Studies on synthesis and reactions of some new five and six-membered heterocycles bearing 5,6,7,8-tetrahydrobenzo[b]thieno[2,3-d]pyrimidin-4(3H)-ones skeleton

Article abstract of DOI:10.1080/00397911.2021.1936058

Thienopyrimidine derivatives are well-known in various pharmaceutical and biomedical domains. In this work, a series of efficacious and novel strategies for the synthesis of thienopyrimidines starting from 2-amino-3-carboethoxy-4,5,6,7-tetrahydrobenzo[b]thiophene has been developed. The regioselectivity of these synthetic strategies was investigated using density functional theory computation and spectroscopic analysis. In addition, the chemical structures of the new thienopyrimidines and their reaction mechanisms, as well as the biological activity of selected compounds were studied.

Full text of DOI:10.1080/00397911.2021.1936058

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: (Print) (Online) Journal homepage: https://www.tandfonline.com/loi/lsyc20
Studies on synthesis and reactions of some
new five and six-membered heterocycles
bearing 5,6,7,8-tetrahydrobenzo[b]thieno[2,3-
d]pyrimidin-4(3H)-ones skeleton
Ahmed F. M. EL-Mahdy, Zeinab A. Hozien, Shimaa Abdelnaser, Ahmed A. K.
Mohammed, Suliman M. El‐Sawaisi & Hassan A. H. El-Sherief
To cite this article: Ahmed F. M. EL-Mahdy, Zeinab A. Hozien, Shimaa Abdelnaser, Ahmed
A. K. Mohammed, Suliman M. El‐Sawaisi & Hassan A. H. El-Sherief (2021): Studies on
synthesis and reactions of some new five and six-membered heterocycles bearing 5,6,7,8-
tetrahydrobenzo[b]thieno[2,3-d]pyrimidin-4(3H)-ones skeleton, Synthetic Communications, DOI:
10.1080/00397911.2021.1936058
To link to this article: https://doi.org/10.1080/00397911.2021.1936058
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https://doi.org/10.1080/00397911.2021.1936058
Studies on synthesis and reactions of some new five and
six-membered heterocycles bearing 5,6,7,8-
tetrahydrobenzo[b]thieno[2,3-d]pyrimidin-4(3H)-
ones skeleton
Ahmed F. M. EL-Mahdya,b , Zeinab A. Hoziena, Shimaa Abdelnasera, Ahmed A. K.
Mohammeda, Suliman M. El-Sawaisic, and Hassan A. H. El-Sheriefa
b
aChemistry Department, Faculty of Science, Assiut University, Assiut, Egypt; Department of Materials
c
and Optoelectronic Science, National Sun Yat-Sen University, Kaohsiung, Taiwan; Chemistry
Department, Faculty of Science, 7th October University, Misurata, Libya
ABSTRACT
ARTICLE HISTORY
Received 10 April 2021
Thienopyrimidine derivatives are well-known in various pharmaceut-
ical and biomedical domains. In this work, a series of efficacious and
novel strategies for the synthesis of thienopyrimidines starting from
KEYWORDS
2-amino-3-carboethoxy-4,5,6,7-tetrahydrobenzo[b]thiophene
has
Biological activity; DFT
computation; Mannich
reaction; regioselectivity;
thienopyrimidines
been developed. The regioselectivity of these synthetic strategies
was investigated using density functional theory computation and
spectroscopic analysis. In addition, the chemical structures of the
new thienopyrimidines and their reaction mechanisms, as well as the
biological activity of selected compounds were studied.
GRAPHIC ABSTRACT
CONTACT Ahmed F. M. EL-Mahdy
H. El-Sherief helsherief@aun.edu.eg
ahmedelmahdy@mail.nsysu.edu.tw, ahmed.ahmed20@science.au.edu.eg; Hassan A.
Chemistry Department, Faculty of Science, Assiut University, Assiut, Egypt.
Supplemental data for this article can be accessed on the publisher’s website.
ß 2021 Taylor & Francis Group, LLC

