Synthesis and structure of some thienopyrimidine derivatives

Article abstract of DOI:10.1007/s00706-007-0823-y

A series of substituted thieno[2,3-d]pyrimidines was synthesized starting from ethyl-2-amino-4-isopropylthiophene-3-carboxlate. Reaction of 2-hydrazino-5-isopropyl-thieno[2,3-d]pyrimidin-4(3H)-one and its 3-methyl analogue with different reagents afforded thieno[2,3-d]triazolo[4,3-a] pyrimidines and thieno[3,2-e]triazolo[4,3-a]pyrimidines, beside open chain derivatives.

Full text of DOI:10.1007/s00706-007-0823-y

Monatsh Chem 139, 809–820 (2008)
DOI 10.1007/s00706-007-0823-y
Printed in The Netherlands
Synthesis and structure of some thienopyrimidine derivatives
Atef A. Hamed, Ibrahim F. Zeid, Hussein H. El-Ganzory, Mohamed T. Abdel Aal
Department of Chemistry, Faculty of Science, Menoufia University, Shebin El Koam, Egypt
Received 5 October 2007; Accepted 8 October 2007; Published online 26 May 2008
# Springer-Verlag 2008
dihydrofolate reductase (DHFR) [18], VEGF kinase
Abstract A series of substituted thieno[2,3-d]pyrim-
idines was synthesized starting from ethyl-2-amino-
4-isopropylthiophene-3-carboxlate. Reaction of
2-hydrazino-5-isopropyl-thieno[2,3-d]pyrimidin-4(3H)-
one and its 3-methyl analogue with different reagents
afforded thieno[2,3-d]triazolo[4,3-a]pyrimidines and
thieno[3,2-e]triazolo[4,3-a]pyrimidines, beside open
chain derivatives.
[19] inhibitors, in addition to prevention of carti-
lage destruction in articular disease [20, 21]. In
continuation of our previous work on searching an-
tiviral compounds [22, 23] and on the title com-
pounds [24], we reported herein the synthesis and
structure elucidation of a new series of thienopyr-
imidine derivatives.
Keywords Thieno[2,3-d]pyrimidines; Thieno[2,3-d]triazolo-
[4,3-a]pyrimidines; Thieno[3,2-e]triazolo[4,3-a]pyrimidines;
Thieno[3,2-e]tetrazolo[1,5-a]pyrimidines; Thiosemicarbazides;
Hydrazones.
Results and discussion
The starting material ethyl 2-amino-4-isopropylthio-
phene-3-carboxylate (1) is prepared according to
the Gewald procedure [25]. Its reaction with thiourea
or potassium thiocyanate in dioxane gave the corre-
sponding thienopyrimidine 3. Subsequent methyla-
tion with dimethylsulfate and aqueous NaOH
afforded 2-methylthio derivative 5 which upon nucle-
ophilic displacement of the SMe group with hydra-
zine furnished the respective hydrazino derivative 7a.
On the other hand, reaction of 3 with two equivalents
of methyl iodide gave the corresponding 5-isopropyl-
3-methyl-2-(methylthio)thieno[2,3-d]-pyrimidin-4-one
(6) which could be prepared by other route via the
thiourea 2 followed by cyclization to thienopyrimi-
dine 4. Subjection of 6 to hydrazine hydrate resulted
in the formation of the hydrazino derivative 7b
(Scheme 1). The structure proposal of the prepared
compounds was derived from the analytical data
(1H NMR, 13C NMR, and IR) and satisfactory ele-
mental analyses.
Introduction
Thienopyrimidine derivatives have received con-
siderable attention due to their wide range of biolog-
ical activities such as antimicrobial [1, 2], antiviral
[3], anticancer [4, 5], anti-inflammatory [6, 7], anti-
histaminic [8], antipyretics [9], antianaphylactic [10],
anticonvulsant [11], and immunostimulant [12] prop-
erties. Besides, many thienopyrimidine compounds
exhibited analgesic [13], neurotropic [14], mollusci-
cidal and larvicidal [15] activities.
In fact, some of them have been reported to dis-
play good activity as Phosphodiesterase [16, 17],
Dedicated to Prof. Dr. Erik B. Pedersen on the occasion of his
63th birthday
Correspondence: Atef A. Hamed, Department of Chemistry,
Faculty of Science, Menoufia University, Shebin El Koam,
Egypt. E-mail: atef2000_99@yahoo.com

810
A. A. Hamed et al.
Scheme 1
Synthesis of thieno[2,3-d]triazolo[4,3-a]pyrimidine
derivatives
lution gave 3-aryl thieno[2,3-d]triazolo[4,3-a]-py-
rimidine derivatives 11a–11h (Scheme 2).
A series of thieno[2,3-d]triazolo[4,3-a]pyrimidine
derivatives was synthesized by condensation of 2-
hydrazino-5-isopropylthieno[2,3-d]pyrimidin-4-one
(7a) with various one-carbon doners. For instance, it
reacted with formic acid to give the triazolothieno-
pyrmidine 9, whereas with triethylorthoformate a
mixture of 9 and its angular isomer 14a in ratio of
2:1 was obtained. Condensation of 7a with aromatic
aldehydes resulted in the formation of hydrazones
10a–10h in good yields. Oxidative cyclization of
the latter compounds by ethanolic ferric chloride so-
Synthesis of thieno[3,2-e]triazolo[4,3-a]pyrimidine
derivatives
Treatment of the hydrazino compound 7b with
formic acid or triethylorthoformate gave exclusively
the isomeric product thieno[3,2-e]triazolo[4,3-a]py-
rimidine (14b), since N-3 is blocked by methyl
group. Condensation of 7b with aromatic alde-
hydes furnished the corresponding hydrazones 15a,
15b. Dehydrogenative cyclization by ethanolic FeCl3

Synthesis and structure of thienopyrimidine
811
Scheme 2
solution afforded the triazolothienopyrimidines 16a,
16b. Addition of 7b to alkyl and aryl isothiocyanates
resulted in the formation of thiosemicarbazides
17a–17c. Reaction of 17b with HgO in ethanol gave
the expected N-methylamino-triazole 18, whereas
with aqueous NaOH (2M) afforded the mercapto de-
rivative 13, which could also be obtained by the
semicarbazides 12a–12c (Scheme 2). Treatment of
12a with aqueous NaOH (2M) did not give the
expected 3-amino derivative 8b. Instead, the 3-mer-
capto derivative 8a was obtained, which could also
be prepared by the action of CS2 on 7a in pyridine.
The IR spectra of [3,2-e]thieno[1,2,4]triazolo[4,3-a]-
pyrimidines 13, 14, 16 and 18 (angular structure)
showed absorption due to C¼O group in the range
of ꢀꢀ¼ 1651–1680 cmꢀ1. Their 1H NMR spectra dis-
played resonance for the thiophene proton in the
range of ꢁ ¼ 7.02–7.18 ppm. However, the IR spectra
of compounds 9 and 11a–11h (linear structure)
showed C¼O absorption between ꢀꢀ¼ 1706 and
1
reaction of 7b with CS2 (Scheme 3). The H NMR
spectra of the hydrazones 15a and 15b indicated its
existence as a mixture of the syn- and anti- confor-
mations as indicated by the presence of two doublets
for HC¼N proton. Aryl and alkyl isothiocyanates
reacted with 7a to provide the corresponding thio-

812
A. A. Hamed et al.
Scheme 3
1713 cmꢀ1 and resonance for thiophene proton in 1H
NMR in the range of ꢁ ¼ 6.55–6.80 ppm. Compound
8a which formed by the action of CS2 in pyridine
on 7a exhibited in its IR spectrum C¼O absorption
at ꢀꢀ¼ 1675 cmꢀ1 and thiophene proton displayed
Miscellaneous reactions of 7a and 7b with different
reagents
Compound 7b reacted with benzophenone to give
the hydrazone 20, while with pentane-2,4-dione,
the pyrazolyl derivative 21 was obtained. Addition
of arylisocyanate to 7a, 7b afforded the correspond-
ing semicarbazides 22a–22d. Treatment of 22a with
aqueous NaOH (2M) did not give the corresponding
triazolo derivative 16c. Instead, 2-unsubstitued thi-
enopyrimidine 23 was formed. Reaction of 7a with
acetic acid furnished the hydrazide 19 wherease with
ethyl chloroformate, ethyl-2-(5-isopropyl-3-methyl-
4-oxo-3,4-dihydrothieno[2,3-d]pyrimidin-2-yl) hydra-
zinecarboxylate 24 was produced. Compound 7a
and 7b reacted with nitrous acid at 0ꢁC to give the
corresponding tetrazolo derivatives 26a and 26b and
27a beside the azido isomer 25a and 25b as indicated
1
singlet at ꢁ ¼ 7.13 ppm in the H NMR spectrum.
Therefore we believe that compound 8a possess
propbably the angular structure 6-isopropyl-3-mer-
captothieno[3,2-e]triazolo[4,3-a]pyrimidin-5-one.
Treatment of 7a with triethylorthoformate afforded
the two isomeric products 9 and 14a, where their
1
thiophene proton displayed resonances in H NMR
spectra at ꢁ ¼ 6.80 and 7.16 ppm. The relatively high
field region (more deshielded) of thiophene proton in
the angular isomer can be attributed to proximity
of the triazole ring. This observation could also be seen
1
in H NMR spectra of the tetrazolo compounds
25a, 25b where the thiophene proton resonated at
ꢁ ¼ 7.37 ppm.
1
by H NMR and IR spectra. Treatment of 25b with
Zinc dust in CH3COOH afforded the corresponding

