7.2 Hz, Ar–H); MS
(70 eV): m/z = 440 (M??1, 24.1), 439 (M?, 100), 411
(33.3), 91 (7.6), 80 (7.9), 65(8.6).
1-(4-Nitrophenyl)-3-(N-phenylcarbamoyl)-6,7,8,
9-tetrahydrobenzo[4,5]thieno[2,3-d]-1,2,4-triazolo
[4,5-a]pyrimidin-5-one (8o, C24H18N6O4S)
M.p. 278–280 °C; yield: 3.55 g (73%) starting from 3.19 g
ꢀ
(10 mmol) 5o; IR (KBr): m ¼ 3; 236ðNHÞ; 1,674, 1,662
1
(2CO) cm-1; H NMR (300 MHz, DMSO-d6): d = 1.17–
1-Phenyl-3-(N-phenylcarbamoyl)-6,7,8,9-tetrahydrobenzo
[4,5]thieno[2,3-d]-1,2,4-triazolo[4,5-a]pyrimidin-5-one
(8l, C24H19N5O2S)
1.23 (m, 4H, 2CH2), 3.01–3.07 (m, 4H, 2CH2), 7.23–7.51
(m, 5H, Ar–H), 7.81 (d, 2H, J = 7.1 Hz, Ar–H), 8.12 (d,
2H, J = 7.1 Hz, Ar–H) 11.64 (s, 1H, NH, D2O-exchange-
able); MS (70 eV): m/z = 488 (M??2, 18), 487 (M??1,
23), 486 (M?, 31), 330 (23), 178 (52), 119 (57), 77 (90), 65
(100).
M.p. 290–292 °C; yield: 3.35 g (76%) starting from
ꢀ
2.74 g (10 mmol) 5l; IR (KBr): m ¼ 3; 287ðNHÞ; 1,690,
1,634 (2CO) cm-1; 1H NMR (300 MHz, DMSO-d6):
d = 1.17–1.23 (m, 4H, 2CH2), 3.01–3.07 (m, 4H, 2CH2),
7.20–8.28 (m, 10H, Ar–H), 11.64 (s, 1H, NH, D2O-
exchangeable); 13C NMR (75 MHz, DMSO-d6): d = 20.6,
21.3, 24.3, 26.8, 118.1, 122.4, 126.0, 128.2, 129.7, 130.1,
131.2, 137.8, 146.0, 150.3, 152.0, 154.2, 157.2, 158.3,
162.0, 166.4 ppm; MS (70 eV): m/z = 442 (M??1, 30),
441 (M?, 99), 294 (18), 181 (6), 119 (51), 91 (51),77
(100), 65 (51).
3-Benzoyl-1-phenyl-6,7,8,9-tetrahydrobenzo[4,5]thieno
[2,3-d]-1,2,4-triazolo[4,5-a]pyrimidin-5-one
(8p, C24H18N4O2S)
M.p. 248–250 °C; yield: 3.15 g (74%) starting from 2.59 g
-1
ꢀ
(10 mmol) 5p; IR (KBr): m ¼ 1; 754; 1,693 (2CO) cm
;
1H NMR (300 MHz, DMSO-d6): d = 1.17–1.23 (m, 4H,
2CH2), 3.01–3.07 (m, 4H, 2CH2), 7.50–8.21 (m, 10H,
Ar–H); 13C NMR (75 MHz, DMSO-d6): d = 20.6, 21.3,
24.4, 26.6, 120.0, 121.3, 123.6, 128.0, 133.3, 146.1, 146.3,
147.1, 150.7, 153.0, 154.1, 156.5, 157.0, 157.8, 166.3,
184.4 ppm; MS (70 eV): m/z = 427 (M??1, 30.1), 426
(M?, 100) 398 (25.3), 105 (52.5), 77 (40.3).