2
A. F. M. EL-MAHDY ET AL.
Introduction
Pyrimidine and its derivatives have been received an attracting interest in medicinal
research due to their biological processes and therapeutic uses.[1] Pyrimidine ring com-
pounds showed numerous biological functions such as anti-inflammatory, antimicrobial,
antibacterial, anti-inflammatory, anticancer, anticonvulsant, sedative, analgesic, anti-
depressant, and antipyretic agents.[1–7] Fused pyrimidines have also a wide range of
pharmacological activity such as antitumor, anticancer, antihypertensive, antifolate and
antioxidant.[7,8] In addition, antimalarial, antimicrobial, anti-inflammatory and analgesic
activity in rats, antibiotic, antiviral influence, insecticide activity, and antimycotoxigenic
activity are only a few of the pharmacological properties of thienopyrimidines.[9–13]
Because of their important biological functions, the production of pyrimidine derivatives
is an appealing scaffold in biomedical, pharmacology, and drug discovery sciences.
Mannich reaction is considered a very useful reaction because of its effectiveness in
the generation of carbon-carbon and carbon-nitrogen covalent building linkers.[14] It is
well documented that the Mannich reaction is usually used in the amino alkylation of
various compounds with one or more active hydrogen atoms in the presence of primary
amines and formaldehyde under mild conditions. Additionally, the double Mannich
reaction has been reported as the reaction of compounds having two adjacent active
hydrogens with primary amines and formaldehyde.[15–18] Recently, we have developed
novel strategies for the synthesis of pyrimidothidiazine,[19] pyrazolopyrimidine,[20] tria-
zolothidiazine,[21] thiadiazinobenzimidazoles,[22] pyrimidopyrimidinones[23] in high
yields via double, triple and quadruple Mannich reactions.
As part of our continuing interest in the development of variously important
compounds,[24–26] herein, we developed several approaches for the construction of thie-
nopyrimidine derivatives starting from 2-amino-3-carboethoxy-4,5,6,7-tetrahydroben-
zo[b]thiophene. Fourier-transform infrared (FTIR), nuclear magnetic resonance (NMR),
and elemental analyses were utilized to elucidate the chemical structures of the new
compounds. The reaction regioselectivity and mechanism were also studied as well as
the biological activity of such compounds.
Results and discussion
Reaction of 2-amino-3-carboethoxy-4,5,6,7-tetrahydrobenzo[b]thiophene (1) with chlor-
oacetyl chloride in dioxane produced 2-chloroacetylamino-3-carboethoxy-4,5,6,7-tetrahy-
drobenzo[b]thiophene (2).[27] Herein we focused on the reaction of
2-chloroacetylamino-3-carboethoxy-4,5,6,7-tetrahydrobenzo[b]thiophene (2) with potas-
sium thiocyanate in acetonitrile, the reaction afforded a pure single product (TLC),
which was identified as 1,2-dihydrothiazolo[3,2-a]-6,7,8,9-tetrahydrobenzo[b]thieno[3,2-
e]pyrimidine-1,5-dione (4) rather than the other isomeric product 1,2-dihydrothia-
zolo[3,2-a]-6,7,8,9-tetrahydrobenzo[b]thieno[2,3-d]pyrimidine-3,5-dione
(3).
The
formation of (4) could be explained via the formation of 2-thiocyanoacetyl-3-carboe-
thoxy-4,5,6,7-tetrahydrobenzo[b]thiophene (A) which was transformed to 2-iminothia-
zolidine-4-one intermediate (B) followed by its cyclization to a tetracyclic compound
(4) as shown in (Scheme 1). The intermediates (A) and (B) were separated in similar
reactions,[28] however compound (4) was not separated previously. In addition, density