Synthesis and structure of thienopyrimidine
813
Scheme 4
AEIMS 30 spectrometer. TLC was performed on Merck silica
gel 60-F 254 precoated plastic plates. Microanalyses were
performed in the unit of microanalysis at the universities of
Cairo (Egypt) and Odense (Denmark); the results were in
satisfactory agreement with the calculated values.
2-aminothienopyrimidine 28 (Scheme 4). The consti-
tution of the prepared compounds was secured by
their NMR, IR, and MS spectra.
Experimental
Ethyl-2-amino-4-isopropylthiophene-3-carboxylate
(1, C10H15NO2S)
To
Melting points were measured with a Kofler Block apparatus.
IR spectra were recorded with Perkin – Elmer Model 1720
FTIR spectrometer. 1H NMR and 13C NMR spectra were
determined with a varian EM 390 and Bruker AC – 250
spectrometers. The chemical shifts in ppm are expressed in the
ꢁ scale using tetramethylsilane as internal standard. Coupling
constants are given in Hz. Mass spectra were recorded on an
a stirred mixture of 8.16 g isopropylmethylketone
(100mmol), 11.30 g ethyl cyanoacetate (100mmol), 9.00g
morpholin (100 mmol) and absolute ethanol 3.00cm3, 3.20 g
sulfur (100 mmol) was added gradually with continuous stir-
ring in a water bath (60ꢁC) for 6 h. The reaction mixture
was cooled and poured into crushed ice (100 cm3). The sep-

814
A. A. Hamed et al.
arated solid was filtered off, washed and crystallized from
ethanol to give yellow sheets. Yield 12.80 g (60%); mp 52–
54ꢁC; 1H NMR (DMSO-d6): ꢁ ¼ 1.13 (d, 6H, 2CH3), 1.27 (t,
J ¼ 7.1 Hz, 3H, CH3), 3.34 (m, 1H, H), 4.20 (q, J ¼ 7.0 Hz,
2H,CH2), 5.93 (s, 1H, CH), 7.29 (s, 2H, NH2) ppm; 13C
NMR (DMSO-d6): ꢁ ¼ 14.14 (CH3), 23.09 (2CH3), 28.38
(CH), 58.73 (OCH2), 99.55, 102.81, 146.75, 164.83 (thio-
phene), 165.52 (C¼O) ppm.
um hydroxide and the solution was heated at 70ꢁC for 10 min.
After cooling, the solution was filtered and neutralized by 2 M
hydrochloric acid. The precipitate was filtered off, dried, and
recrystallized from ethanol as brown crystals. Yield 2.88g
1
(80%); mp 178–180ꢁC; H NMR (DMSO-d6): ꢁ ¼ 1.23 (d,
6H, 2CH3), 2.49 (s, 3H, SCH3), 3.55 (m, 1H, CH), 7.00 (s,
1H, CH), 12.51 (bs, 1H, NH) ppm.
5-Isopropyl-3-methyl-2-(methylthio)thieno[2,3-d]pyrimidin-
4-one (6, C11H14N2OS2)
Ethyl-4-isopropyl-2-(3-methylthiourenyl)-3-carboxylate
(2, C12H18N2O2S2)
Method A: A mixture of 2.26g 3 (10 mmol) and 2.76g potas-
sium carbonate (20 mmol) in 50cm3 dry acetone was stirred
for 2 h. Methyliodid (2.84 g, 20 mmol) was added gradually
with stirring over night. The reaction mixture was filtered and
the solvent was evaporated under vacuum. The solid residue
was washed and crystallized from ethanol as brown crystals.
Yield 1.39 g (67%); mp 178–180ꢁC; IR (KBr): ꢀꢀ¼ 1561
A mixture of 2.13 g 1 (10 mmol) and 0.73g methyl isothiocy-
anate (10 mmol) in 10cm3 absolute ethanol, was boiled under
reflux for 3 h. The reaction mixture was cooled and poured
onto cold water. The separated solid was filtered off, washed
with H2O, dried and crystallized from ethanol to give brown
crystals. Yield 2.03 g (71%); mp 118–120ꢁC; IR (KBr):
(C¼C, C¼N), 1667 (C¼O) cmꢀ1
;
1H NMR (DMSO-d6):
1
ꢀꢀ¼ 1574 (C¼C), 1639 (C¼O), 3243 (NH) cmꢀ1; H NMR
ꢁ ¼ 1.22 (d, 6H, 2CH3), 2.57 (s, 3H, SCH3), 3.45 (s, 3H,
NCH3), 3.61 (m, 1H, CH), 6.99 (s, 1H, CH) ppm.
Method B: A mixture of 2.08g 4 (10mmol) and 1.38g
potassium carbonate (10 mmol) in 50 cm3 dry acetone was
stirred for 1 h. Methyliodide (1.42 g, 10mmol) was added
gradually. Working up as described before afforded brown
crystals. Yield 1.45 (70%).
(DMSO-d6): ꢁ ¼ 1.12 (m, 9H, CH3), 1.33 (d, 3H, NCH3), 2.91
(q, 2H, CH2), 4.30 (m, 1H, CH), 6.52 (s, 1H, CH), 9.40, 11.51
(2bs, 2H, 2NH) ppm.
5-Isopropyl-2-mercaptothieno[2,3-d]pyrimidin-4(3H)-one
(3, C9H10N2OS2)
A mixture of 4.26 g 1 (20 mmol) and excess of potassium
thiocyanate (3.88 g, 40mmol) in 25cm3 dioxan and 5 cm3
absolute ethanol was stirred with gradually addition of 5 cm3
hydrochloric acid 37%. The reaction mixture was boiled under
reflux for 6 h. Then, it was cooled and poured into cold water.
The separated solid was boiled in sodium hydroxide (1M,
50cm3) for 10 min, then cooled and neutralized by addition
of 1 M hydrochloric acid. The precipitate was filtered off,
washed, and crystallized from ethanol as colorless crystals.
Yield 2.26 g (50%); mp 52–54ꢁC; IR (KBr): ꢀꢀ¼ 1536
(C¼C), 1671 (C¼O) cmꢀ1; 1H NMR (DMSO-d6): ꢁ ¼ 1.18 (d,
6H, 2CH3), 3.46 (m, 1H, CH), 6.88 (s, 1H, CH), 12.34, 13.44
(2s, 2H, 2NH) ppm; 13C NMR (DMSO-d6): ꢁ ¼ 22.62 (2CH3),
27.85 (CH), 11.37, 115.90, 145.59, 152.83 (thiophene), 156.89
(C¼O), 172.95 (C¼S) ppm.
2-Hydrazino-5-isopropylthieno[2,3-d]pyrimidin-4(3H)-one
(7a, C9H12N4OS)
A mixture of 0.24g 5 (1mmol) and 5 cm3 NH2NH2 ꢂ H2O in
15cm3 absolute ethanol was boiled under reflux for 3 h. The
colorless product that separated on cooling was filtered off and
recrystallized from ethanol to provide colorless crystals. Yield
0.15g (70%); mp 244–246ꢁC; IR (KBr): ꢀꢀ¼ 1614 (C¼C,
C¼N), 1778 (C¼O), 3264 (NH) cmꢀ1; 1H NMR (DMSO-d6):
ꢁ ¼ 1.21 (d, 6H, 2CH3), 3.47 (m, 1H, CH), 4.80 (bs, 2H, NH2),
6.58 (s, 1H, CH) 8.29, (bs, 1H, NH) ppm; 13C NMR (DMSO-
d6): ꢁ ¼ 22.72 (2CH3), 28.23 (CH), 107.70, 113.16, 145.07,
154.62 (thiophene), 157.80, (C¼N), 168.72 (C¼O) ppm.
2-Hydrazino-5-isopropyl-3-methylthieno[2,3-d]pyrimidin-4-
one (7b, C10H14N4OS)
5-Isopropyl-2-mercapto-3-methylthieno[2,3-d]pyrimidin-4-
one (4, C10H12N2OS2)
From 0.22g 6 (1mmol) and hydrazine hydrate as described
for 7a to give colorless crystyals. Yield 0.17g (72%); mp
250–252ꢁC; IR (KBr): ꢀꢀ¼ 1530 (C¼C, C¼N), 1675 (C¼O)
A solution of 2.86 g 2 (10 mmol) in 15cm3 2 M sodium hy-
droxide was boiled under reflux for 1 h. After cooling the
reaction mixture was neutralized by 2 M hydrochloric acid.
The precipitate was filtered off, dried, and crystallized from
ethanol as white crystals. Yield 1.39g (67%); mp 178–180ꢁC;
IR (KBr): ꢀꢀ¼ 1266 (C¼S), 1543 (C¼C), 1568 (C¼N), 1693
3210 (NH) cmꢀ1
2CH3), 3.29 (s, 1H, CH3), 3.50 (m, 1H, CH), 4.42 (bs, 2H,
NH2) 6.62 (s, 1H, CH), 8.23 (bs, 1H, NH) ppm.
;
1H NMR (DMSO-d6): ꢁ ¼ 1.20 (d, 6H,
6-Isopropyl-3-mercaptothieno[3,2-e][1,2,4]triazolo[4,3-a]-
pyrimidin-5(1H)-one (8, C10H10N4OS2)
1
(C¼O) cmꢀ1; H NMR (DMSO-d6): ꢁ ¼ 1.20 (d, 6H, 2CH3),
3.33 (s, 3H, NCH3), 3.53 (m, 1H, CH), 6.90 (s, 1H, CH), 13.64
(s, 1H, SH) ppm.
Method A: A mixture of 2.24 g 7a (10 mmol) and 0.91g CS2
(12 mmol) in 15cm3 pyridine was heated under reflux for 6 h
and then allowed to cool. The solid product was washed and
recrystallized from ethanol to give white powder. Yield 1.86 g
(70%);mp282–284ꢁC;IR(KBr):ꢀꢀ¼ 1647 (C¼C, C¼N), 1676
5-Isopropyl-2-(methylthio)thieno[2,3-d]pyrimidin-4(3H)-one
(5, C10H12N2OS2)
A solution of 3.39g 3 (15 mmol) in 150 cm3 0.1 M sodium
hydroxide and 15 cm3 dimethylsulfate was stirred for 5 min.
The precipitated solid was dissolved by addition of 4 M sodi-
1
(C¼O), 3118 (NH) cmꢀ1; H NMR (DMSO-d6): ꢁ ¼ 1.25 (s,
6H, 2CH3), 3.72 (m, 1H, CH), 7.15 (s, 1H, CH), 12.54, 13.83
(2bs, 2H, 2NH) ppm; 13C NMR ꢁ ¼ 23.01 (2CH3), 27.16 (CH),

