The utility of 2-(5,6,7,8-tetrahydrobenzo[b]thieno-[2,3-d]pyrimidin-4- yloxy) acethydrazide in heterocyclic synthesis

Article abstract of DOI:10.1080/10426500500326834

Because of being a versatile synthon, the title compound 2 was utilized to construct different heterocyclic systems including pyrazol-4-carbonitrile 3, pyrazolone 4, triazole-5(4H)-thione 7, aminotriazole 9, oxadiazoles 10 and 12, thiazolidine 13, and oxa

Full text of DOI:10.1080/10426500500326834

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Phosphorus, Sulfur, and Silicon
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The Utility of 2-(5,6,7,8-
Tetrahydrobenzo[b]thieno-
[2,3-d]pyrimidin-4-yloxy)
Acethydrazide in Heterocyclic
Synthesis
M. E. Azab a , H. M. F. Madkour a & M. A. E.
Ibraheem a
a Synthetic Organic Chemistry Laboratory, Chemistry
Department , Ain Shams University , Abbassiya,
Cairo, Egypt
Published online: 01 Feb 2007.
To cite this article: M. E. Azab , H. M. F. Madkour & M. A. E. Ibraheem (2006)
The Utility of 2-(5,6,7,8-Tetrahydrobenzo[b]thieno-[2,3-d]pyrimidin-4-yloxy)
Acethydrazide in Heterocyclic Synthesis, Phosphorus, Sulfur, and Silicon and the
Related Elements, 181:6, 1299-1313, DOI: 10.1080/10426500500326834
To link to this article: http://dx.doi.org/10.1080/10426500500326834
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Phosphorus, Sulfur, and Silicon, 181:1299–1313, 2006
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500500326834
The Utility of 2-(5,6,7,8-Tetrahydrobenzo[b]thieno-
[2,3-d]pyrimidin-4-yloxy) Acethydrazide
in Heterocyclic Synthesis
M. E. Azab
M. A. E. Ibraheem
H. M. F. Madkour
Synthetic Organic Chemistry Laboratory, Chemistry Department,
Ain Shams University, Abbassiya, Cairo, Egypt
Because of being a versatile synthon, the title compound 2 was utilized to con-
struct different heterocyclic systems including pyrazol-4-carbonitrile 3, pyrazolone
4, triazole-5(4H)-thione 7, aminotriazole 9, oxadiazoles 10 and 12, thiazolidine 13,
and oxatriazole 14. All new synthesized compounds were structurally confirmed by
elemental analyses and spectroscopic data.
Keywords Acethydrazide; oxadiazole; oxatriazole; pyrazolone; thiazole; triazole
INTRODUCTION
Thieno[2,3-d]pyrimidines are well known in the literature for their
biological activity and diversity of applications. For example, these
compounds are used in medicine as antibiotics,1 and antiulcer,2 anti-
allergic,3 antihypertensive,4 bactericidal,5 blood, and platelet aggrega-
tion inhibitory agents.6 In other fields, they are used as herbicides7 and
insecticides.8
For the growing worldwide interest in the synthesis of new
thieno[2,3-d]-pyrimidine derivatives and in continuation of our re-
search program aiming to the synthesis of new heterocyclic com-
pounds of potentail biological activities,9−17 we report herein the syn-
thesis of some new thieno[2,3-d]pyrimidines attached to five-membered
heterocyclic systems using 2-(5,6,7,8-tetrahydrobenzo[b]thieno[2,3-d]-
pyrimidin-4-yloxy)acethydrazide (2) as a versatile starting material.
Received March 29, 2005; accepted June 21, 2005.
Address correspondence to H. M. F. Madkour, Ain Shams University, Chemistry De-
partment, Faculty of Science, Cairo, Egypt. E-mail: nfmakour@yahoo.com
1299

1300
M. E. Azab et al.
RESULTS AND DISCUSSION
Compound 2 was prepared by condensation of the corresponding ethyl
ester 1 with hydrazine hydrate in refluxing ethanol (Scheme 1). Com-
pound 2 gave compatible elemental analysis and IR and 1H-NMR spec-
troscopic data.
SCHEME 1 (a) N2H4·H2O, (b) EtO-CH C(CN)2, (c) RCOCl, (d) Ac2CH2/AcOH,
(e) Ac2O/ꢀ, and (f) Ac2 CH2/EtOH.
The hydrazide group in the versatile synthon 2 could be utilized
to build up several five-membered rings attached to position-4 of the
benzothienopyrimidine moiety. Thus, the pyrazole ring was obtained by
reacting compound 2 with ethoxymethylenemalononitrile in refluxing
ethanol18 to afford the pyrazole derivative 3 (Scheme 1).
Another reaction that led to the formation of a pyrazole ring was
carried out by heating compound 2 with acetyl and/or benzoyl chloride