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Scheme 1. Formation of 1,2-dihydrothiazolo[3,2-a]-6,7,8,9-tetrahydrobenzo[b]thieno[3,2-e]pyrimidine-
1,5-dione (4) and 2-benzylidene-6,7,8,9-tetrahydrobenzo[b]thiazolo[3,2-a]thieno[3,2-e]pyrimidine-1,5-
dione (5).
functional theory (DFT) calculations support the formation of isomer (4) rather than
(3). As shown in Figure S21, the FTIR spectrum of (4) lacked the vibration bands over
3000 cmꢀ1 and exhibited absorption bands at 2920–2840 cmꢀ1 for the (C–H) aliphatic,
at 1735 cmꢀ1 for the (C ¼ O) of thiazolidinone, and at 1650 cmꢀ1 for the (C ¼ O) of
1
pyrimidinone ring. The H-NMR spectrum of the reaction product (4) was character-
ized by the occurrence of a singlet signal at 3.84 ppm which attributed to the (CH2)
group of thiazolidinone moiety in addition to the other protons at the expected chem-
ical shifts (Figure S22). Further, its mass spectrum and elementary analysis were found
to be consistent with the proposed structure (Figure S23).
Scheme 1 also showed that 2-mercapto-5,6,7,8-tetrahydrobenzo[b]thieno[2,3-d]pyri-
midin-4(3H)-one (6) can be reacted with chloroacetic acid and benzaldehyde in a mix-
ture of acetic acid/acetic anhydride to produce a single isolated product, which was
identified as 2-benzylidene-6,7,8,9-tetrahydrobenzo[b]thiazolo[3,2-a]thieno[3,2-e]pyrimi-
dine-1,5-dione (5). Due to the insolubility of product (5) in common NMR solvents, we
confirmed its molecular structure chemically through the condensation of compound
(4) with benzaldehyde under the same reaction condition. Both reactions gave similar
products which having identical melting points, mixed melting point, and FTIR spectra
(Figure S24). As shown in Figure S25, mass spectrum of the product (5) showed an
expected molecular ion peak at (m/z) value of 366.65.
The reaction of (2) with KSCN in acetonitrile followed by the addition of suitable
alcohols or primary amines afforded the corresponding esters (7a–d) and amides
(8a–d), respectively. Further, refluxing of (2) with KSCN in boiling alcohols gave the
corresponding esters (7a–d) directly, which can consider as a one-pot reaction for
the synthesis of ester derivatives. The formation of these esters may be explained via the
formation of (4) followed by nucleophilic attacking of alcohols. This assumption was
confirmed by refluxing of (4) with the corresponding alcohols to give (7a-d). Further,

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A. F. M. EL-MAHDY ET AL.
Scheme 2. One-pot reaction for synthesis of esters (7a–d) and amides (8a–d) derivatives.
refluxing of (7a–d) with suitable amines afforded the corresponding amides (8a-d)
(Scheme 2).
Previously, Santagati et al. have been reported that the compound 3-amino-2-phenyl-
amino-5,6,7,8-tetrahydrobenzo[b]thieno[2,3-d]pyrimidin-4(3H)-one was isolated as a
single pure product by the refluxing of N-(3-carboethoxy-4,5,6,7-tetrahydrobenzo[b]-
thien-2-yl)-Nꢀ-phenylthiourea with neat hydrazine hydrate (NH2NH2) or with NH2NH2
in ethanol.[29] Interestingly, El-Sherief et al. have reinvestigated this reaction and found
that the refluxing of N-(3-carboethoxy-4,5,6,7-tetrahydrobenzo[b]thien-2-yl)-Nꢀ-phenyl-
thiourea with NH2NH2 yielded three products—2-hydrazino-3-phenyl-5,6,7,8-tetrahy-
drobenzo[b]thieno
[2,3-d]pyrimidin-4(3H)-one,
3-amino-2-phenylamino-5,6,7,8-
tetrahydrobenzo[b]thieno[2,3-d]pyrimidin-4(3H)-one and 2- mercapto-3-phenyl-5,6,7,8-
tetrahydrobenzo[b]thieno[2,3-d]pyrimidin-4(3H)-one (Scheme 3).[30] To investigate a