Synthesis and structure of thienopyrimidine
815
114.51, 117.30, 142.04, 145.35 (thiophene), 149.49 (C¼N),
157.18 (C¼O), 158.50 (C¼S) ppm.
3365 (NH) cmꢀ1
;
1H NMR (DMSO-d6): ꢁ ¼ 1.21 (d, 6H,
2CH3), 2.97 (s, 6H, 2CH3), 3.53 (m, 1H, CH), 6.66 (s, 1H,
CH), 6.73 (d, J ¼ 9.8 Hz, 2H, Ar–H), 7.71 (d, J ¼ 9.0 Hz, 2H,
Ar–H), 7.93 (s, 1H, N¼CH), 10.97, 11.42 (2s, 2H, 2NH) ppm;
13CNMR (DMSO-d6): ꢁ ¼ 22.50 (2Me), 27.98 (CH), 39.44
(2CH3), 108.46, 113.97, 143.86, 145.08 (thiophene), 111.23,
121.33, 128.34, 149.79 (Ar–C), 150.87, 157.84 (2C¼N),
167.88 (C¼O) ppm.
Method B: A solution of 0.36g 12a (1mmol) and 25cm3
2 M sodium hydroxide was boiled for 20min and then neutral-
ized by addition of 2 M hydrochloric acid. The precipitate
formed was collected, washed and crystallized from ethanol
as white crystals. Yield 0.19 g (71%).
6-Isopropylthieno[2,3-d][1,2,4]triazolo[4,3-a]pyrimidin-
5(1H)-one (9, C10H10N4OS)
Benzaldehyde (5-isopropyl-4-oxo-3,4-dihydrothieno[2,3-d]-
pyrimidine-2-yl)hydrazone (10c, C16H16N4OS)
Method A: A solution of 2.24 g 7a (10 mmol) in 10 cm3 formic
acid was heated under reflux for 8 h. The reaction mixture was
allowed to cool and then poured onto 100 cm3 ice cold water.
The separated product was filtered off, washed with water,
dried, and crystallized from ethanol as colorless crystals.
Yield 1.63 g (70%); mp 203–205ꢁC; IR (KBr): ꢀꢀ¼ 1620
From 7a and 1.06 g benzaldehyde (10 mmol). Yield 2.34
(75%) as yellow crystals; mp 250–252ꢁC; IR (KBr): ꢀꢀ¼
1610 (C¼C, C¼N), 1656 (C¼O), 3153 (NH) cmꢀ1
;
1H
NMR (DMSO-d6): ꢁ ¼ 1.24 (d, 6H, 2CH3), 3.55 (m, 1H,
CH), 6.72 (s, 1H, CH), 7.40, 7.95 (m, 5H, Ar–H), 8.06
(s, 1H, N¼CH), 11.17, 11.60 (2s, 2H, 2NH) ppm; 13C
NMR (DMSO-d6): ꢁ ¼ 22.78 (2CH3), 28.26 (CH), 109.37,
114.85, 143.08, 145.40 (thiophene), 127.32, 128.40,
129.46, 134.17 (Ar–C), 150.03, 158.21 (2C¼N), 167.76
(C¼O) ppm.
(C¼C, C¼N), 1704 (C¼O), 3097 (NH) cmꢀ1
;
1H NMR
(DMSO-d6): ꢁ ¼ 1.25 (d, 6H, 2CH3), 3.58 (m, 1H, CH), 6.80
(s, 1H, CH), 9.08 (s, 1H, N¼CH), 13.84 (bs, 1H, NH) ppm;
13C NMR (DMSO-d6): ꢁ ¼ 22.69 (2CH3), 28.47 (CH), 109.68,
111.09, 144.64, 148.47 (thiophene), 131.96, 151.49 (2C¼N),
169.74 (C¼O) ppm.
Method B: A solution of 0.67g 7a (3mmol) in 20cm3
triethyl orthoformate was boiled under reflux for 4 h. The re-
action mixture showed two spots on TLC plate using 2%
CH2Cl2=MeOH as eluent. A solid product was precipitated
on hot and filtered off as white powder (14a). Evaporating
of the solvent from the mother liquor, washing the solid resi-
due, and crystallization from methylene chloride afforded pale
green crystals. Yield 0.38g (53%).
4-Fluorobenzaldehyde (5-isopropyl-4-oxo-3,4-dihydro-thieno-
[2,3-d]pyrimidine-2-yl)hydrazone (10d, C16H15FN4OS)
From 7a and 1.24 g 4-fluorobenzaldehyde (10 mmol). Yield
2.44g (74%) as colorless crystals; mp 269–271ꢁC; IR (KBr):
1
ꢀꢀ¼ 1608 (C¼C, C¼N), 1663 (C¼O), 3282 (NH) cmꢀ1; H
NMR (DMSO-d6): ꢁ ¼ 1.09 (d, 6H, 2CH3), 3.40 (m, 1H, CH),
6.55 (s, 1H, CH), 7.10 (d, J ¼ 8.7 Hz, 2H, Ar–H), 7.87
(d, J ¼ 2.1 Hz, 2H, Ar–H), 7.90 (s, 1H, N¼CH), 11.27, 11.54
(2s, 2H, 2NH) ppm; 13C NMR (DMSO-d6): ꢁ ¼ 22.78 (2CH3),
28.26 (CH), 109.33, 114.85, 145.40, 150.06 (thiophene),
115.24, 129.59, 130.87, 141.88 (Ar–C), 158.28, 161.17
(2C¼N), 167.76 (C¼O) ppm.
General procedure for the synthesis of compounds 10a–10h
A solution of 10 mmol 7a and 10mmol appropriate aromatic
aldehyde in 30 cm3 ethanol containing a few drops of glacial
acetic acid, was boiled under reflux for 3 h. The product that
separated on cooling was filtered off, dried, and crystallized
from ethanol.
2-Fluraldehyde (5-isopropyl-4-oxo-3,4-dihydrothieno[2,3-
d]pyrimidine-2-yl)hydrazone (10e, C14H14N4O2S)
From 7a and 0.96 g 2-furaldehyde (10 mmol). Yield 2.02
(67%) as pale brown crystals; mp 246–248ꢁC; IR (KBr):
ꢀꢀ¼ 1612 (C¼C, C¼N), 1654 (C¼O), 3396, 3569 (NH)
4-Methoxybenzaldehyde (5-isopropyl-4-oxo-3,4-dihydro-thi-
eno[2,3-d]pyrimidine-2-yl)hydrazone (10a, C17H18N4O2S)
From 2.24g 7a (10 mmol) and 1.36 g p-anisaldehyde
(10 mmol) as described before. Yield 2.56g (75%) as yellow
crystals; mp 208–211ꢁC; IR (KBr): ꢀꢀ¼ 1591 (C¼C, C¼N),
1
cmꢀ1; H NMR (DMSO-d6): ꢁ ¼ 1.24 (d, 6H, 2CH3), 3.53
(m, 1H, CH), 6.64 (s, 1H, CH), 6.72 (s, 1H, Ar–H), 7.10
(d, 1H, Ar–H), 7.82 (s, 1H, Ar–H), 7.98 (s, 1H, N¼CH),
10.64, 11.70 (2s, 2H, 2NH) ppm; 13C NMR (DMSO-d6):
ꢁ ¼ 22.77 (2CH3), 28.26 (CH), 109.60, 114.90, 145.36,
149.95 (thiophene), 111.94, 112.19, 133.18, 144.60 (Furan),
150.00, 157.75 (2C¼N), 167.75 (C¼O) ppm.
1
1662 (C¼O), 3164, 3353 (NH) cmꢀ1; H NMR (DMSO-d6):
ꢁ ¼ 1.10 (d, 6H, 2CH3), 3.40 (m, 1H, CH), 3.67 (s, 3H,
OCH3), 6.54 (s, 1H, CH), 6.84 (d, J ¼ 8.5Hz, 2H, Ar–H),
7.74 (d, J ¼ 8.4 Hz, 2H, Ar–H), 7.86 (s, 1H, N¼CH), 11.07,
11.42 (2s, 2H, 2NH) ppm; 13C NMR (DMSO-d6): ꢁ ¼ 22.79
(2Me), 28.27 (CH), 55.19 (OMe), 109.08, 114.59, 145.39,
150.10 (thiophene), 113.92, 126.85, 128.96, 143.05 (Ar–C),
158.22, 160.43 (2C¼N), 167.95 (C¼O) ppm.
4-Bromobenzaldehyde (5-isopropyl-4-oxo-3,4-dihydrothieno-
[2,3-d]pyrimidine-2-yl)hydrazone (10f, C16H15BrN4OS)
From 7a and 1.85g 4-bromobenzaldehyde (10 mmol). Yield
3.04 (78%) as yellow crystals; mp 295–297ꢁC; IR (KBr):
ꢀꢀ¼ 1599 (C¼C, C¼N), 1662 (C¼O), 3156, 3347 (NH)
4-(Dimethylamino)benzaldehyde (5-isopropyl-4-oxo-3,4-
dihydrothieno[2,3-d] pyrimidine-2-yl)hydrazone
(10b, C18H21N5OS)
1
cmꢀ1; H NMR (DMSO-d6): ꢁ ¼ 1.24 (d, 6H, 2CH3), 3.55
(m, 1H, CH), 6.72 (s, 1H, CH), 7.62 (d, J ¼ 8.4 Hz, 2H, Ar–
H), 7.93 (d, J ¼ 8.6Hz, 2H, Ar–H), 8.02 (s, 1H, N¼CH),
11.46, 11.76 (2s, 2H, 2NH); 13C NMR (DMSO-d6): ꢁ ¼
22.79 (2CH3), 28.26 (CH), 109.49, 114.98, 141.75, 145.41
From 7a and 1.49 g 4-(dimethylamino)benzaldehyde
(10 mmol). Yield 2.84 g (80%) as yellow crystals; mp 247–
249ꢁC; IR (KBr): ꢀꢀ¼ 1590 (C¼C, C¼N), 1661 (C¼O), 3227,