2-(5,6,7,8-Tetrahydrobenzo[b]thieno[2,3-d]pyrimidin-4-yloxy) Acethydrazide 1301
in refluxing pyridine to produce the pyrazolone derivatives 4a and 4b,
respectively.
The pyrazole 6 was also obtained when compound 2 was allowed to
react with 2,4-pentanedione in refluxing dry ethanol.19 On the other
hand, compound 6 could be prepared in a two-step process. Thus, hy-
drazide 2 reacted with 2,4-pentanedione in refluxing acetic acid19 to
yield the acyclic monohydrazone 5, which was then cyclized to 6 by heat-
ing under reflux with freshly distilled acetic anhydride (Scheme 1). The
IR spectrum of 5 showed, besides the expected absorption bands due to
NH, aliphatic and aromatic stretching CH groups, two strong absorp-
tion bands at 1724 and 1665 cm−1 corresponding to ketonic C O and
acyclic amide C O, respectively. That of 6, on the other hand, showed
only one absorption band in the carbonyl region at 1675 cm−1 attributed
to the amidic C O, among other expected absorption bands suitable for
the assigned cyclized structure. The 1H-NMR spectra of 5 and 6 agreed
with the structures.
The hydrazide 2 could also be used as a precursor for the synthesis
of 1,2,4-triazoles. Thus, when compound 2 was allowed to react with
phenyl isothiocyanate20,21 in refluxing dry pyridine, the triazole-5(4H)-
thione derivative 7 was isolated (Scheme 2).
When the hydrazide 2 reacted with carbon disulfide at r.t. in the
presence of potassium hydroxide22,23 followed by stirring the produced
potassium salt 8 with hydrazine hydrate in situ at r.t., the product was
identified as the triazol 9 (Scheme 2).
Another new heterocyclic system was obtained when reaction con-
ditions of the reaction of carbon disulfide with the hydrazide 2 were
altered. Thus, when hydrazide 2 was heated under reflux with carbon
disulfide in alcoholic potassium hydroxide solution, 1,3,4-oxadiazole
derivative 10 was obtained (Scheme 2).
The condensation of 2 with selected aromatic aldehydes, namely
benzaldehyde, 4-chloro-benzaldehyde and/or salicylaldehyde in
ethanol,21,24 in the presence of a catalytic amount of piperidine
furnished the benzylidene hydrazide derivatives 11a–c, respectively
1
(Scheme 3). The H-NMR spectrum of 11c revealed its presence in an
(E)- and (Z)-isomer mixture (Scheme 4).
In the 1H-NMR spectrum of 11c (DMSO-d6), the protons of N CH,
CONH , O CH2 CO , and phenolic OH appear twice due to the
presence of both isomers. In the E-isomer, these protons are generally
more deshielded due to H-bonding and a lack of steric hindrance that
leads to planarity and consequently to a stronger mesomeric effect.
Stirring the hydrazones 11a and/or 11b with bromine24 in acetic
acid containing anhydrous sodium acetate at r.t. afforded the oxadi-
azole derivatives 12a,b. An alternative route to obtain oxadiazoles

1302
M. E. Azab et al.
SCHEME 2 (a) PhNCS, (b) CS2/KOH/rt, (c) N2H4/rt, and (d) CS2/alc·KOH/ꢀ.
12a,b consists in heating the hydrazide 2 with benzoic acid and/or 4-
chlorobenzoic acid in phosphorus oxychloride25 (Scheme 3).
On the other hand, when the hydrazone 11a was heated under reflux
with thioglycollic acid in dry benzene, the addition of the nucleophilic
sulphur atom to the C N bond took place, followed by cyclization to
furnish the thiazole derivative 13 (Scheme 3).
The oxatriazole derivative 14 was obtained with good yield via the
treatment of the hydrazide 2 with nitrous acid26 (Scheme 3). The IR
spectrum of oxatriazole 14 showed that the compound is most probably
present as two isomers in dynamic equilibrium as in Scheme 5.
The presence of the enimine form was confirmed by the appearance
of absorption bands at 3373 and 1669 cm−1 corresponding to NH and
C N groups, respectively.