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Scheme 3. Reactions of N-(3-carboethoxy-4,5,6,7-tetrahydrobenzo[b]thien-2-yl)-Nꢀ-phenylthiourea with
hydrazine hydrate.
Scheme 4. Mechanism of formation of 2-hydrazino-5,6,7,8-tetrahydrobenzo[b]thieno[2,3-d]pyrimidin-
4(3H)-one (10).
similar reaction with N-(3-carboethoxy-4,5,6,7-tetrahydrobenzo[b] thien-2-yl)-Nꢀ-thio-
urea (9), we firstly synthesized compound 9 through the treatment of (1) with KSCN in
dioxane (Scheme 4). Treatment of (9) with NH2NH2 in ethanol produced 2-hydrazino-
5,6,7,8-tetrahydrobenzo[b]thieno[2,3-d]pyrimidin-4(3H)-one (10) and 2-mercapto-
5,6,7,8-tetrahydrobenzo[b]thieno[2,3-d]pyrimidin-4(3H)-one (6) as a mixed products
(Scheme 4). Product 10 was isolated in 52.0% yield by cooling the reaction mixture fol-
lowed by its isolation via a simple filtration, while compound 6 was isolated in 42.3%
yield by the neutralization of the basic filtrate. The other isomeric product 2,3-diamino-
5,6,7,8-tetrahydrobenzo [b]thieno[2,3-d]pyrimidin-4(3H)one (100) not formed. The yield
of the compound 6 was reduced either by utilization of the higher boiling solvent n-
butanol instead of ethanol or by extending the reaction time. This action might be

6
A. F. M. EL-MAHDY ET AL.
Scheme 5. Synthesis of 2-hydrazino-5,6,7,8-tetrahydrobenzo[b]thieno[2,3-d]pyrimidin-4(3H)-one (10).
attributed to the nucleophilic NH2NH2 attack on the electrophilic core C2 that con-
verted (6) to (10). This assumption was confirmed by treatment of S-alkylated com-
pound (11) with NH2NH2 in a boiling ethanol to give (10) in 90.0% yield. Also,
cyclization of N-(3-carboethoxy-4,5,6,7-tetrahydrobenzo[b]thien-2-yl)-Nꢀ-thiourea (9) in
a boiling alcoholic KOH yielded (6) in a high yield.
Over recent years, microwave irradiation had used as a powerful tool for the alter-
native heating sources due to certain advantages such as minimizing the energy con-
sumption required for heating, reducing the reaction time, improving yield and
purity of the products, operation simplicity, and avoiding a large quantity of sol-
vents.[31,32] So, we repeated the reaction of (9) with hydrazine hydrate under micro-
wave conditions of 500 W and 75 ꢁC. The reaction was completed in few minutes
(15 min) instead of a long time (10–50 hours) to give (10) and (6) in 52.8% and
35.0% yields, respectively (Scheme 5). However, the yield of (10) was increased to
63.4%, and (6) was decreased to 25.9% under microwave conditions of 500 W, 75 ꢁC,
and 60 minutes.
We then investigated the tolerance of compound (10) toward ring closure reactions
with various reagents (Scheme 6). On the treatment of compound (10) with triethyl
orthoformate or formic acid, the product 1,2,4-triazolo[4,3-a]-6,7,8,9-tetrahydroben-
zo[b]thieno[3,2-e]pyrimidin-5-one (12) was formed rather than the other isomer (120).
In addition, the condensation of compound (10) with acetic acid and acetylacetone
afforded 1-methyl-1,2,4-triazolo[4,3-a]-6,7,8,9-tetrahydrobenzo[b]thieno[3,2-e]pyrimidin-
5-one (13) and 2-[3,5-dimethylpyrazol-1-yl]-5,6,7,8-tetrahydrobenzo[b]thieno[2,3-d]pyri-
midin-4(3H)-one (14), respectively. Moreover, the reaction with HNO2 gave the
tetrazole derivative (15) which present in equilibrium with its azide form (150).
Conversion of (10) to 1-mercaptotriazolo[4,3-a]thienopyrimidine (16) via its reaction
with carbon disulfide in boiling alcoholic KOH, which was converted to (17) by reflux-
ing with ethyl iodide in alcoholic KOH. Furthermore, the Shiff-base reaction of com-
pound (10) with excessive benzaldehyde gave 2-benzylidenehydrazino-5,6,7,8-
tetrahydrobenzo[b]thieno[2,3-d]pyrimidin-4(3H)-one (18) (Scheme 6).
On the other hand, as a part of our ongoing interest in the synthesis of fused 1,3,5-
thiadiazine heterocycles using Mannich type reaction.[19] We studied the susceptibility
of 2-mercapto-5,6,7,8-tetrahydrobenzo[b]thieno[2,3-d]pyrimidin-4(3H)-one (6) as a pol-
yfunctional nucleophile under Mannich reaction conditions. On Mannich condensation
reaction of compound (6) with an equivalent of primary aliphatic, aromatic amine ana-
logues and an aqueous formaldehyde (35%) in ethanol or dioxane for 3-5 h, the
reaction may proceed to afford 3-N-substituted-7,8,9,10- tetrahydrobenzo[b]thieno
[2,3-d]pyrimido[2,1-b]-1,3,5-thiadiazine-6-one (19a–j) or other possible isomeric prod-
ucts
3-N-substituted-7,8,9,10-tetrahydrobenzo[b]thieno[2,3-d]pyrimido[2,3-b]-1,3,5-

