Green synthesis of some new thiopyrano[2,3-d][1,3]thiazoles using lemon juice and their antibacterial activity

Article abstract of DOI:10.1080/00397911.2018.1495234

A simple green method has been developed for the synthesis of a series of new 3-phenyl-6-(substituted)-thiopyrano[2,3-d]thiazole-2,5,7(6H)-triones, 6-cyano-2-oxo-3-phenyl-thiopyrano[2,3-d]thiazoles, 3-phenyl-3,5,5a,11b-tetrahydro-2H,6H-chromeno-[4′,3′:4,5

Full text of DOI:10.1080/00397911.2018.1495234

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: http://www.tandfonline.com/loi/lsyc20
Green synthesis of some new thiopyrano[2,3-d]
[1,3]thiazoles using lemon juice and their
antibacterial activity
Nadia Hanafy Metwally, Mohamed Ahmed Badawy & Doha Samir Okpy
To cite this article: Nadia Hanafy Metwally, Mohamed Ahmed Badawy & Doha Samir Okpy
(2018): Green synthesis of some new thiopyrano[2,3-d][1,3]thiazoles using lemon juice and their
antibacterial activity, Synthetic Communications, DOI: 10.1080/00397911.2018.1495234
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https://doi.org/10.1080/00397911.2018.1495234
Green synthesis of some new thiopyrano
[2,3-d][1,3]thiazoles using lemon juice and their
antibacterial activity
Nadia Hanafy Metwally, Mohamed Ahmed Badawy, and Doha Samir Okpy
Chemistry Department, Faculty of Science, Cairo University, Giza, Egypt
ABSTRACT
ARTICLE HISTORY
Received 20 April 2018
A simple green method has been developed for the synthesis of a ser-
ies of new 3-phenyl-6-(substituted)-thiopyrano[2,3-d]thiazole-2,5,7(6H)-
triones, 6-cyano-2-oxo-3-phenyl-thiopyrano[2,3-d]thiazoles, 3-phenyl-
3,5,5a,11b-tetrahydro-2H,6H-chromeno-[40,30:4,5]thiopyrano[2,3-d]thia-
zole-2,6-dione and 5-amino-6-cyano-2-oxo-3-phenyl-3,7-dihydro-2H-
thiopyrano[2,3-d]thiazoles via hetero-Diels–Alder reaction by conven-
tional method and green method using lemon juice as natural acid.
The structure of all the newly synthesized compounds was inter-
preted by elemental analyses and spectral data. The synthesized
compounds were evaluated for their in vitro antibacterial activity
against some pathogenic bacteria. This study is a platform for the
future design of more potent antimicrobial agents.
KEYWORDS
4-thioxo-3-phenyl-2-thiazoli-
dinones; antibacterial
activity; lemon juice;
thiopyrano[2,3-d]thiazoles
GRAPHICAL ABSTRACT
Introduction
4-Thiazolidinones and their derivatives having valuable biological activities as antimicro-
bial,[1–3] antidiabetic,[4,5] anticancer,[6,7] analgesic,[8] anticonvulsant,[9,10] anti HIV,[11]
antitubercular[12] and anti-inflammatory.[13,14] The improvement of the biological activ-
ity of 4-thiazolidinones based on the variation in the substituent in C-5 position of the
ring and the conjugation between 5-ene exocyclic double bond with carbonyl group at
position-4. Also, thiopyrano[2,3-d]thiazoles attracted a great attention in medicinal
CONTACT Nadia Hanafy Metwally
nhmmohamed@yahoo.com
Chemistry Department, Faculty of Science, Cairo
University, Giza 12613, Egypt.
Supplemental data for this article can be accessed on the publisher’s website.
ß 2018 Taylor & Francis Group, LLC