1-(4-Methylphenyl)-3-(N-phenylcarbamoyl)-6,7,8,
9-tetrahydrobenzo[4,5]thieno[2,3-d]-1,2,4-triazolo[4,5-a]
pyrimidin-5-one (8m, C25H21N5O2S)
M.p. 264–266 °C; yield: 3.59 g (79%) starting from 2.88 g
ꢀ
(10 mmol) 5m; IR (KBr): m ¼ 3; 244ðNHÞ; 1,694, 1,642
3-Benzoyl-1-(4-tolyl)-6,7,8,9-tetrahydrobenzo[4,5]thieno
[2,3-d]-1,2,4-triazolo[4,5-a]pyrimidin-5-one
(8q, C25H20N4O2S)
1
(2CO) cm-1; H NMR (300 MHz, DMSO-d6): d = 1.18–
1.23 (m, 4H, 2CH2), 2.39 (s, 3H, CH3), 3.01–3.07 (m, 4H,
2CH2), 7.22–7.4 (m, 5H, Ar–H), 7.73 (d, 2H, J = 7.0 Hz,
Ar–H), 8.21(d, 2H, J = 7.1 Hz, Ar–H), 11.62 (s, 1H, NH,
D2O-exchangeable); 13C NMR (75 MHz, DMSO-d6):
d = 20.6, 21.3, 22.1, 24.3, 26.6, 118.5, 122.2, 124.9,
128.3, 129.3, 130.1, 131.5, 138.1, 146.3, 150.3, 152.0,
154.2, 157.0, 157.8, 161.8, 166.2 ppm; MS (70 eV):
m/z = 455 (M?, 15), 294 (10), 330 (46), 118 (51), 91
(100).
M.p. 222–224 °C; yield: 3.17 g (72%) starting from 2.73 g
-1
ꢀ
(10 mmol) 5q; IR (KBr): m ¼ 1; 740; 1,693 (2CO) cm
;
1H NMR (300 MHz, DMSO-d6): d = 1.18–1.23 (m, 4H,
2CH2), 2.36 (s, 3H, CH3), 3.01–3.07 (m, 4H, 2CH2), 7.42–
8.43 (m, 9H, Ar–H); 13C NMR (75 MHz, DMSO-d6):
d = 20.6, 21.2, 21.8, 24.5, 26.3, 120.3, 121.3, 124.2, 127.6,
132.6, 146.0, 146.5, 147.0, 150.8, 153.4, 154.0, 156.5,
157.0, 158.1, 166.3, 184.1 ppm; MS (70 eV): m/z = 441
(M?, 4), 101 (17) 86 (100), 58 (30).
1-(4-Chlorophenyl)-3-(N-phenylcarbamoyl)-6,7,8,
9-tetrahydrobenzo[4,5]thieno[2,3-d]-1,2,4-triazolo[4,5-a]
pyrimidin-5-one (8n, C24H18ClN5O2S)
3-Benzoyl-1-(3-chlorophenyl)-6,7,8,9-tetrahydrobenzo
[4,5]thieno[2,3-d]-1,2,4-triazolo[4,5-a]pyrimidin-5-one
(8r, C24H17ClN4O2S)
M.p. 272–274 °C; yield: 3.71 g (78%) starting from 3.08 g
ꢀ
(10 mmol) 5n; IR (KBr): m ¼ 3; 242ðNHÞ; 1,693, 1,647
M.p. 238–240 °C; yield: 3.31 g (72%) starting from 2.93 g
1
(2CO) cm-1; H NMR (300 MHz, DMSO-d6): d = 1.18–
-1
ꢀ
(10 mmol) 5r; IR (KBr): m ¼ 1; 736; 1,693 (2CO) cm
;
1H NMR (300 MHz, DMSO-d6): d = 1.18–1.23 (m, 4H,
2CH2), 3.01–3.07 (m, 4H, 2CH2), 7.5–8.44 (m, 9H, Ar–H);
MS (70 eV): m/z = 462 (M??2, 58), 461 (M??1, 39),
460 (M?, 100), 432 (27), 105 (48), 77 (33).