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Scheme 6. Reactions of 2-hydrazino-5,6,7,8-tetrahydrobenzo[b]thieno[2,3-d]pyrimidin-4(3H)-one (10).
thiadiazine-11-one (20a–j) or a mixture of them. A simple TLC experiment indicated
that such a reaction afforded only a single product (Scheme 7).
The FTIR spectra of the isolated products lacked the vibration band of the NH group
and exhibited absorption bands at 2953–2832 cmꢀ1 for the aliphatic (C–H), at
1671–1659 cmꢀ1 for the (C ¼ O), at 1558–1515 cmꢀ1 for (C ¼ N), and at
1
1498–1449 cmꢀ1 for (C–S) of the thiadiazine ring. the H-NMR spectra of the reaction
products were characterized by the occurrence of two singlet signals at 5.5–4.6 and
5.8–5.1 ppm attributed to the aliphatic (CH2) groups of thiadiazine moieties; SCH2N
and NCH2N, respectively, in companied with the other protons at the expected chem-
ical shifts. The mass spectra and elementary analyses of the double Mannich products
were found to be consistent with the proposed structures. These findings cannot indi-
cate which of these isomers (19a–j) or (20a–j) are the formed products, therefore, a
solid argument is needed to confirm the formed isomeric products. This made us to
think about the relative stability of tautomer A and B of compound (6) as well as the
electronic charge density on N-1 and N-3. DFT calculations using Gaussian 09 program
confirmed the higher stability of tautomer A as well as the highest electron density is
located on N-3 than tautomer B (Scheme 8). Accordingly, tautomer A is more favorable

8
A. F. M. EL-MAHDY ET AL.
Scheme 7. Mannich reaction of 2-mercapto-5,6,7,8-tetrahydrobenzo[b]thieno[2,3-d]pyrimidin-4(3H)-
one (6).
Scheme 8. Tautomerism of 2-mercapto-5,6,7,8-tetrahydrobenzo[b]thieno[2,3-d]pyrimidin-4(3H)-one
derivative (6).
to start Mannich reaction via N-3 to form (19a–j) rather than (20a–j) (Scheme 9). This
assumption was supported by DFT calculations which confirmed the higher stability of
isomer (19a–j) than (20a–j) (Figures S1–S20, Table 1). The energy difference between
the derivatives of isomers (19a–j) and (20a–j) in kcal/mol were calculated using DFT at