2
N. HANAFY METWALLY ET AL.
Figure 1. Background for the preparation of the target compounds.
chemistry due to their diverse biological activity such as antimycobacterial,[15,16] anti-
bacterial,[17,18] antiviral[19] and anticancer[20–22] as shown in Figure 1. Moreover, N-
aryl maleimide derivatives displayed an efficient antimicrobial effect.[23,24] The trad-
itional reaction conditions using in organic synthesis increases the environmental
pollution posed by utility of toxic, volatile organic solvents, so in recent years, many
organic researches are working on development of green methods to prepare various
organic compounds by replacing hazardous acidic or basic catalyst by alternative
green catalyst. Nowadays, some organic synthesis has been carried out using fruit
juice of citrus lemon as a natural[25,26] because it is inexpensive, easy prepared and
handling, eco-friendly and easier waste material are among the most common char-
acteristics that make it a green catalyst. Lemon juice acts as an acidic catalyst
(pH ¼ 2–3) because percentage of citric acid (5–7%) is more than other acids.[27] An
extension to our work[28–36] toward the synthesis of some new substituted thiopyr-
ano[2,3-d]thiazoles via hetero-Diels–Alder reaction of interest biological activity, we
synthesized some novel 5-arylmethylene-4-thioxo-2-thiazolidines and their thiopyr-
ano[2,3-d]thiazoles using glacial acetic acid as conventional method and lemon juice
as natural green method (Scheme 1).
Results and discussion
The target compounds, 5-arylidene-4-thioxo-2-thiazolidinones 3a–c, were synthesized
€
via
Knoevenagel
condensation
of
3-phenyl-4-thioxo-2-thiazolidinone
with

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3
Scheme 1. Synthetic pathway for target thiopyrano[2,3-d][1,3]thiazoles.
Scheme 2. Synthesis of 5-arylmethylene-4-thioxo-2-thiazolidinones 3a–c.
€
Table 1. Knoevenagel condensation of aromatic aldehydes
2a-c and 3-phenyl-4-thioxo-2-thiazolidinone.
AcOH Lemon juice
yield
(%)
yield
(%)
Entry
X
Y
Z
Product
1
2
3
H
H
OH
H
OCOPh
3a
3b
3c
99
97
75
99
98
80
OMe OCOPh
H
H
4-formylphenyl benzoate 2a, 4-formyl-2-methoxyphenyl benzoate 2b [prepared from
alkylation for hydroxyl benzaldehyde derivatives 1a,b with benzoyl chloride and triethyl-
amine under stirring in methylene chloride] (Scheme 2)[37] and salicylaldehyde 1c under
stirring in lemon juice at room temperature or in refluxing glacial acetic acid with cata-
lytic amount of fused sodium acetate (Table 1). The structure of compounds 3a–c was
proved using elemental analyses and spectral data. The IR spectrum of the isolated

4
N. HANAFY METWALLY ET AL.
Table 2. Cycloadducts thiopyrano[2,3-d][1,3]thiazoles 5a–o.
Product AcOH Lemon juice
yield
(%)
yield
(%)
Entry
X
Y
Z
R
5
1
2
3
4
5
6
7
8
H
H
H
H
H
H
H
H
H
H
OH
OH
OH
OH
OH
H
H
H
H
H
OCOPh
H
a
b
c
d
e
f
g
h
i
j
k
l
m
n
o
60
40
30
36
45
40
43
48
35
40
50
45
55
50
55
68
55
40
41
50
46
51
56
47
54
55
49
61
66
67
OCOPh Me
OCOPh OMe
OCOPh Cl
OCOPh Br
OMe OCOPh
H
OMe OCOPh Me
OMe OCOPh OMe
OMe OCOPh Cl
OMe OCOPh Br
H
H
H
H
H
9
10
11
12
13
14
15
H
H
H
H
H
H
Me
OMe
Cl
Br
Table 3. Cycloadducts thiopyrano[2,3-d][1,3]thiazoles
7a-d.
Product AcOH Lemon juice
yield
(%)
yield
(%)
Entry
X
Rꢀ
CN
OMe CN
7
1
2
3
4
H
a
b
c
50
47
45
56
–
–
7
9
H
COOEt
OMe COOEt
d
1
product 3a showed carbonyl absorption bands at ꢀmax 1717 and 1584 cmꢀ1. Its H
NMR spectrum displayed a singlet signal at d ¼ 8.36 ppm due to vinylic proton, in add-
ition to the aromatic multiplet signal in the region d ¼ 7.43-8.18 ppm. The elemental
analysis together with spectral data are in agreement with the proposed structure 3
(Scheme 2).
The hetero-Diels–Alder reaction of 3a–c with N-arylmaleimides 4a–e in lemon juice
at room temperature under stirring or in refluxing glacial acetic acid (Table 2) yielded
a series of novel thiopyrano[2,3-d]thiazole derivatives 5a–o (Scheme 3). The synthe-
1
sized novel thiopyrano[2,3-d]thiazoles 5a–o were confirmed using IR, H NMR, 13C
NMR, MS and elemental analyses. The IR spectrum of the isolated product 5c taken as
a typical example of the prepared series showed absorption bands at ꢀmax ¼ 1728, 1682
1
and 1598 cmꢀ1 corresponding to the three CO groups, respectively. Its H NMR spec-
trum revealed two doublets at d ¼ 4.12 with J values 9 and 6 Hz, assigned to H-6,
another doublet signal at d ¼ 4.72 ppm with J value 6 Hz due to H-5 and a doublet sig-
nal at d ¼ 5.18 ppm with J value 9 Hz attributed to H-7. Also, 13C NMR spectrum of 5c
showed the characteristic signals at 55.3, 164.4, 168.7, 173.5 and 173.6 ppm assigned
1
for methoxy and carbonyl carbons, respectively. The absence of signal doubling in H
NMR spectra confirmed that the only one stereoisomer was present for all cycload-
ducts 5a–o, and based on the values of coupling constant, the cis-configuration[36,38] was
assigned to the cycloadducts 5 taking into account a previously studied stereochemical
configuration of analog derivatives 8-(3-(4-methoxyphenyl)-1-phenyl-1H-pyrazol-4-yl)-