2-(5,6,7,8-Tetrahydrobenzo[b]thieno[2,3-d]pyrimidin-4-yloxy) Acethydrazide 1303
SCHEME 3 (a) ArCH, (b) ArCOOH/POCl3, (c) NaNO2/AcOH, (d) HS-CH2-
COOH, and (e) Br2/AcOH.
Moreover, attempts were made to cyclize the hydrazide moiety
of 2 using ethyl orthoformate or formic acid to obtain 1,3,4-oxadi-
azoles26 and ethyl acetoacetate to obtain a pyrazolone.27 However,
these attempts failed to produce the desired ring systems. In-
stead, the products were the Nꢀ-ethoxymethylene derivative 15, the
benzothienopyrimidinyl-oxyacetic acid derivative 16, and the hydra-
zonobutanoate derivative 17, respectively. Alkaline hydrolysis of the
butanoate ester 17 afforded the acetic acid derivative 16 (Scheme 6).
EXPERIMENTAL
All melting points reported are uncorrected. The IR spectra were mea-
sured on a Unicam (200 Spectrometer) or Mattson infinity series FT-IR

1304
M. E. Azab et al.
SCHEME 4
SCHEME 5
SCHEME 6 (a) HC(OEt)3, (b) HCOOH, (c) MeCOCH2CO2Et, and (d) aq.
NaOH/ꢀ.

2-(5,6,7,8-Tetrahydrobenzo[b]thieno[2,3-d]pyrimidin-4-yloxy) Acethydrazide 1305
using KBr wafer technique. The 1H-NMR spectra were recorded in
CDCl3 or DMSO-d6 solutions on a Varian Gemini 200 MHz instrument
using TMS as an internal standard. Mass spectra were recorded on
Shimadzu GC-MS-QP 1000 EX instrument operating at 70 eV. TLC
was preformed on ready-to-use silica gel plates Merck 60 to moniterate
reactions and test the purity of the new synthesized compounds.
Ethyl (5,6,7,8-Tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-
Yloxy)acetate (1)
An equimolar mixture of 4,5,6,7-tetrahydrobenzo[b]thieno[2,3-d]pyri-
midin-4(3H)-one28,29 (30 mmol; 6.18 g), ethyl chloroacetate (30 mmol;
3 mL) and excess K2CO3 (8 g) in 100 mL of dry acetone was refluxed
on a water bath for 24 h. Most of the solvent was evaporated, and the
reaction mixture was then poured onto ice water to give a solid product.
Crystallization of the crude product from light petroleum (60–80◦C)
yielded the title product 1 as white crystals; m.p: 102–105◦C; yield:
64%. IR: ν 3046 (CHar), 2933 (CHal), 1739 (C O), 1677 cm−1 (C N); 1H-
NMR (CDCl3) : δ 1.30 (t, 3H, OCH2CH3, J = 4.4 Hz), 1.85 (m, 4H, C-6H
and C-7H), 2.79 (br.s, 2H, C-5H), 2.98 (br.s, 2H, C-8H), 4.26 (q, 2H,
OCH2CH3, J = 4.8 Hz), 4.67 (s, 2H, O-CH2-CO), 7.85 (s, 1H, C-2H);
anal. calcd. for C14H16N2O3S (292): C, 57.53; H, 5.52; N, 9.48; found: C,
57.44; H, 5.41; N, 9.39.
2-(5,6,7,8-Tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-Yloxy)-
acetohydrazide (2)
A mixture of 1 (10 mmol; 2.92 g) and hydrazine hydrate (10 mmol;
0.5 ml) in ethanol (60 mL) was heated under reflux for 2 h, left to cool,
filtered off, dried, and then recrystallized from ethanol to afford 2 as
white crystals; m.p: 253–255◦C; yield: 61.14%. IR: ν 3321 and 3277
(NH2 and NH), 3036 (CHar), 2930 (CHal), 1663 (C O acyclic amide)
1622 cm−1 (C N); 1H-NMR (DMSO-d6) : δ 1.78 (m, 4H, C-6H and
C-7H), 2.74 (dxd, 2H, C-5H), 2.85 (dxd, 2H, C-8H), 4.30 (s, 2H, NH2),
4.56 (s, 2H, OCH2CO), 8.24 (s, 1H, C-2H), 9.40 (s, 1H, CONH); anal.
calcd. for C12H14N4O2S (278): C, 51.80; H, 5.04; N, 20.14; found: C,
51.61; H, 4.97; N, 19.97.
5-Amino-1-[(5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-
4-Yloxy)acetyl]-1-H-pyrazole-4-carbonitrile (3)
To a solution of hydrazide 2 (10 mmol; 2.78 g) in 50 mL of ethanol,
ethoxy-methylene malononitrile (10 mmol; 1.22 g) was added, and