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9
Scheme 9. The suggested mechanism for formation of (19a–j).
Table 1 Energy difference between compounds (19a–j) and (20a–j).
-1
ꢂ
Compound
R
(kcal mol )
a
b
c
d
e
f
g
h
i
CH2CH2CH3
CH2CH2CH2CH3
CH2CH(CH3)2
CH2C6H5
C6H5
C6H4Cl-p
15.58
14.74
17.67
13.58
14.18
14.41
14.30
14.04
13.55
14.88
C6H4Br-p
C6H4CH3-p
C6H4OCH3-p
2-naphthylamine
j
ꢂ
E20a–20j–E19a–19j
the B3LYP-D3BJ/6-312G(d,p) level of theory. Isomer (19a–j) is more stable than all
derivatives.
The generality of the Mannich reaction of compound (6) with primary aliphatic, aro-
matic amine analogues, was investigated. The primary aliphatic amines (propylamine,
butylamine and isobutylamine) in addition to benzylamine produced the desired prod-
ucts (19a–d) in very good yields. Aliphatic amines are more active than aromatic
amines. Therefore, aniline and 2-napthylamine gave the corresponding products (19e
and 19j) in good yields. Aromatic amines with electron-donating groups (p-methylani-
line and p-methoxyaniline) gave the desired products (19h and 19i) in very good yields,
while aromatic amines with halides (p-chloroaniline and p-bromoaniline) produced the
products (19f and 19 g) in good yields. The fragmentation pattern of the compounds
(19a–j) were found to be consistent with the proposed fragmentation pattern from A to
E (Scheme 10) (Table S1).

10
A. F. M. EL-MAHDY ET AL.
Figure 1. Comparison illustration of inhibition zone diameters for the antibacterial activity of our
novel compounds at a concentration of 2.5 mg/0.1mL.
Scheme 10. Fragmentation pattern of compounds (19a–j)
Antimicrobial activity
Pyrimidine derivatives have been shown to have a wide variety of antimicrobial proper-
ties.[33] Also, compounds containing a 1,3,5-thiadiazine moieties have been to possess
antifungal properties.[34] The in vitro antimicrobial activity is divided into two catego-
ries; antibacterial and antifungal activities. The in vitro antimicrobial activities of our
novel compounds were examined against six strains of bacteria, namely Bacillus cereus

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Figure 2. Comparison illustration of inhibition zone diameters for the antifungal activity of our novel
compounds at a concentration of 2.5 mg/0.1 mL.
(þve), Escherichia coli (ꢀve), Micrococcus luteus (þve), Pseudomonas aeruginosa (ꢀve),
Serratia marcescens (ꢀve) and Staphylococcus aureus (þve) as well as six fungal species,
namely Aspergillus flavus, Candida albicans, Fusarium oxysporum, Geotrichum candi-
dum, Scopular brevicaulis and Trichophyton rubrum (Figures 1 and 2). New pyrimidine
derivatives were synthesized and checked for antibacterial activities using the well diffu-
sion method by measuring the zone of inhibition in millimeters. The inhibition zone
diameters were clear agreement with good definition. The concentration of the tested
compounds was 25 mg/ml and their inhibitions were measured at the end of 24 hours
for bacteria by calculating the diameter of the inhibition region.[35] To measure the effi-
cacy of the studied products under the same conditions, the references used
Chloramphenicol as an antibacterial agent and Clotrimazole as an antifungal agent.
Different compounds have varying antimicrobial action depending on the type of
microorganism species and the compound itself.
Data from antibacterial and antifungal screening showed the following: the tested
compound (19c) showed comparatively good activity against all the bacterial and fungal
strains. Compounds (2), (5), (7c), (8), (9) and (12) showed no antibacterial activity, but
compounds (2), (5), (7c), (8), (9), (12), (19a), (19e), (19 h) and (19i) exhibited no anti-
fungal activity. The rest of compounds exhibited moderate antimicrobial activity. The
finding results are depicted in (Table S2, S3).
Conclusions
In summary, we developed a series of efficacious and novel strategies for the synthesis
of thienopyrimidines starting from 2-amino-3-carboethoxy-4,5,6,7-tetrahydrobenzo[b]-
thiophene. Density functional theory computation and spectroscopic analyses were
applied to investigate the regioselectivity of these synthetic strategies. The mechanisms
and chemical structures of the final products were studied. Some of the synthesized
compounds exhibited biological activities against different strains of bacterial and fungal