816
A. A. Hamed et al.
(thiophene), 122.68, 129.24, 131.34, 133.53 (Ar–C), 149.96,
158.28 (2C¼N), 167.65 (C¼O) ppm.
6.74 (s, 1H, CH), 6.76, 7.56 (m, 4H, Ar–H), 14.00 (s, 1H,
NH) ppm; 13C NMR (DMSO-d6): ꢁ ¼ 22.79 (2CH3), 28.37
(CH), 39.76 (2NCH3), 109.17, 111.36, 145.06, 145.18
(thiophene), 110.44, 114.03, 131.24, 149.64 (Ar–C),
150.99, 152.85 (2C¼N), 168.82 (C¼O) ppm.
4-Hydroxybenzaldehyde (5-isopropyl-4-oxo-3,4-dihydro-thi-
eno[2,3-d]pyrimidine-2-yl)hydrazone (10g, C16H16N4O2S)
From 7a and 1.22 g 4-hydroxybenzaldehyde (10 mmol). Yield
1
2.42 (74%) as colorless crystals; mp 277–279ꢁC; H NMR
6-Isopropyl-3-phenylthieno[2,3-d][1,2,4]triazolo[4,3-a]-
pyrimidin-5(1H)-one (11c, C16H14N4OS)
(DMSO-d6): ꢁ ¼ 1.24 (d, 6H, 2CH3), 3.55 (m, 1H, CH), 6.67
(s, 1H, CH), 6.83 (d, J ¼ 8.7 Hz, 2H, Ar–H), 7.76 (d,
J ¼ 8.7 Hz, 2H, Ar–H), 7.97 (s, 1H, N¼CH), 9.85 (bs, 1H,
OH), 11.11, 11.53 (2s, 2H, 2NH) ppm; 13C NMR (DMSO-d6):
ꢁ ¼ 22.78 (2CH3), 28.27 (CH), 108.94, 114.48, 145.39, 150.11
(thiophene), 115.33, 125.36, 129.09, 143.52 (Ar–C), 158.17,
159.00 (2C¼N), 168.03 (C¼O) ppm.
From 0.62 g 10c (2 mmol) and FeCl3. Yield 0.37 g (60%) as
brown powder; mp 180–182ꢁC; IR (KBr): ꢀꢀ¼ 1626 (C¼C,
1
C¼N), 1709 (C¼O) cmꢀ1; H NMR (DMSO-d6): ꢁ ¼ 1.09
(d, 6H, 2CH3), 3.40 (bm, 1H, CH), 6.55 (s, 1H, CH), 7.10,
7.90 (m, 5H, Ar–H), 12.55 (bs, 1H, NH) ppm; m=z ¼ 310
(Mþ).
3,4-Dihydroxybenzaldehyde (5-isopropyl-4-oxo-3,4-dihydro-
thieno[2,3-d]pyrimidine-2-yl)hydrazone (10h, C16H16N4O3S)
From 7a and 1.38 g 3,4-dihydroxybenzaldehyde (10 mmol).
Yield 2.44 (71%) as colorless crystals; mp 273–275ꢁC; IR
(KBr): ꢀꢀ¼ 1578 (C¼C, C¼N), 1632 (C¼O), 3318, 3413
3-(4-Fluorophenyl)-6-isopropylthieno[2,3-d][1,2,4]triazolo-
[4,3-a]pyrimidin-5(1H)-one (11d, C16H13F N4OS)
From 0.66 g 10d (2 mmol) and FeCl3. Yield 0.42 g (65%) as
brownish yellow powder; mp 215–217ꢁC; IR (KBr):
ꢀꢀ¼ 1613 (C¼C, C¼N), 1709 (C¼O) cmꢀ1
;
1H NMR
1
(NH), 3651 (OH) cmꢀ1; H NMR (DMSO-d6): ꢁ ¼ 1.24 (d,
(DMSO-d6): ꢁ ¼ 1.20 (d, 6H, 2CH3), 3.69 (m, 1H, CH),
6.76 (s, 1H, CH), 7.34, 7.80 (m, 4H, Ar–H), 12.75 (bs,
1H, NH) ppm.
6H, 2CH3), 3.54 (m, 1H, CH), 6.68 (s, 1H, CH), 6.79, 7.10
(2d, 2H, Ar–H), 7.40 (s, 1H, Ar–H), 7.90 (s, 1H, N¼CH),
9.10, 9.40 (2bs, 2H, 2OH), 10.89, 11.46 (2s, 2H, 2NH) ppm;
13C NMR (DMSO-d6): ꢁ ¼ 22.79 (2Me), 28.27 (CH), 109.01,
114.48, 145.46, 147.53 (thiophene), 113.65, 115.30, 120.28,
125.68, 143.94, 145.36 (Ar–C), 150.04, 158.03 (2C¼N),
168.08 (C¼O) ppm.
3-(2-Furyl)-6-isopropylthieno[2,3-d][1,2,4]triazolo[4,3-a]-
pyrimidin-5(1H)-one (11e, C14H12N4O2S)
From 0.60g 10e (2mmol) and FeCl3. Yield 0.34 g (67%) as
brown crystals; mp 235–237ꢁC; IR (KBr): ꢀꢀ¼ 1624 (C¼C,
C¼N), 1712 (C¼O) cmꢀ1; 1H NMR (DMSO-d6): ꢁ ¼ 1.25 (d,
6H, 2CH3), 3.58 (m, 1H, CH), 6.71 (s, 1H, CH), 6.80 (d, 1H,
Ar–H), 7.46 (d, 1H, Ar–H), 7.95 (s, 1H, Ar–H), 14.25 (s, 1H,
NH) ppm; m=z ¼ 300 (Mþ).
General procedure for the synthesis of compounds 11a–11h
A solution of 0.4 g ferric chloride in 5 cm3 ethanol was
added dropewise to a boiling solution of 2 mmol aldehyde
hydrazones 10a–10h in 50 cm3 ethanol. Heating was con-
tinued for 30 min and the mixture was then kept overnight
at room temperature. Evaporation of the solvent under re-
duced pressure, washing the residue with water, and drying
afforded a solid product which could be crystallized from
ethanol.
3-(4-Bromophenyl)-6-isopropylthieno[2,3-d][1,2,4]triazolo-
[4,3-a]pyrimidin-5(1H)-one (11f, C16H13BrN4OS)
From 0.78g 10f (2mmol) and FeCl3. Yield 0.50g (65%)
as pale yellow crystals; mp 228–230ꢁC; IR (KBr): ꢀꢀ¼ 1622
(C¼C, C¼N), 1710 (C¼O) cmꢀ1
;
1H NMR (DMSO-d6):
ꢁ ¼ 1.21 (d, 6H, 2CH3), 3.68 (bm, 1H, CH), 6.78 (bs, 1H,
CH), 7.00, 7.70 (m, 4H, Ar–H), 12.80 (bs, 1H, NH) ppm;
13C NMR (DMSO-d6): ꢁ ¼ 22.37 (2CH3), 27.85 (CH),
108.98, 113.21, 142.91, 145.29 (thiophene), 123.05, 126.03,
129.95, 131.87 (Ar–C), 149.40, 151.94 (2C¼N), 167.50
(C¼O) ppm.
6-Isopropyl-3-(4-methoxyphenyl)thieno[2,3-d][1,2,4]tri-
azolo[4,3-a]pyrimidin-5(1H)-one (11a, C17H16N4O2S)
From 0.68g 10a (2mmol) and FeCl3 as described before.
Yield 0.47g (70%) as colorless crystals; mp 223–225ꢁC; IR
1
(KBr): ꢀꢀ¼ 1624 (C¼C, C¼N), 1713 (C¼O) cmꢀ1; H NMR
(DMSO-d6): ꢁ ¼ 1.22 (d, 6H, 2CH3), 3.53 (m, 1H, CH), 3.85
(s, 3H, OCH3), 6.77 (s, 1H, CH), 7.07, 7.66 (2d, 4H, Ar–H),
14.15 (s, 1H, NH) ppm; 13C NMR (DMSO-d6): ꢁ ¼ 22.80
(2Me), 28.38 (CH), 55.24 (OCH3), 109.38, 111.47, 144.40,
145.07 (thiophene), 112.84, 119.51, 124.22, 131.88 (Ar–C),
149.63, 152.78 (C¼N), 160.42 (C¼O) ppm.
3-(4-Hydroxyphenyl)-6-isopropylthieno[2,3-d][1,2,4]triazolo-
[4,3-a]pyrimidin-5(1H)-one (11g, C16H14N4O2S)
From 0.66 g 10g (2 mmol) and FeCl3. Yield 0.39 g (60%)
as white powder; mp 248–250ꢁC; IR (KBr): ꢀꢀ¼ 1614
(C¼C, C¼N), 1685 (C¼O), 3107 (NH), 3326 (OH) cmꢀ1
;
1H NMR (DMSO-d6): ꢁ ¼ 1.20 (d, 6H, 2CH3), 3.51 (m, 1H,
CH), 6.61 (s, 1H, CH), 6.83, 7.60 (m, 4H, Ar–H), 9.90 (bs,
1H, OH), 14.00 (bs, 1H, NH) ppm; 13C NMR (DMSO-d6):
ꢁ ¼ 22.69 (2CH3), 28.23 (CH), 108.85, 111.06, 144.89,
150.11 (thiophene), 114.05, 118.00, 131.77, 143.50 (Ar–
C), 152.50, 158.75 (2C¼N), 168.59 (C¼O) ppm; m=z ¼
326 (Mþ).
3-[4-(Dimethylamino)phenyl]-6-isopropylthieno[2,3-d][1,2,4]-
triazolo[4,3-a]pyrimidin-5(1H)-one (11b, C18H19N5OS)
From 0.71 g 10b (2mmol) and FeCl3. Yield (0.44 g, 63%) as
green crystals; mp 215–217ꢁC; IR (KBr): ꢀꢀ¼ 1611 (C¼C,
1
C¼N), 1708 (C¼O) cmꢀ1; H NMR (DMSO-d6): ꢁ ¼ 1.21
(d, 6H, 2CH3), 3.00 (s, 6H, N(CH3)2), 3.54 (m, 1H, CH),