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5
Scheme 3. Synthesis of 3-phenyl-thiopyrano[2,3-d]thiazole-2,5,7(6H)-triones 5a–o.
Scheme 4. Synthesis of cycloadducts 7a–d.
3,6-diphenyl-7a,8-dihydropyrrolo[30,40:5,6]-thiopyrano[2,3-d]thiazole-2,5,7(3H,4aH,6H)-
trione, which was established using X-ray crystallography analysis.[35]
Extending to our work, the reaction of 3a,b with acrylonitrile 6a and ethylacrylate 6b
in refluxing glacial acetic acid (Table 3) furnished the cycloadducts 7a–d (Scheme 4).

6
N. HANAFY METWALLY ET AL.
Scheme 5. Synthesis of 3-phenyl-3,5,5a,11b-tetrahydro-2H,6H-chromeno[40,30:4,5]-thiopyrano[2,3-
d]thiazole-2,6-dione 8.
The structure of the cycloadducts was proved using elemental analyses and spectral
data. For example, the IR spectrum of 7a showed absorption bands corresponding to
1
cyano and carbonyl groups at ꢀmax ¼ 2240, 1745 and 1625 cmꢀ1, respectively. Its H
NMR spectrum revealed doublets at d ¼ 4.50 with J value 5.4 Hz corresponding to H-7,
another triplet signal at d ¼ 4.0 ppm with J value 5.4 Hz assigned for H-6 in addition to
a multiplet signal at d ¼ 3.75–3.81. Also, 13C NMR spectrum of 7a showed the charac-
teristic three signals at d ¼ 118.0, 164.2 and 168.3 ppm assigned for cyano and carbonyl
1
carbons, respectively. Also, the absence of signal doubling in H NMR spectra con-
firmed that the only one stereoisomer was present for all cycloadducts 7a–d. The mass
spectrum together with the elemental analyses confirmed the proposed structure 7
(Scheme 4).
On the other hand, when compound 3c reacted with acrylonitrile 6a in lemon juice
or refluxing in acetic acid furnished the cycloadduct 8 (Scheme 5). The structure of the
cycloadduct 8 was established using elemental analyses and spectral data. For example,
the IR spectrum of 8 showed disappearance of an absorption band corresponding to
cyano group in the expected region instead two absorption bands corresponding to car-
1
bonyl groups at ꢀmax ¼ 1767 and 1671 cmꢀ1, respectively. Its H NMR spectrum showed
two doublet signals at d ¼ 3.47 and 4.46 ppm with J values 3.6 and 6.0 Hz corresponding
to H-5 and H-7, respectively. The collective data of cycloadduct 8 suggested the forma-
tion of 8 through 4 þ 2 cycloaddition of acrylonitrile as dienophile on the exocyclic
double bond of thiazolidinone ring followed by heterocyclization, via addition of
hydroxyl group on cyano function in acrylonitrile afforded the non-isolable imino inter-
mediate, which converted into the desired cycloadduct 8 via acid hydrolysis (Scheme 5).
The same product was resulted by the reaction of 3c with ethylacrylate under the same