1306
M. E. Azab et al.
the reaction mixture was heated under reflux for 10 h and left to
cool. The solid product that deposited was collected by filtration,
washed, dried, and recrystallized from benzene to give 3 as yel-
low crystals; m.p: over 300◦C; yield: 55.33%. IR: ν 3323 and 3277
(NH2), 3055 (CHar), 2934 (CHal), 2217 (C N), 1666 (C O), 1625 cm−1
(C N); 1H-NMR (DMSO-d6) : δ 1.77 (m, 4H, C-6 and C-7H), 2.75
(br.s, 2H, C-5H), 2.85 (br.s, 2H, C-8H of tetrahydrobenzothienopy-
rimidine), 4.30 (br.s, 2H, NH2), 4.56 (s, 2H, O-CH2CO), 8.24 (s, 1H,
pyrimidine moiety), 9.38 (s, 1H, pyrazole moiety); anal. calcd. for
C16H14N6O2S (354): C, 54.23; H, 3.89; N, 23.71; found: C, 53.89; H, 3.64;
N, 23.54.
4-[3-Methyl-1H-5(4H)-pyrazolon-4-Yl]-oxy-5,6,7,8-
tetrahydro[b]benzothieno[2,3-d]-pyrimidine (4a)
To a solution of acetohydrazide 2 (10 mmol; 2.78 g) in 5 mL of
pyridine, acetyl chloride (5 mL) was added, and the reaction mix-
ture was stirred for 1 h and acidified with cold diluted HCl. The
precipitated solid product was filtered off, dried, and then recrys-
tallized from light petroleum (40–60◦C) to give 4a as white solid;
m.p: 162–164◦C; yield: 58.2%. IR: ν 3480 (OH), 3250 (NH), 3050
(CHar), 2940 (CHal), 1732 (C O), 1673 cm−1 (C N); anal. calcd. for
C14H14N4O2S (302): C, 55.63; H, 4.67; N, 18.53; found: C, 55.42; H, 4.35;
N, 18.34.
4-[3-Phenyl-1H-5(4H)pyrazolon-4-Yl]oxy-5,6,7,8-
tetrahydro[1]benzothieno[2,3-d]-pyrimidine (4b)
To a solution of acetohydrazide 2 (5 mmol; 1.39 g) in 5 mL of pyri-
dine benzoyl chloride (5 mL) was added, and the reaction mixture
heated under reflux on a water bath for 10 h, left to cool, and acidi-
fied with cold diluted HCl. The solid product that separated out was
filtered off. Crystallization of the crude product from benzene yielded
compound 4b as white crystals; m.p: 148–151◦C; yield: 60.7%. IR:
ν 3455 (OH), and 3200 (NH), and 3018 (CHar), and 2939 (CHal), 1736
(C O),1672 cm−1 (C N); 1H-NMR (DMSO-d6) : δ 1.80 (br.s, 4H, C-
6 and C-7H), 2.77 (br.s, 2H, C-5H), 2.88 (br.s, 2H, C-8H), 4.77 (s,
1H, CH of pyrazole moiety), 5.18 (s, 1H, OH of lactim form), 8.46–
6.88 (m, 6H, 5ArH and C-2H), 11.75 (br.s, 1H, NH); anal. calcd. for
C19H16N4O2S (364): C, 62.63; H, 4.40; N, 15.38; found: C, 62.43; H, 4.15;
N, 15.14.