Synthesis and structure of thienopyrimidine
817
3-(3,4-Dihydroxyphenyl)-6-isopropylthieno[2,3-d][1,2,4]-tri-
azolo[4,3-a]pyrimidin-5(1H)-one (11h, C16H12N4O3S)
From 0.69g 11h (2mmol) and FeCl3. Yield 0.42 g (61%) as
brown powder; mp >300ꢁC; IR (KBr): ꢀꢀ¼ 1609 (C¼C,
3-Isopropylthieno[3,2-e]triazolo[4,3-a]pyrimidin-4(5H)-one
(14a, C10H10N4OS)
A solution of 2.24 g 7a (10 mmol) in 10 cm3 triethyl ortho-
formate was heated under reflux for 4 h. A solid was pre-
cipitated on hot which was filtered off, washed with
methylenechloride, and crystallized from ethanol to give
white crystals. Yield 0.38 g (53%); mp 258–260ꢁC; IR
(KBr): ꢀꢀ¼ 1625 (C¼C, C¼N), 1692 (C¼O), 3104 (NH)
C¼N), 1694 (C¼O), 3350 (OH) cmꢀ1
.
General procedure for the synthesis of compounds 12a–12c
A solution of 0.22 g 7a (1mmol) and an excess of isothiocya-
nate (2.5mmol) in 10cm3 ethanol was boiled under reflux for
4 h. The product that separated on cooling was filtered off, and
recrystallized from ethanol.
1
cmꢀ1; H NMR (DMSO-d6): ꢁ ¼ 1.25 (d, 6H, 2CH3), 3.68
(m, 1H, CH), 7.16 (s, 1H, CH), 9.18 (s, 1H, N¼CH), 12.71
(bs, 1H, NH) ppm.
2-(5-Isopropyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidin-2-
yl)-N-phenylhydrazine carbothioamide (12a, C16H17N5OS2)
From 7a and 0.30 g phenyl isothiocyanate (2.5mmol). Yield
0.27g (75%) as colorless crystals; mp 270–272ꢁC; IR (KBr):
3-Isopropyl-5-methylthieno[3,2-e]triazolo[4,3-a]pyrimidin-
4-one (14b, C11H12N4OS)
Method A: A solution of 0.24 g 7b (1 mmol) in 10 cm3
formic acid was heated under reflux for 8 h. The reaction
mixture was allowed to cool and poured onto 100 cm3 ice
cold water. The separated product was filtered off, wash-
ed with water, dried, and crystallized from ethanol as
colorless crystals. Yield 0.17 g (70%); mp 160–162ꢁC;
IR (KBr): ꢀꢀ¼ 1600 (C¼C, C¼N), 1671 (C¼O), 3097
ꢀꢀ¼ 1608 (C¼C, C¼N), 1659 (C¼O), 3170, 3280 (NH) cmꢀ1
;
1H NMR (DMSO-d6): ꢁ ¼ 1.22 (d, 6H, 2CH3), 3.49 (m, 1H,
CH), 6.74 (s, 1H, CH), 7.14 (m, 1H, Ar–H), 7.32 (m, 2H,
Ar–H), 7.35 (m, 2H, Ar–H), 8.66, 9.58, 9.85, 11.15 (4s, 4H,
4NH) ppm; 13C NMR (DMSO-d6): ꢁ ¼ 22.80 (2CH3), 28.27
(CH), 109.94, 115.24, 145.19, 152.34 (thiophene), 124.84,
128.04, 139.05 (Ar–C), 158.29 (C¼N), 167.78 (C¼O),
181.61 (C¼S) ppm.
(NH) cmꢀ1
;
1H NMR (DMSO-d6): ꢁ ¼ 1.25 (d, 6H,
2CH3), 3.56 (s, 3H, NCH3), 3.69 (m, 1H, CH), 7.17 (s,
1H, CH), 9.21 (s, 1H, N¼CH) ppm; 13C NMR (DMSO-
d6): ꢁ ¼ 22.82 (2CH3), 27.78 (CH), 113.78, 116.61,
141.64, 148.23 (thiophene), 135.69, 155.49 (2C¼N),
169.74 (C¼O).
2-(5-Isopropyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidin-2-
yl)-N-methylhydrazine carbothioamide (12b, C11H15N5OS2)
From 7a and 0.18g methyl isothiocyanate (2.5mmol). Yield
0.22g (74%) as pale yellow crystals; mp 202–204ꢁC; IR
(KBr) ꢀꢀ¼ 1609 (C¼C, C¼N), 1664 (C¼O), 3168, 3304
Method B: A solution of 0.24g 7b (1mmol) in 10cm3
triethyl orthoformate was boiled under reflux for 4 h. After
cooling the reaction mixture was poured into ice water. The
separated product was filtered off, washed, dried, and crystal-
lized from ethanol.
1
(NH) cmꢀ1; H NMR (DMSO-d6): ꢁ ¼ 1.21 (d, 6H, 2CH3),
2.88 (d, 3H, NCH3), 3.50 (m, 1H, CH), 6.73 (s, 1H, CH), 8.13
(m, 1H, NH), 8.47, 9.21, 11.00 (3s, 3H, 3NH) ppm; 13C NMR
(DMSO-d6): ꢁ ¼ 22.73 (2CH3), 28.20 (CH), 30.82 (N–CH3),
109.79, 115.21, 145.10, 152.50 (thiophene), 157.85 (C¼N),
167.88 (C¼O), 182.50 (C¼S) ppm.
General procedure for the synthesis of compounds 15a and 15b
A solution of 2.38 g 7b (10mmol) and 10mmol appropriate
aromatic aldehyde in 30 cm3 ethanol containing a few drops of
glacial acetic acid, was boiled under reflux for 3 h. The prod-
uct that separated on cooling was filtered off, dried, and crys-
tallized from ethanol.
N-Allyl-2-(5-isopropyl-4-oxo-3,4dihydrothieno[2,3-d]-pyri-
midin-2-yl)hydrazine carbothioamid (12c, C13H17N5OS2)
From 7a and 0.25g allyl isothiocyanate (2.5mmol). Yield
0.23g (71%) as yellow crystals; mp 170–172ꢁC; IR (KBr):
4-Methoxybenzaldehyde (5-isopropyl-3-methyl-4-oxo-dihydro-
thieno[2,3-d]pyrimidin-2-yl) hydrazone (15a, C18H20N4O2S)
From 7b and 1.36g 4-methoxybenzaldehyde (10mmol).
Yield 2.63g (74%) as orange crystals; mp 115–117ꢁC; IR
(KBr): ꢀꢀ¼ 1608 (C¼C, C¼N), 1665 (C¼O), 3222 (NH)
ꢀꢀ¼ 1606 (C¼C, C¼N), 1665 (C¼O), 3160, 3289 (NH) cmꢀ1
;
1H NMR (DMSO-d6): ꢁ ¼ 1.21 (d, 6H, 2CH3), 3.51 (m, 1H,
CH), 4.10 (d, 2H, CH2), 5.05 (q, 2H, N–CH2), 5.81 (m,
1H, CH), 6.73 (s, 1H, CH), 8.33, 8.50, 9.30, 11.00 (4s, 4H,
4NH) ppm.
1
cmꢀ1; H NMR (DMSO-d6): ꢁ ¼ 1.20 (d, 6H, 2CH3), 3.33
(s, 3H, NCH3), 3.49 (m, 1H, CH), 3.81 (s, 3H, OCH3), 7.00
(s, 1H, CH), 7.65, 7.87 (2d, 4H, Ar–H), 8.31 (d, 1H, CH), 1.61
(s, 2H, 2NH) ppm.
3-Isopropyl-8-mercapto-5-methylthieno[3,2-e][1,2,4]-tri-
azolo-[4,3-a]pyrimidin-4(5H)-one (13, C13H14N2OS2)
From 2.38 g 7b (10 mmol) and 0.91 g CS2 (12 mmol)
in 15 cm3 pyridine, Yield 2.04 g (73%); mp 257–259ꢁC;
IR (KBr): ꢀꢀ¼ 1615 (C¼C, C¼N), 1651 (C¼O), 3202 (NH)
1,3-Benzodioxole-5-carbaldehyde (5-isopropyl-3-methyl-4-
oxo-3,4-dihydrothieno[2,3-d] pyrimidin-2-yl)hydrazone
(15b, C18H18N4O3S)
1
cmꢀ1; H NMR (DMSO-d6): ꢁ ¼ 1.24 (d, 6H, 2CH3), 3.39
(s, 3H, NCH3), 3.72 (m, 1H, CH), 7.15 (s, 1H, CH), 14.09
(s, 1H, NH) ppm; 13C NMR (DMSO-d6): ꢁ ¼ 23.00 (2CH3),
27.21 (CH), 27.90 (N–CH3), 114.69, 116.73, 141.11,
145.30 (thiophene), 156.04 (C¼N), 159.39 (C¼O), 162.02
(C¼S) ppm.
From 2.38g 7b (10 mmol) and 1.50 g 1,3-benzodioxole-5-car-
baldehyde (10 mmol). Yield 2.74g (74%) as orange crystals;
mp 110–112ꢁC; IR (KBr): ꢀꢀ¼ 1601 (C¼C, C¼N), 1675
(C¼O), 3240 (NH) cmꢀ1
.