1.23 (m, 4H, 2CH2), 3.01–3.07 (m, 4H, 2CH2), 7.23–7.51
(m, 5H, Ar–H), 7.81 (d, 2H, J = 7.3 Hz, Ar–H), 8.12 (d,
2H, J = 7.1 Hz, Ar–H) 11.64 (s, 1H, NH, D2O-exchange-
able); 13C NMR (75 MHz, DMSO-d6): d = 20.6, 21.3,
123

A facile one-pot synthesis
219
3-Benzoyl-1-(4-chlorophenyl)-6,7,8,9-tetrahydrobenzo
[4,5]thieno[2,3-d]-1,2,4-triazolo[4,5-a]pyrimidin-5-one
(8s, C24H17ClN4O2S)
2CH2), 4.48 (s, 1H, CH), 10.46 (s, 1H, NH, D2O-
exchangeable), 2.11 (s, 6H); MS (70 eV): m/z = 336
(M?, 8.7), 237 (38), 151(28), 95(62), 57(100).
M.p. 230–232 °C; yield: 3.59 g (78%) starting from 2.93 g
Ethyl 2-[(4-oxo-5,6,7,8-tetrahydrobenzo[4,5]thieno
[2,3-d]pyrimidin-2-yl)thio]-3-oxobutanoate
(11b, C16H18N2O4S2)
-1
;
ꢀ
(10 mmol) 5s; IR (KBr): m ¼ 1; 747; 1,697 (2CO) cm
1H NMR (300 MHz, DMSO-d6): d = 1.18–1.23 (m, 4H,
2CH2), 3.01–3.07 (m, 4H, 2CH2), 7.48–8.50 (m, 9H, Ar–
H); 13C NMR (75 MHz, DMSO-d6): d = 20.6, 21.3, 24.4,
26.3, 120.0, 121.5, 123.7, 126.3, 133.3, 146.0, 146.5,
147.0, 151.4, 152.6, 153.9, 156.2, 157.0, 157.6, 166.7,
184.3 ppm; MS (70 eV): m/z = 460 (M?, 2), 364 (12), 105
(21), 80 (100), 58 (26).
M.p. 177–179 °C; yield: 2.64 g (72%) starting from 1.65 g
ꢀ
(10 mmol) 10b; IR (KBr): m ¼ 3; 398ðNHÞ; 1,740, 1,666
1
(3CO) cm-1; H NMR (300 MHz, DMSO-d6): d = 1.18–
1.23 (m, 4H, 2CH2), 1.41 (t, 3H, J = 7.3 Hz, CH3), 2.55 (s,
3H, CH3), 3.01–3.07 (m, 4H, 2CH2), 4.12 (q, 2H,
J = 7.3 Hz, CH2), 4.34 (s, 1H, CH), 10.47 (s, 1H, NH,
D2O-exchangeable); MS (70 eV): m/z = 366 (M?, 22),
349 (20), 322(26), 321(78), 367(19), 320(100), 238(54),
278(52), 179(39).
3-Benzoyl-1-(4-methoxyphenyl)-6,7,8,9-tetrahydrobenzo
[4,5]thieno[2,3-d]-1,2,4-triazolo[4,5-a]pyrimidin-5-one
(8t, C25H20N4O3S)
M.p. 262–264 °C; yield: 3.33 g (73%) starting from 2.89 g
N-Phenyl-2-[(5,6,7,8-tetrahydrobenzo[4,5]thieno
[2,3-d]pyrimidin-2-yl)thio]-3-oxobutamide
(11c, C20H19N3O3S2)
(10 mmol) 5t; IR (KBr): m ¼ 1; 746; 1,667 (2CO) cm-1; 1H
ꢀ
NMR (300 MHz, DMSO-d6): d = 1.17–1.23 (m, 4H,
2CH2), 3.01–3.07 (m, 4H, 2CH2), 3.63 (s, 3H, CH3),
7.44–8.42 (m, 9H, Ar–H); MS (70 eV): m/z = 457
(M??1, 35), 456 (M?, 32), 105 (16), 77 (34).