2-(5,6,7,8-Tetrahydrobenzo[b]thieno[2,3-d]pyrimidin-4-yloxy) Acethydrazide 1307
2-{[(5,6,7,8-Tetrahydro[b]benzo-thieno[2,3-d]pyrimidin-4-
yloxy)acetyl]hydrazono}pentan-2,4-dione (5) and
4-[2-(3,5-dimethyl-1H-pyrazol-1-Yl)-2-oxoeth
Oxy]-5,6,7,8-tetrahydro-[1]benzothieno-[2,3-d]-pyrimidine (6)
(1) In Acetic Acid
An equimolar mixture of hydrazide 2 (10 mmol; 2.78 g) and acety-
lacetone (10 mmol; 1 mL) in 30 mL of glacial acetic acid was refluxed
for 6 h. Most of the solvent was evaporated, and the reaction mixture
was left to cool; the solid product that separated out was filtered off.
Crystallization of the crude product from ethanol yielded 5 as pale
yellow crystals; m.p: 278–280◦C; yield: 48.5%. IR: ν 3393 (OH), 3228
(NH), 3049 (CHar), 2937 (CHal), 1724 (C O ketone) 1665 cm−1(C O
1
acyclic amide); H-NMR (DMSO-d6) : δ 1.77 (br.s, 4H, C-6 and C-7H of
tetrahydrothienopyrimidine residue), 1.81 (s, 3H, N C-CH3), 1.85 (s,
2H, N C CH2 ), 2.75 (br.s, 2H, C-5H), 2.84 (br s, 2H, C-8H), 4.69 (s,
2H, OCH2 CO), 8.28 (s, 1H, C-2H) and 9.97 and 10.28 (two s, 1H,
ꢁ
lactam-lactim dynamic mixture, NH-C O
N C-OH); anal. calcd. for
ꢂ
C17H20N4O3S (360): C, 56.67; H,5.56; N, 15.56; found: C, 56.86; H, 5.69;
N, 15.74.
(2) In Ethanol
Acetylacetone (10 mmol; 1 mL) was added to the hydrazide 2 (10
mmol; 2.78 g) in 50 mL of absolute ethanol and refluxed for 10 h. Most
of the solvent was evaporated, and the reaction mixture was left to
cool; the solid product that deposited was filtered off. Crystallization
from ethanol gave 6 as white crystals; m.p: 222–225◦C; yield: 50.58%.
IR: ν 3226 (enolic OH), 3083 and 3019 (CHar), 2942 (CHal), 1675 (C O)
1
and 1660 cm−1(C N); H-NMR (DMSO-d6) : δ 1.76 (br.s, 7H, C-6 and
C-7H of thienopyrimidine nucleus and CH3 at C-5 of pyrazole nucleus),
2.03 (s, 3H, CH3 at C-3 of pyrazole), 2.76 (br.s, 2H, C-5H of thienopy-
rimidine), 2.87 (br.s, 2H, C-8H of thieno-pyrimidine), 3.31 (s, 1H, enolic
OH), 4.99 (s, 2H, OCH2CO), 6.45 (s, 1H, CH C-OH), 6.53 (s, 1H, C-
4 of pyrazole) and 8.24 (s, 1H, C-2H thienopyrimidine); anal. calcd. for
C17H18N4O2S (342): C, 59.65; H, 5.26; N, 16.37; found: C, 59.56; H, 5.17;
N, 16.25.
Converting Compound 5 Into 6
Compound 5 (5 mmol; 1.8 g) was refluxed in acetic anhydride for 6 h.
The reaction mixture was poured into ice water with vigorus stirring;
the solid product that deposited was filtered off and recrystalled from
ethanol to give 6.

1308
M. E. Azab et al.
3-[(5,6,7,8-Tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-
Yloxy)methyl]-4-Phenyl-1,2,4-Triazole-5(4H)-thione (7)
A mixture of hydrazide 2 (10 mmol; 2.78 g) and phenylisothiocyanate
(10 mmol; 0.5 mL) in pyridine (20 mL) was heated under reflux for
12 h. Most of the solvent was evaporated, left to cool, and acidified
with cold diluted HCl. The solid product that separated out was fil-
tered off, dried, and then recrystallised from benzene to give 7 as white
solid; m.p: 188–190◦C; yield: 36.8%. IR: ν 3232 (NH), 3053 (CHar), 2933
1
(CHal), 1663 cm−1 (C N); H-NMR (CDCl3) : δ 1.84 (br.s, 4H, C-6 and
C-7H of tetrahydrobenzothienopyrimidine nucleus), 2.73 (br.s, 2H, C-
5H), 2.95 (br.s, 2H, C-8H), 4.65 and 7.86 (two s exchangeable, NH-C S
ꢁ
ꢂ
N C-SH), 4.97 (s, 2H, OCH -), 7.26–7.52 (m, 5H, ArH) and 8.10 (s,
2
1H, C-2H of tetrahydrobenzothieno-pyrimidine nucleus); anal. calcd.
for C19H17N5OS2 (395): C, 57.72; H, 4.30; N, 17.72; found: C, 57.59; H,
4.21; N, 17.68.
4-[(4-Amino-5-thioxo-1,2,4-triazol-3-yl)methoxy]-5,6,7,8-
tetrahydro[1]benzothieno[2,3-d]-pyrimidine (9)
A mixture of hydrazide 2 (10 mmol; 2.78 g), CS2 (3 mL), and ethanolic
KOH solution (10%; 40 mL) was stirred at r.t. for 3 h. The solid product
8 that separated out was filtered off and disolved in water (20 mL);
hydrazine hydrate (100%; 3 mL) was added, and the reaction mixture
was stirred at r.t. for 24 h and acidified with cold diluted HCl. The
solid product that precipitated down was filtered off by suction, washed
with cold water, dried, and then recrystallized from ethanol to afford
9 as white crystals; m.p: 280–282◦C; yield: 82.3%. IR: ν 3324 and 3277
1
(NH2), 3030 (CHar), 2933 (CHal), 1664 cm−1 (C N); H-NMR (DMSO-
d6) : δ 1.79 (br s, 4H, C-6 and C-7H), 2.25 (s, 2H, NH2), 2.77 (br.s, 2H,
C-5H), 2.86 (br.s, 2H, C-8H), 5.21 (s, 2H, O-CH2-C ), 7.18 (s, 1H, NH),
8.27 (s, 1H, C-2H), anal. calcd. for C13H14N6OS2 (334): C, 46.71; H, 4.19;
N, 25.15; found: C, 46.59; H, 4.01; N, 24.97.
4[(5-Mercapto-1,3,4-oxadiazol-2-yl)methoxy]-5,6,7,8-
tetrahydro[1]benzothieno[2,3-D]pyrimidine (10)
An equimolar mixture of hydrazide 2 (10 mmol; 2.78 g) and CS2
(10 mmol; 0.9 mL) in 50 mL of ethanol was refluxed for 8 h. Most
of the solvent was evaporated, and the reaction mixture was left to
cool to give a solid product. Crystallization of the crude product from
ethanol yielded the title product 10 as pale yellow crystals; m.p: 236–
238◦C; yield: 31.25%. IR: ν 3088 (CHar), 2935 (CHal), 1657 cm−1 (C N);