818
A. A. Hamed et al.
General procedure for the synthesis of compounds 16a and 16b
A solution of 0.4 g ferric chloride in 5 cm3 ethanol was added
dropwise to a boiling solution of 2 mmol aldehyde hydrazone
15 in 30 cm3 ethanol. Heating was continued for 30 min and
the mixture was then kept overnight at room temperature.
Evaporation of the solvent under reduced pressure, washing
with water, and drying afforded a solid product which could
be crystallized from ethanol.
N-Allyl-2-(5-isopropyl-3-methyl-4-oxo-3,4-dihydrothieno-
[2,3-d]pyrimidin-2-yl)hydrazine carbothioamide
(17c, C14H19N5OS2)
From 7b and 0.25g allyl isothiocyanate (2.5mmol). Yield
0.24g (71%) as white crystals; mp 168–170ꢁC; 1H NMR
(DMSO-d6): ꢁ ¼ 1.22 (d, 6H, 2CH3), 3.40 (s, 3H, NCH3),
3.54 (m, 1H, CH), 4.12 (d, 2H, CH2), 5.03 (q, 2H, N–CH2),
5.81 (m, 1H, CH), 6.75 (s, 1H, CH), 8.36, 9.31, 9.44 (3s, 3H,
3NH) ppm; 13C NMR (DMSO-d6): ꢁ ¼ 22.74 (2CH3), 27.16
(CH), 28.19 (N–CH3), 45.60 (CH2), 110.17, 114.91, 145.10,
151.41 (thiophene), 113.72 (CH), 134.75 (N–CH2), 157.68
(C¼N), 166.03 (C¼O), 181.66 (C¼S) ppm.
3-Isopropyl-8-(4-methoxyphenyl)-5-methylthieno[3,2-e]-
[1,2,4]triazolo[4,3-a]pyrimidin-4-one (16a, C18H18N4O2S)
From 0.71g 15a (2mmol) and FeCl3 as described before.
Yield 0.51g (72%) as brown powder; mp 178–180ꢁC; IR
1
(KBr): ꢀꢀ¼ 1594 (C¼C, C¼N), 1680 (C¼O) cmꢀ1; H NMR
3-Isopropyl-5-methyl-8-(methylamino)thieno[3,2-e][1,2,4]-
triazolo[4,3-a]pyrimidin-4-one (18, C12H15N5OS)
(DMSO-d6): ꢁ ¼ 1.21 (d, 6H, 2CH3), 3.31 (s, 3H, NCH3), 3.60
(m, 1H, CH), 3.88 (s, 3H, OCH3), 7.02 (s, 1H, CH), 7.17, 7.65
(2d, 4H, Ar–H) ppm.
A mixture of 0.31g 17b (1mmol) and 0.26 g mercuric oxide
(1.2mmol) in 25cm3 ethanol was heated under reflux for 2 h.
The precipitate formed after cooling was filtered off, washed,
and crystallized from ethanol as white crystals. Yield 0.22g
(70%); mp 192–194ꢁC; IR (KBr): ꢀꢀ¼ 1580 (C¼C, C¼N),
8-(1,3-Benzodioxol-5-yl)-3-isopropyl-5-methylthieno[3,2-e]-
[1,2,4]triazolo[4,3-a]pyrimidin-4-one (16b, C18H16N4O3S)
From 0.74g 15b (2mmol) and FeCl3. Yield 0.47 g (64%) as
brown powder; mp 175–177ꢁC; IR (KBr): ꢀꢀ¼ 1596 (C¼C,
C¼N), 1676 (C¼O) cmꢀ1; 1H NMR (DMSO-d6): ꢁ ¼ 1.21 (d,
6H, 2CH3), 3.40 (m, 1H, CH), 3.60 (s, 3H, NCH3), 6.20 (s,
1H, CH), 7.20 (m, 3H, Ar–H) ppm; m=z ¼ 368 (Mþ).
1674 (C¼O), 3255 (NH) cmꢀ1
;
1H NMR (DMSO-d6):
ꢁ ¼ 1.21 (d, 6H, 2CH3), 2.87 (d, 3H, NHCH3), 3.46 (s, 3H,
NCH3), 3.72 (m, 1H, CH), 7.16 (s, 1H, CH) ppm; m=z ¼ 277
(Mþ).
N-(5-Isopropyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidin-2-
yl)acetohydrazide (19, C11H14N4O2S)
General procedure for the synthesis of compounds 17a and 17b
A solution of 0.24g 7b (1mmol) and an excess of isothiocya-
nate (2.5mmol) in 10cm3 ethanol was boiled under reflux for
4 h. The product that separated after cooling was filtered off
and recrystallized from ethanol.
A mixture of 2.24g 7a (10 mmol) in 15cm3 glacial acetic acid
was boiled under reflux for 6 h. The reaction mixture was
allowed to cool and poured into 100 cm3 water. The separated
solid was filtered off, dried, and crystallized from ethanol as
pale brown powder. Yield 1.19g (71%); mp 140–142ꢁC; IR
(KBr): ꢀꢀ¼ 1603 (C¼C, C¼N), 1661 (C¼O), 3255 (NH)
2-(5-Isopropyl-3-methyl-4-oxo-3,4-dihydrothieno[2,3-d]-
pyrimidin-2-yl)-N-phenylhydrazine carbothioamide
(17a, C17H19N5OS2)
cmꢀ1
;
1H NMR (DMSO-d6): ꢁ ¼ 1.21 (s, 6H, 2CH3), 1.91
(s, 3H, COCH3), 3.49 (m, 1H, CH), 6.69 (s, 1H, CH), 8.73,
9.83, 11.27 (3s, 3H, 3NH) ppm; 13C NMR (DMSO-d6):
ꢁ ¼ 20.78 (CH3), 22.76 (2CH3), 28.22 (CH), 109.24, 113.50,
145.13, 153.14 (thiophene), 158.41 (C¼N), 168.09, 169.57
(2C¼O) ppm.
From 7b and 0.34g phenyl isothiocyanate (2.5mmol) as de-
scribed before. Yield 0.27 g (73%) as colorless crystals; mp
1
264–266ꢁC; H NMR (DMSO-d6): ꢁ ¼ 1.25 (d, 6H, 2CH3),
3.39 (s, 3H, NCH3), 3.71 (m, 1H, CH), 7.15 (s, 1H, CH), 7.18,
7.33, 7.49 (m, 5H, Ar–H), 9.78 (s, 1H, NH), 14.06 (bd, 2H,
2NH) ppm; 13C NMR (DMSO-d6): ꢁ ¼ 22.97 (2CH3), 27.20
(CH), 27.90 (N–CH3), 114.66, 116.71, 141.09, 145.29 (thio-
phene), 123.48, 124.26, 128.29, 139.33 (Ar–C), 156 (C¼N),
159.42 (C¼O), 179.46 (C¼S) ppm.
2-[2-(Diphenylmethylene)hydrazino]-5-isopropyl-3-methyl-
thieno[2,3-d]pyrimidin-4-one (20, C23H22N4OS)
From 0.24 g 7b (1 mmol) and 0.20 g benzophenone
(1 mmol) as described for 10 as brown powder. Yield
(0.32 g, 79%); mp 45–47ꢁC; IR (KBr): ꢀꢀ¼ 1652 (C¼C,
1
C¼N), 1674 (C¼O), 3238 (NH) cmꢀ1; H NMR (DMSO-
2-(5-Isopropyl-3-methyl-4-oxo-3,4-dihydrothieno[2,3-d]-
pyrimidin-2-yl)-N-methylhydrazine carbothioamide
(17b, C12H17N5OS2)
d6): ꢁ ¼ 1.18 (d, 6H, 2CH3), 3.29 (s, 3H, NCH3), 3.56 (m,
1H, CH), 6.62 (s, 1H, CH), 7.58, 7.72 (m, 10H, 2Ph), 14.00
(bs, 1H, NH) ppm.
From 7b and 0.18g, methyl isothiocyanate (2.5mmol). Yield
0.22g (70%) as colorless crystals; mp 201–203ꢁC; IR (KBr):
ꢀꢀ¼ 1562 (C¼C, C¼N), 1672 (C¼O), 3137, 3325 (NH) cmꢀ1
;
2-(3,5-Dimethyl-1-H-pyrazol-1-yl)-5-isopropyl-3-methyl-
thieno[2,3-d]pyrimidin-4(3H)-one (21, C14H18N4OS)
1H NMR (DMSO-d6): ꢁ ¼ 1.21 (d, 6H, 2CH3), 2.89 (d, 3H,
NHCH3), 3.40 (s, 3H, NCH3), 3.54 (m, 1H, CH), 6.75 (s, 1H,
CH), 8.14, 9.27, 9.38 (3s, 3H, 3NH) ppm; 13C NMR (DMSO-
d6): ꢁ ¼ 22.74 (2CH3), 27.14 (CH), 28.19, 30.69 (2N–CH3),
110.18, 113.76, 145.12, 151.46 (thiophene), 157.63 (C¼N),
165.96 (C¼O), 181.91 (C¼S) ppm.
A mixture of 0.24 g 7b (1mmol) and 0.12g pentane-2,4-
dione (1.2mmol) was heated under reflux for 6 h in 30cm3
absolute ethanol. The reaction mixture was allowed to cool.
The solid product that separated was filtered off and recrys-
tallized from ethanol as pale orange crystals. Yield 0.20g