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7
Scheme 6. Synthesis of 5-amino-6-cyano-2-oxo-3-phenyl-3,7-dihydro-2H-thiopyrano[2,3-d]-thia-
zoles 9a,b.
Scheme 7. Synthesis of 5-amino-3-phenyl-3,11b-dihydro-2H,6H-chromeno[40,30:4,5]-thiopyrano[2,3-
d]thiazole-2,6-dione.
reaction conditions (mp., m.mp, TLC), which supported the formation of cycloadduct 8
(Scheme 5).
The behavior of 3a–c toward the action of malononitrile has been investigated. Thus,
the refluxing of 3a–c with malononitrile in absolute ethanol and in the presence of few
drops of triethylamine afforded products 9a–b (Scheme 6) and 10 (Scheme 7). The reac-
tion proceeds via Micheal addition of active methylene to double bond. Then tautomer-
ism occurred through proton transfer in an intramolecular fashion from methylene
group to the sulfur of thiazole ring followed by cyclization by addition of SH proton to
the cyano group to yield the novel compounds 9a-b. In case of 3c, the reaction com-
pleted by another cyclization afforded the final product 10.

8
N. HANAFY METWALLY ET AL.
Table 4. Zone of inhibition for synthesized compounds 3a–c, 5a–d, 5f–I and 5k–n expressed in the form of mean-
standard deviation (mm).
Klebsiella
pneumonia
ATCC 4415
Pseudomonas
aeruginosa
ATCC 27853
Staphylococcus
aureus
ATCC 6538
Streptococcus
mutans
ATCC 25175
Escherichia coli
ATCC 3008
Compound
3a
3b
3c
5a
5b
5c
5d
5f
19.3 0.6
10.7 0.6
14.3 1.5
12.3 0.5
16.0 1.0
16.7 0.6
14.3 0.5
12.7 0.6
NA
14.3 0.5
12.7 0.5
17.6 0.5
NA
16.3 1.5
11.3 0.5
14.7 0.5
17.7 0.6
NA
NA
NA
25 0.5
NA
NA
NA
NA
19.7 0.5
NA
NA
NA
10.5 0.7
NA
11.3 0.5
NA
24.5 0.7
NA
14.3 0.5
14.3 0.6
11.7 1.5
NA
NA
NA
NA
14.7 0.5
NA
5g
NA
5h
5i
5k
5l
NA
NA
NA
NA
NA
25 0.5
NA
NA
35
30 0.5
–
10.7 0.6
12.3 0.5
10.5 0.7
NA
NA
NA
24.5 0.7
11.3 0.5
NA
20 1
–
35 0.6
10.7 0.5
17.6 0.5
14.3 0.5
12.7 0.5
12.6 0.1
34 0.5
–
14.3 1.5
19.3 0.6
10.7 0.6
NA
35 0.6
–
5m
5n
Gentamicin
Ampicilin
NA
NA
–
1
30 0.5
Zone of inhibition is expressed in the form of mean standard deviation (mm).
NA: No activity.
Well diameter (6 mm) and 100 mL was tested.
Antibacterial activity
The synthesized compounds 3a–c, 5a–d, 5f–i and 5k–n were screened for their in vitro
antibacterial activity against Gram-negative (Escherichia coli ATCC 3008, Pseudomonas
aeruginosa ATCC 27853 and Klebsiella pneumonia ATCC 4415) and Gram-positive
(Staphylococcus aureus ATCC 6538 and Streptococcus mutans ATCC 25175) microor-
ganisms (Table 4). The reference drugs are Gentamicin for Gram-negative bacteria and
Ampicilin for Gram-positive bacteria. Also, the minimal inhibitory concentrations (MIC
in mg/mL) or the lowest drug concentrations that stop the growth of bacteria (Table 4)
were determined. The results of MIC tests against Gram-positive and Gram-negative
bacteria showed that compound 3a exhibited highest activity against E. coli ATCC 3008
with MIC; 15.6 mg/mL followed by compounds 5b and 5c with MIC; 62.5 mg/mL then
compounds 5m and 5n with MIC; 250, 500 mg/mL, respectively. Also, compounds 3a,
3c, 5f and 5n have the same activity against K. pneumonia ATCC 4415 with MIC;
125 mg/mL followed by compounds 5b, 5c and 5m with MIC; 250 mg/mL. On the other
hand, compounds 5f and 5l exhibited the same activity against P. aeruginosa ATCC
27853 with MIC; 125 mg/mL. Compound 5l showed the highest activity against S. aureus
ATCC 6538 with MIC; 250 mg/mL followed by 5m and 5n with MIC; 500 mg/mL.
Additionally, compounds 3a, 3c, 5b, 5c, 5k and 5l showed selective activities against S.
mutans ATCC 25175 whereas compound 3a exhibited the highest activity with
31.25 mg/mL followed by compounds 5b, 5c and 5l MIC 62.5 mg/mL (Table 5).
Antimicrobial assay
The antimicrobial activity of synthesized compounds was determined using agar well
diffusion method.[39] All the compounds were tested in vitro for their antibacterial activ-
ity against S. aureus and S. mutans (Gram-positive bacteria), E. coli, P. aeruginosa and