2-(5,6,7,8-Tetrahydrobenzo[b]thieno[2,3-d]pyrimidin-4-yloxy) Acethydrazide 1309
1H-NMR (DMSO-d6) : δ 1.79 (br s, 4H, C-6 and C-7H), 2.51 (br.s, 2H,
C-5H), 2.80 (br.s, 2H, C-8H), 4.72 (s, 1H, SH), 5.32 (s, 2H, O-CH2-C ),
8.27 (s, 1H, C-2H); anal. calcd. for C13H12N4O2S2 (320): C, 48.75; H,
3.75; N, 17.50; found: C, 48.56; H, 3.57; N, 17.36.
Nꢀ[(4-Substitutedphenyl)methylene]-2-[5,6,7,8-
tetrahydro[1]benzothieno[2,3-D]-pyrimidin-4-yl-oxy]-
acetohydrazide (11a–c)
The hydrazide 2 (10 mmol; 2.78 g) and aromatic aldehydes, namely
benzaldehyde, p-chlorobenzaldehyde, and salicylaldehyde (10 mmol), in
ethanol (30 mL) were heated under reflux for 3–7 h. A solid product was
precipitated during reflux, which was filtered off, washed well, dried and
then recrystallized from a suitable solvent to afford 11a–c, respectively.
11a, white crystals; m.p: 256–258◦C; solvent of crystallisation
ethanol, yield: 51.3%; anal. calcd. for C19H18N4O2S (366): C, 62.29; H,
4.92; N, 15.30; found: C, 62.41; H, 5.09; N, 15.46.
11b, white crystals; m.p: 261–263◦C; solvent of crystallisation n-
butanol, yield: 45.4%; anal. calcd. for C19H17ClN4O2S (400.5): C, 56.93;
H, 4.24; Cl, 8.86; N, 13.98; found: C, 56.73; H, 4.06; Cl, 8.67; N,
13.80.
11c, pale yellow crystals; m.p. 272–2744◦C; solvent of crystallisation
dioxane; yield: 54.2%; anal. calcd. for C19H18N4O3S (382): C, 59.69; H,
4.71%; N, 14.66; found: C, 59.55; H, 4.53; N, 14.49.
IR of 11a–c: ν 3444 and 3432 (OH), 3231 and 3185 (NH), 3088 and
3062 (CHar), 2986 and 2937 (CHal), 1674 and 1668 (CO), and 1618 and
1616 cm−1 (C N). 1H-NMR of 11c (DMSO-d6): the protons of N CH,
CONH, O CH2CO, and phenolic OH groupings in the two isomers
appear twice. In the E-isomer, protons are more deshielded due to H-
bonding: δ 1.79 (m, 4H, C-6 and C-7H), 2.77 (s, 2H, C-5H), 2.87 (s, 2H,
C-8H), 5.18 and 4.78 (s, 2H, O-CH2CO), 7.77–6.88 (m, 4H, Ar-H), 8.33 (s,
1H, C-2H of tetrahydrobenzothienopyrimidine moiety), 8.46 and 8.39
(s, 1H, N CH), 10.96 and 10.10 (s, 1H, NH), 12.12 and 11.74 (s, 1H,
OH).
4-{[5-Phenyl-1,3,4-oxadiazol-2-yl]methoxy}-5,6,7,8-
tetrahydro[1]benzothieno[2,3-d-]pyrimidine (12a) and
4-{[2-(4-Chlorophenyl)-1,3,4-oxadiazol-5-yl]methoxy}-5,6,7,8-
tetrahydro[1]benzothieno[2,3-D]pyrimidine (12b)
A mixture of acetohydrazide 2 (10 mmol; 2.78 g) and benzoic acid acid
and/or 4-chlorobenzoic (10 mmol) in POCl3 (40 mL) was heated on a