M.p. 186–188 °C; yield: 3.1 g (75%) starting from 2.12 g
ꢀ
(10 mmol) 10c; IR (KBr): m ¼ 3; 431; 3,225 (2NH), 1,728,
1,682 (3CO) cm-1
;
1H NMR (300 MHz, DMSO-d6):
3-Benzoyl-1-(4-nitrophenyl)-6,7,8,9-tetrahydrobenzo
[4,5]thieno[2,3-d]-1,2,4-triazolo[4,5-a]pyrimidin-5-one
(8u, C24H17N5O4S)
d = 1.18–1.23 (m, 4H, 2CH2), 2.54 (s, 3H, CH3), 3.01–
3.07 (m, 4H, 2CH2), 4.58 (s, 1H, CH), 7.21–8.13 (m, 5H),
10.33 (s, 1H, NH, D2O-exchangeable), 10.56 (s, 1H, NH,
D2O-exchangeable); MS (70 eV): m/z = 413 (M?, 6), 400
(1.3), 320 (100), 179 (77), 151 (28), 77 (13).
M.p. 254–256 °C; yield: 3.72 g (79%) starting from 3.04 g
-1
;
ꢀ
(10 mmol) 5u; IR (KBr): m ¼ 1; 731; 1,686 (2CO) cm
1H NMR (300 MHz, DMSO-d6): d = 1.18–1.23 (m, 4H,
2CH2), 3.01–3.07 (m, 4H, 2CH2), 7.17–8.24 (m, 9H, Ar–
H); MS (70 eV): m/z = 471 (M?, 6) 311 (3), 211 (5), 116
(7), 75 (100).
Alternate synthesis of 8b, 8g, and 8l
To a solution of the appropriate 11a–11c (10 mmol) in
ethanol (40 cm3) was added 1.36 g sodium acetate trihy-
drate (10 mmol) and the mixture was cooled to 0–5 °C in
an ice bath. To the resulting cold solution was added
portion-wise a cold solution of benzenediazonium chloride
[32], prepared by diazotizing aniline (10 mmol) dissolved
in hydrochloric acid (6 M, 6 cm3) with a solution of 0.7 g
sodium nitrite (10 mmol) in 10 cm3 water. After complete
addition of the diazonium salt, the reaction mixture was
stirred for further 30 min in an ice bath. The precipitated
solid was isolated by filtration, washed with water, dried,
and crystallized from DMF to give the corresponding
products, 8b, 8g, and 8l, which were identical in all
respects (m.p., mixed m.p. and IR spectra) with those
obtained from reaction of 3 with 5b, 5g, and 5l.
Synthesis of 11a–11c: general procedure
To 2.63 g 3 (10 mmol) in 100 cm3 ethanol was added
1 cm3 of an aqueous solution of KOH (75%). The mixture
was warmed for 10 min in a water bath at 80 °C and
cooled. To the resulting clear solution was added
the appropriate chloromethylene compound 10a–10c
(10 mmol) drop-wise while stirring the reaction mixture.
After complete addition, the reaction mixture was stirred
for further 18 h at room temperature. The solid that pre-
cipitated was isolated by filtration, washed with water,
dried, and finally crystallized from DMF to give pure 11a–
11c with the following physical and spectral data.