12
A. F. M. EL-MAHDY ET AL.
strains. The positive results obtained would allow for the fast synthesis of libraries of
such derivatives for future modifications.
Experimental
Synthesis of 2-alkoxycarbonylmethylthio-5,6,7,8-tetrahydrobenzo[b]thieno[2,3-
d]pyrimidin-4(3H)-one (7a-d) (general method)
Method A
A mixture of N-chloroacetyl derivative (2) (0.01 mol) and KSCN (0.03 mol) was refluxed
in acetonitrile (50 ml) for 4 hours, followed by the addition of 10 ml suitable alcohol.
The reaction mixture was cooled, poured into water, filtered to produce (7a–d) which
washed with water several times, dried, and recrystallized from ethanol, to give (7a–d)
in high yield.
Method B
Refluxing of a mixture of N-chloroacetyl derivative (2) (0.01 mol) and KSCN (0.03 mol)
in a suitable alcohol (20 ml) for 4 hours, gave the same products of method A.
Compound (7a) was also obtained by refluxing (6) (0.01 mol) with ethyl chloroacetate
(0.012 mol) in ethanol (50 ml) for 3 hours in high yield and the product was identical
with those obtained by method A and B, in terms of melting point (296 ꢁC), mixed
melting point, TLC and spectral analysis.
Synthesis of 2-carboxamidomethylthio-5,6,7,8-tetrahydrobenzo[b]thieno[2,3-
d]pyrimidin-4(3H)-one (8a–d) (general method)
Method A
A mixture of N-chloroacetyl derivative (2) (0.01 mol) and KSCN (0.03 mol) was refluxed
in CH3CN (50 ml) for 4 hours, followed by the addition of appropriate amine
(0.012 mol). After cooling, the solid was collected, rinsed with water, dried, and crystal-
lized from ethanol to produce (8a–d) in high yields.
Method B
A mixture of ester derivative (7a–d) (0.01 mol) and appropriate amine (0.012 mol) was
heated in ethanol (50 ml) until boiling for 3 hours. After cooling, the solid was collected,
rinsed with water, dried, and crystallized from ethanol to produce (8a–d) in high yields.
Synthesis of 3-N-substituted-7,8,9,10-tetrahydrobenzo[b]thieno[2,3-d]pyrimido[2,1-
b]-1,3,5-thiadiazine-6-one (19a–j) (general method)
General procedure. 2-mercapto-5,6,7,8-tetrahydrobenzo[b]thieno[2,3-d]pyrimidin-4(3H)-
one (6) (0.001 mol), appropriate aliphatic or aromatic primary amines (0.0011 mol) and
formaldehyde (2 ml) was refluxed in ethanol or ethanol/dioxane mixture (20 ml) for
3–5 hours. The resultant precipitate was obtained by filtration, treated several times with
water, and thoroughly dried. To obtain the final product (19a–j) as colorless or yellow

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13
needles in 50–78% yield, the crude product was crystallized from the appropri-
ate solvent.
ORCID
Ahmed F. M. EL-Mahdy
http://orcid.org/0000-0002-5237-750X
References
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