1310
M. E. Azab et al.
water bath under reflux for 5–8 h and left to cool; the reaction mixture
was then treated with ice water to afford an oily substance, which, on
trituration with ethanol, gave solid products.
12a, white crystals; m.p: 188–190◦C; solvent of crystallisation
ethanol; yield: 33.3%; anal. calcd. for C19H16N4O2S (364): C, 62.64; H,
4.40; N, 15.38; found: C, 62.45; H, 4.23; N, 15.22.
12b, white crystals; m.p.: 228–230◦C; solvent of crystallisation ben-
zene; yield: 58.6%; anal. calcd. for C19H15ClN4O2S (398.5): C, 57.21;
H, 3.76; Cl, 8.91; N, 14.05; found: C, 56.99; H, 3.64; Cl, 8.72; N,
13.86.
IR spectra of 12a,b: ν 3068 (CHar), 2933 (CHal), 1675 cm−1 (C N);
1H-NMR (DMSO-d6) of 12a: δ 1.77 (m, 4H, C-6 and C-7 H), 2.76 (br.s,
2H, C-5H), 2.84 (br.s, 2H, C-8H), 5.54 (s, 2H, OCH2-C N), 7.99–7.60
(m, 5H, Ar-H), 8.53 (s, 1H, C-2H).
Reaction of Schiff’s Bases 11a,b with Bromine; Formation
of 12a & b
A solution of 0.25 mL of bromine in 1.5 mL of acetic acid was added
dropwise to a solution of Schiff’s bases 11a and/or 11b (5 mmol) in 10 mL
of acetic acid and excess anhydrous sodium acetate (4 g). The reaction
mixture was stirred for 1 h, then poured onto ice water and neutralized
by Na2CO3 solution. The solid product was filtered off, washed, dried,
and then recrystallized from a suitable solvent yielding 12a and b,
respectively.
4-[2-(4-Chlorophenyl)-4-oxo-3H-1,3-thiazol-3-yl)-
oxyacetamido]-5,6,7,8-tetrahydro[1]-benzothieno-
[2,3-d]pyrimidine (13)
An equimolar mixture of Schiff’s base 11b (10 mmol; 3.66 g) and thio-
glycollic acid (10 mmol; 1 mL) in 60 mL of dry benzene was refluxed
for 8 h. Most of the solvent was evaporated, and the reaction mixture
was left to cool; the solid product that separated out was filtered off and
washed with light petroleum (60–80◦C). Crystallization of the crude
product from benzene afforded 13 as white crystals; m.p: 210–212◦C;
yield: 48.94%. IR: ν 3424 (OH), 3199 (NH), 1720 (C O of cyclic five mem-
bered amide), 1685 (C O of acyclic amide), 1650 cm−1 (C N). MS: m/e:
474 (M+., 3.4), 249 (6.1), 248 (16.5), 247 (100), 219 (77.4), 189 (38.5), 163
(8.7), 162 (7.6), 160 (4.0), 142 (3.2), 126 (1.5), 122 (16.13) and 77 (16.2);
anal. calcd. for C21H19ClN4O3S2 (474.5): C, 53.11; H, 4.00; Cl, 7.48; N,
11.80; found: C, 52.98; H, 3.89; Cl, 7.26; N, 11.63.