Synthesis and structure of thienopyrimidine
819
(66%); mp 115–117ꢁC; IR (KBr): ꢀꢀ¼ 1577 (C¼C, C¼N),
0.26g (73%); mp 207–209ꢁC; 1H NMR (DMSO-d6): ꢁ ¼
1.22 (d, 6H, 2CH3), 3.45 (s, 3H, NCH3), 3.55 (m, 1H, CH),
6.72 (s, 1H, CH), 6.96 (m, 1H, Ar–H), 7.26 (m, 2H, Ar–H),
7.49 (m, 2H, Ar–H), 8.28, 8.81, 9.19 (3s, 3H, 3NH) ppm.
1
1677 (C¼O) cmꢀ1; H NMR (DMSO-d6): ꢁ ¼ 1.22 (d, 6H,
2CH3), 2.22, 2.34 (2d, 6H, 2CH3), 3.32 (s, 3H, NCH3), 3.68
(m, 1H, CH), 6.16, 7.31 (2s, 2H, 2CH) ppm.
General procedure for the synthesis of compounds 22a–22d
A solution of 1 mmol 7a or 7b and an excess of the appropri-
ate isocyanate (2.5mmol) in 10 cm3 ethanol was boiled under
reflux for 4 h. The product that separated after cooling was
filtered off and recrystallized from ethanol.
5-Isopropylthieno[2,3-d]pyrimidine-4(3H)-one
(23, C9H10N2OS)
A solution of 0.69 g 22a (2mmol) and 25cm3 2 M sodium
hydroxide was boiled for 1 h, then cooled and neutralized
by addition of 2 M hydrochloric acid. The precipitate formed
was collected, washed, and crystallized from ethanol as
white powder. Yield 0.27 g (70%); mp 210–212ꢁC; 1H
NMR (DMSO-d6): ꢁ ¼ 1.27 (s, 6H, 2CH3), 3.59 (m, 1H, CH),
7.18, 8.05 (2s, 2H, 2CH), 12.39 (bs, 1H, NH) ppm.
2-(5-Isopropyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidin-2-
yl)-N-phenylhydrazine carboxamide (22a, C16H17N5O2S)
From 7a and 0.30g phenyl isocyanate (2.5mmol). Yield
0.26g (75%) as white crystals; mp 218–220ꢁC; IR (KBr):
ꢀꢀ¼ 1548 (C¼C, C¼N), 1623 (NHCONH), 1670 (C¼O),
Ethyl-2-(5-isopropyl-3-methyl-4-oxo-3,4-dihydrothieno[2,3-
d]pyrimidin-2-yl)hydrazine carboxylate (24, C13H18N4O3S)
A mixture of 0.24g 7b (1mmol) and 20 cm3 ethyl chlorofor-
mate was heated under reflux for 4 h. The reaction mixture
was allowed to cool. Evaporation of the solvent under reduced
pressure and washing of the residue with n-hexane afforded a
solid product, which was collected by filtration as yellow pow-
der. Yield 0.20g (65%); mp 143–145ꢁC; IR (KBr): ꢀꢀ¼ 1530
1
3321, 3386 (NH) cmꢀ1; H NMR (DMSO-d6): ꢁ ¼ 1.22 (d,
6H, 2CH3), 3.50 (m, 1H, CH), 6.69 (s, 1H, CH), 6.96 (m, 1H,
Ar–H), 7.75 (m, 2H, Ar–H), 7.46 (m, 2H, Ar–H), 8.15, 8.52,
8.77, 11.12 (4s, 4H, 4NH) ppm; 13C NMR (DMSO-d6):
ꢁ ¼ 22.77 (2CH3), 28.24 (CH), 109.42, 114.79, 145.18,
153.63 (thiophene), 118.41, 121.89, 128.58, 139.55 (Ar–C),
155.49 (C¼N), 158.35, 168.06 (2C¼O) ppm.
(C¼C, C¼N), 1669 (NHCO), 1728 (C¼O), 3258 (NH) cmꢀ1
;
1H NMR (DMSO-d6): ꢁ ¼ 1.19 (t, 3H, CH3), 1.21 (d, 6H,
2CH3), 3.53 (m, 1H, CH), 4.09 (q, 1H, CH), 6.73 (s, 1H,
CH), 9.17, 9.25 (2s, 2H, 2NH) ppm; m=z ¼ 310 (Mþ).
N-(4-Chlorophenyl)-2-(5-isopropyl-4-oxo-3,4-dihydrothieno-
[2,3-d]pyrimidin-2-yl)hydrazine carboxamide
(22b, C16H16ClN5O2S)
From 7a and 0.38 g 4-chlorophenyl isocyanate (2.5mmol).
Yield 0.28g (76%) as white crystals; mp 200–202ꢁC; 1H
NMR (DMSO-d6): ꢁ ¼ 1.22 (d, 6H, 2CH3), 3.50 (m, 1H,
CH), 6.70 (s, 1H, CH), 7.32, 7.52 (2d, 4H, Ar–H), 8.24,
8.54, 8.94, 11.15 (4s, 4H, 4NH) ppm; 13C NMR (DMSO-
d6): ꢁ ¼ 22.76 (2CH3), 28.23 (CH), 109.41, 114.79, 145.15,
153.53 (thiophene), 119.97, 125.38, 128.37, 138.61 (Ar–C),
155.43 (C¼N), 158.32, 167.99 (2C¼O) ppm.
Synthesis of compounds 25a and 26a
A solution of 1.12 g 7a or 7b (5mmol) in 10cm3 acetic acid
was treated with a solution of 0.15 g sodium nitrite in 3 cm3
H2O at 5ꢁC. The reaction mixture was allowed to stand at
room temperature for 24h with stirring. The solid product
was filtered off and crystallized from ethanol to furnish color-
less crystals. Yield 0.82g (70%), mp 100–102ꢁC.
2-(5-Isopropyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidin-2-
yl)-N-(2-methylphenyl)hydrazine carboxamide
(22c, C17H19N5O2S)
2-Azido-5-isopropylthieno[2,3-d]pyrimidin-4(3H)-one
(25a, C9H9N5OS) (Major product)
IR (KBr): ꢀꢀ¼ 1573 (C¼C, C¼N), 1663 (C¼O), 2154 (N3),
3445 (NH) ppm; 1H NMR (DMSO-d6): ꢁ ¼ 1.26 (d, 6H,
2CH3), 3.61 (m, 1H, CH), 7.00 (s, 1H, CH), 12.60 (bs, 1H,
NH) ppm; 13C NMR (DMSO-d6): ꢁ ¼ 22.67 (2CH3), 28.23
(CH), 111.20, 113.64, 115.81, 145.32 (thiophene), 147.45
(C¼N), 165.00 (C¼O) ppm.
From 7a and 0.33 g o-tolyl isocyanate (2.5mmol). Yield
0.27g (76%) of white crystals; mp 166–168ꢁC; IR (KBr):
1
ꢀꢀ¼ 1607 (C¼C, C¼N), 1656 (C¼O), 3237 (NH) cmꢀ1; H
NMR (DMSO-d6): ꢁ ¼ 1.22 (d, 6H, 2CH3), 2.22 (s, 3H, CH3),
3.51 (m, 1H, CH), 6.70 (s, 1H, CH), 7.00 (m, 1H, Ar–H), 7.15
(m, 2H, Ar–H), 7.65 (d, 1H, Ar–H), 8.00, 8.39, 8.54, 11.12
(4s, 4H, 4NH) ppm; 13C NMR (DMSO-d6): ꢁ ¼ 17.68 (CH3),
22.76 (2CH3), 28.24 (CH), 109.38, 114.75, 145.16, 153.61
(thiophene), 121.92, 122.99, 123.19, 125.99, 130.08, 137.04
(Ar–C), 155.74 (C¼N), 158.34, 168.06 (2C¼O) ppm.
6-Isopropyltetrazolo[1,5-a]thieno[3,2-e]pyrimidine-5(4H)-
one (26a, C9H9N5OS) (Minor product)
1H NMR (DMSO-d6): ꢁ ¼ 1.28 (d, 6H, 2CH3), 4.15 (m, 1H,
CH), 7.35 (s,1H,CH), 13.50 (bs, 1H, NH) ppm; 13C NMR
(DMSO-d6): ꢁ ¼ 22.80 (2CH3), 27.71 (CH), 111.20, 113.64,
115.81, 145.32 (thiophene), 147.45 (C¼N), 165.00 (C¼O)
ppm.
2-(5-Isopropyl-3-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyr-
imidin-2-yl)-N-phenylhydrazine carboxamide
(22d, C17H19N5O2S)
Synthesis of compounds 25b and 26b
A solution of 0.24 g 7b (1mmol) and an excess of phenyl
isocyanate (0.30 g, 2.5mmol) in 10cm3 ethanol was boiled
under reflux for 4 h. The separated product was filtered off
and recrystallized from ethanol as colorless crystals. Yield
From 1.19 g 7b (5mmol) in 10cm3 acetic acid as described
before to give colorless crystals. Yield 1.06g (73%), mp 130–
132ꢁC.