2-(2,4-Pentandione-3-yl)thio-5,6,7,8-tetrahydro-3H-
benzo[4,5]thieno[2,3-d]pyrimidin-4-one
(11a, C15H16N2O3S2)
Antimicrobial assay
Cultures of four fungal species—Aspergillus fumigatus
(AF), Penicillium italicum (PI), Syncephalastrum racemo-
sum (SR), and Candida albicans (CA)—and four bacterial
species—Staphylococcus aureus (SA), Pseudomonas
aeruginosa (PA), Bacillus subtilis (BS), and Escherichia
M.p. 148–150 °C; yield: 2.55 g (76%) starting from 1.35 g
ꢀ
(10 mmol) 10a; IR (KBr): m ¼ 3; 385ðNHÞ; 1,744, 1,708
1
(3CO) cm-1; H NMR (300 MHz, DMSO-d6): d = 1.18–
1.23 (m, 4H, 2CH2), 2.13 (s, 6H, 2CH3), 3.01–3.07 (m, 4H,
123

220
S. M. Gomha
8. Holla BS, Poorjary NK, Rao SB, Shivananda MK (2002) Eur J
Med Chem 37:511
9. Holla BS, Akberali PM, Shivananda MK (2001) Farmaco 56:919
10. Abbas IM, Riyadh SM, Abdallah MA, Gomha SM (2006) J Het
Chem 43:935
11. Shawali AS, Gomha SM (2000) J Prakt Chem 342:599
12. Shawali AS, Gomha SM (2000) Tetrahedron 58:8559
13. Shawali AS, Abdallah MA, Abbas IM, Eid GM (2004) J Chin
Chem Soc 51:351
14. Shawali AS, Abdallah MA, Mosselhi MAN, Farghaly TA (2002)
Heteroatom Chem 13:136
15. Ahmed EK (1995) Monatshefte fu¨r Chemie 126:953
16. Vinogradoff AP (1986) J Het Chem 23:129
17. Gewald K, Schinke E, Bottcher H (1966) Chem Ber 99:94
18. Sauter F, Deinhammer W (1973) Monatshefte fu¨r Chemie
104:1593
19. Shishoo CJ, Devani MB, Pathak US, Amamthan S, Bhadti VS,
Ullas CV, Jair KS, Rathod IS, Talati DS, Doshi NH (1984) J Het
Chem 21:375
20. Greenhill JV, Ismail MJ, Bedford GR, Edwards PN, Taylor PJ
(1985) J Chem Soc Perkin Trans II 1265
21. Bedford GRP, Taylor J, Webb GA (1995) Magnetic Res Chem
33:389
coli (EC)—were used to investigate the antimicrobial
activity of the compounds. The antimicrobial activity was
assayed biologically using agar diffusion assay. The latter
technique was carried out by pouring a spore suspension of
the fungal species (1 cm3 sterile water containing approx-
imately 108 conidia) or spreading bacterial suspension over
a solidified malt agar medium. The layer was allowed to
settle for 30 min. A solution of the tested compounds
(1 cm3, 5.0 mg/cm3) was placed on to sterile 5-mm filter
paper discs and allowed to dry; The discs were then placed
on the center of the malt agar plate and incubated at the
optimum incubation temperature, 28 °C. Test organism
growth may be affected by the inhibitory action of the test
compounds, so a clean zone around the disc appears as an
indication of inhibition of growth of the test organism. The
size of the clean zone is proportional to the inhibitory
action of the compound under investigation. The fungicide
terbinafin and the bactericide chloroamphenicol were used
as standards under the same conditions. Measurements
were considered after 72 h for fungi and 24 h for bacteria.
The results are summarized in Table 1.
22. Reiter J, Bongo L, Dyortsak P (1987) Tetrahedron 43:2497
23. Elwan NM, Awad EM, Hassaneen HM, Linden A, Heimgartner H
(2003) Helv Chim Acta 86:739
24. Phillip RR (1959) Org React 10:143
25. Elliott AJ, Callaghan PD, Gibson MS, Nemeth ST (1975) Can J
Chem 53:1484
26. Elliott AJ, Gibson MS, Kayser MM, Pawelchack GA (1973) Can
J Chem 51:4115
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123