2-(5,6,7,8-Tetrahydrobenzo[b]thieno[2,3-d]pyrimidin-4-yloxy) Acethydrazide 1311
4-[(1,2,3,4-Oxatriazol-5-yl)methoxy]-5,6,7,8-
tetrahydro[1]benzothieno[2,3-d]pyrimidine (14)
To an ice-cold solution of acetohydrazide 2 (10 mmol; 2.78 g) in 10 mL
of acetic acid (50% w/v) and NaNO2 (0.76 g in 10 mL of H2O) was
added dropwise, the reaction mixture was stirred for 1 h and allowed to
stand for 2 h at r.t. The deposited solid product was filtered off by suc-
tion, dried, and then recrystallized from benzene to give 14 as a white
solid; m.p: 239–240◦C; yield: 37.37%. IR: ν 3373 (NH), 3056 (CHar), 2932
1
(CHal), 1669 (C N) and 1648 (N N); H-NMR (DMSO-d6) : δ 1.78 (m,
4H, C-6 and C-7 H), 2.79 (br.s, 2H, C-5H), 2.82 (br.s, 2H, C-8H), 5.52 (s,
2H, OCH2-C N), 6.62 (s, 1H, olefinic HC C, enimine), 7.78 (s, 1H, NH
enimine), 8.53 (s, 1H, C-2H). MS: m/e : 290 (M+., 3.5), 220 (1.69), 219
(5.90), 206 (100), 205 (24.55), 189 (5.83), 179 (11.05), 177 (17.35) and 70
(2.01). Anal. calcd. for C12H11N5O2S (289): C, 49.82; H, 3.83; N, 24.21;
found: C, 49.58; H, 3.57; N, 23.99.
N-Ethoxymethylene-2-(5,6,7,8-tetrahydro[1]benzothieno-
[2,3-d]pyrimidin-4-yloxy)aceto-hydrazide (15)
The solution of acetohydrazide 2 (5 mmol; 1.39 g) in 10 mL of triethyl
orthoformate was heated under reflux on a water bath for 7 h, left to
cool, and then poured onto ice water. The solid product that separated
out was filtered off and crystallized from a benzene/ethanol mixture af-
forded the product 15 as white crystals; m.p: 141–143◦C; yield: 22.7%.
IR: ν 3503 (OH), 3224 (NH), 3049 (CHar), 2979 (CHal), 1677 (CO acyclic
1
amide), 1657 cm−1 (C N); H-NMR (CDCl3): δ 1.32 (t, 3H, CH2CH3),
1.85 (br.s, 4H, C-6H and C-7H of tetrahydrobenzothienopyrimidine moi-
ety), 2.78 (br.s, 2H, C-5H), 2.99 (br.s, 2H, C-8H), 4.15 (q, 2H, CH2CH3),
ꢁ
ꢂ
6.51 and 8.91 (two s, 1H, N-NH-C O
N-N C-OH) and 8.06 (s, 1H,
C-2H); anal. calcd. for C15H18N4O3S (334): C, 53.89; H, 5.39; N, 16.77;
found: C, 53.69; H, 5.26; N, 16.59.
(5,6,7,8-Tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-yloxy)-
acetic Acid (16)
The solution of acetohydrazide 2 (5 mmol; 1.39 g) in 15 mL of formic acid
was heated under reflux for 6 h, left to cool and poured onto ice water; the
solid product that separated out was filtered off. Crystallization from
benzene yielded the title product 16 as white crystals; m.p: 240–242◦C;
yield: 69.3%. IR: ν 3446 (OH), 3053 (CHar), 2856 (CHal), 1729 (CO acid),
1670 (C N) with the disappearance of νNH; 1H-NMR (DMSO-d6) : δ 1.70
(br.s, 4H, C-6 and C-7H), 2.76 (br.s, 2H, C-5H), 2.87 (br.s, 2H, C-8H),

1312
M. E. Azab et al.
4.71 (s, 2H, OCH2CO), 8.32 (s, 1H, C-2H), 13.08 (br.s, 1H, COOH); anal.
calcd. for C12H12N2O3S (264): C, 54.55; H, 4.55; N, 10.60; found: C,
54.35; H, 4.47; N, 10.44.
Ethyl 3-{[(5,6,7,8-Tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-
yloxy)acetyl]hydrazono}-butanoate (17)
A mixture of hydrazide 2 (10 mmol; 2.78 g) and ethyl acetoacetate (10
mmol; 1.3 mL) in NaOEt (0.23 g of Na metal in 30 mL of absolute
ethanol) was heated under reflux for 8 h. Most of the solvent was evap-
orated, left to cool, and acidified with cold diluted HCl. The solid product
was filtered off, dried, and then recrystallized from benzene to give 17
as white solid; m.p: 288–290◦C; yield: 44.61%. IR: ν 3219 (NH), 3050
(CHar), 2935 (CHal), 1735 (C O ester), 1682 cm−1 (C O acyclic amide);
1H-NMR (DMSO-d6): δ 1.21 (t, 3H, OCH2CH3), 1.77 (br.s, 4H, C-6 and
C-7H), 1.97 (s, 3H, N C-CH3), 2.76 (br.s, 2H, C-5H), 2.85 (br.s, 2H, C-
8H), 3.37 (s, 2H, N C-CH2-CO), 4.10 (q, 2H, O-CH2-CH3), 5.00 (s, 2H,
O-CH2CO), 8.27 (s, 1H, C-2H) and 10.82 and 7.38 (2s, 1H, of lactam-
ꢁ
lactim mixture, NH-C O
N C-OH); anal. calcd. for C H N O S
18 22 4 4
ꢂ
(390): C, 55.38; H, 5.64; N, 14.36; found: C, 55.19; H, 5.48; N, 14.23.
(5,6,7,8-Tetrahydro[1]benzothieno[2,3-d]pyrimidin-4-yloxy)-
acetic Acid (16)
The solution of derivative 17 (10 mmol; 3.9 g) in 50 mL of NaOH (20%)
was heated under reflux for 4 h. Most of the solvent was evaporated and
left to cool. Acidification with cold diluted HCl produced a solid product,
which was filtered off, dried, and then recrystallized from benzene to
give 16 in a 71.8% yield.
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