820
A. A. Hamed et al.
5. Baraldi PG, Pavani MG, Nunez M, Brigidi P, Vitali B,
Gambari R, Romagnoli R (2002) Bioorg Med Chem
10:449
6. Modica M, Santagati M, Santagati A, Cutuli V, Mangano
N, Caruso A (2000) Pharmazie 55:500
7. Romeo G, Russo F, Caruso A, Cutuli V, Amico-Roxas M
(1998) Arzneim Forsch 48:167
8. Shishoo CJ, Shirsath VS, Rathod IS, Patil MJ, Bhargava
SS (2001) Arzneim Forsch 51:221
2-Azido-5-isopropyl-3-methylthieno[2,3-d]pyrimidin-4-one
(25b, C10H11N5OS) (Minor product)
IR (KBr): ꢀꢀ¼ 1604 (C¼C, C¼N), 1676 (C¼O), 2205 (N3),
3120 (NH) cmꢀ1
;
1H NMR (DMSO-d6): ꢁ ¼ 1.22 (d, 6H,
2CH3), 3.33 (s, 3H, NCH3), 3.59 (m, 1H, CH), 7.05 (s, 1H,
CH) ppm; 13C NMR (DMSO-d6): ꢁ ¼ 22.76 (Me), 27.79
(CH), 30.04 (N–Me), 113.94, 116.02, 40.57, 147.29 (thio-
phene), 150.45 (C¼N), 156.13 (C¼O) ppm.
9. Bousquet E, Romero G, Guerrera F, Caruso A, Roxas MA
(1989) Farmaco Ed Sci 40:869
10. Wagner G, Vieweg H, Leistner S (1993) Pharmazie
48:667
11. Oganisyan AS, Noravyan AS, Dzhagatspanyan IA,
Akopyan AG (2001) Pharm Chem J 35:127
12. Guetschow M, Droessler K, Leistner S (1995) Arch
Pharm 328:231
6-Isopropyl-4-methyletrtazolo[1,5-a]thieno[3,2-e]pyrimidin-
5-one (26b, C10H11N5OS) (Major product)
1H NMR (DMSO-d6): ꢁ ¼ 1.26 (d, 6H, 2CH3), 3.61 (s, 3H,
NCH3), 3.66 (m, 1H, CH), 7.38 (s, 1H, CH) ppm.
2-Amino-5-isopropyl-3-methylthieno[2,3-d]pyrimidine-4-
(3H)-one (28, C10H13N3OS)
13. Bruno O, Brullo C, Schenone S, Ranise A, Bondavalli F,
Barocelli E, Tognolini M, Magnanini F, Bollabeni V
(2002) Farmaco 57:753
14. Oganisyan AS, Noravyan AS, Dzhagatspanyan IA,
Akopyan AG (2001) Pharm Chem J 35:650
15. Hosni HM, Basyouni WM, El-Nahaszb HA (1999) J
Chem Res 646
16. Chakraborti AK, Gopalakrishnan B, Sobhia ME, Malde
A (2003) Bioorg Med Chem Lett 13:1403
17. Crespo M, Pages L, Vega A, Segarra V, Lopez M,
Domenech T, Miralpeix M, Beleta J, Ryder H, Palacios
JM (1998) J Med Chem 41:4021
Zinc dust (0.08 g, 1.2mmol) was added to a solution of 0.28g
26b (1mmol) in 20 cm3 acetic acid with stirring. The reaction
mixture was heated at 80ꢁC for 5 h and then left to cool
at room temperature. The solid product that separated was
filtered off and crystallized from ethanol to furnish pale brown
crystals. Yield 0.08 g (35%); mp 180–182ꢁC; IR (KBr):
1
ꢀꢀ¼ 1640 (C¼C, C¼N), 1675 (C¼O), 3132 (NH) cmꢀ1; H
NMR (DMSO-d6): ꢁ ¼ 1.18 (d, 6H, 2CH3), 3.41 (s, 3H,
NCH3), 3.51 (m, 1H, CH), 6.54 (s, 1H, CH), 7.03 (s, 2H,
NH2) ppm.
18. Donkor IO, Li H, Queener SF (2003) Euro J Med Chem
38:605
Acknowledgements
Danish International Development Agency (DANIDA) is
gratefully acknowledged for financial support.
19. Munchhof MJ, Beebe JS, Casavant JM, Cooper BA, Doty
JL, Higdon RC, Hillerman SM, Soderstrom CI, Knauth
EA, Marx MA, Rossi AM, Sobolov SB, Sun J (2004)
Bioorg Med Chem Lett 14:21
20. Panico A, Cardile V, Santagati A, Gentile B (2001)
Farmaco 56:959
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