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9
Table 5. The minimal inhibitory concentrations (MIC in mg/ml) of compounds 3a–c, 5a–d, 5f–I and 5k–n.
Klebsiella
pneumonia
ATCC 4415
Pseudomonas
aeruginosa
ATCC 27853
Staphylococcus
aureus
ATCC 6538
Streptococcus
mutans
ATCC 25175
Escherichia coli
ATCC 3008
Compound
3a
3b
3c
5a
5b
5c
5d
5f
5g
5h
5i
5k
5l
15.6
Stock
–
Stock
62.5
62.5
Stock
–
–
–
–
–
125
Stock
125
–
250
250
Stock
125
–
–
–
–
–
–
–
31.25
–
250
–
62.5
62.5
Stock
–
–
Stock
–
–
–
–
125
–
–
–
–
Stock
Stock
–
Stock
Stock
–
250
500
500
–
–
–
–
Stock
–
–
250
125
Stock
125
Stock
–
125
62.5
–
Stock
250
500
5m
5n
Stock
Stock concentration 1 mg/mL.
Concentrations unit of MIC are represented as mg/mL.
klebsiella (Gram-negative bacteria) using nutrient agar medium. Ampicillin and
Gentamicin were used as standard drugs for Gram-positive and Gram-negative, respect-
ively. DMSO was used as a solvent control. The compounds were tested at a concentra-
tion of 15 mg/mL against both bacterial and fungal strains.
Method of testing
The sterilized media was poured onto the sterilized Petri dishes (20–25 mL, each petri
dish) and allowed to solidify at room temperature. Microbial suspension was prepared
in sterilized saline equivalent to McFarland 0.5 standard solution (1.5 ꢁ 105 CFU mLꢀ1
)
and its turbidity was adjusted to OD ¼ 0.13 using spectrophotometer at 625 nm.
Optimally, within 15 min after adjusting the turbidity of the inoculums suspension, a
sterile cotton swab was dipped into the adjusted suspension and was flooded on the
dried agar surface then allowed to dry for 15 min with lid in place. Wells of 6 mm
diameter was made in the solidified media with the help of sterile borer. 100 lL of the
solution of the tested compound was added to each well with the help of micropipette.
The plates were incubated at 37 ꢂC for 24 h in case of antibacterial activity. This experi-
ment was carried out in triplicate and zones of inhibition were measured in milli-
meter scale
Methodology of MIC
For each strain, three to five isolated colonies were selected from the fresh agar plate
and were transferred into a tube containing 3–4 mL of sterile broth medium. The bac-
terial suspension was mixed well and incubated at 35–37 ꢂC for 2–6 h. The turbidity of
the bacterial suspension should be equal to or greater than the turbidity of a McFarland
Standard 0.5. After that, 1 mg of the tested compound (antimicrobial agent) was dis-
solved in 1 mL DMSO and two-fold serial dilution was done using broth medium. A
fixed volume of the prepared bacterial inoculums was added to each tube and incubated

10
N. HANAFY METWALLY ET AL.
for at 37 ꢂC 16–20 h. The MIC is defined as the lowest concentration of the antimicro-
bial agent that inhibits visible growth of the tested isolate as observed with the
unaided eye.[40]
Conclusion
The aim of our study was to synthesis of some new thiopyrano[2,3-d][1,3]thiazole deriv-
atives from 5-arylmethylene-3-phenyl-4-thioxo-2-thiazolidinones and some dienophiles.
The structures of the final cycloadducts were elucidated by elemental analyses and spec-
tral data. Some of the newly synthesized adducts are investigated their antibacterial
activity against one or more type of bacteria. 4-[(2-Oxo-3-phenyl-4-thioxothiazolidin-5-
ylidene)methyl]phenyl benzoate 3a and its cycloadducts 5b and 5c exhibited highest
activity among other compounds, this may be due to alkylation for hydroxyl benzalde-
hyde that raising the antibacterial activity. On the other hand, addition of methoxy
group in meta-position as in compound 3b reduce the antibacterial activity toward
Gram-positive and Gram-negative bacteria.
Experimental
Chemistry
All melting points were measured using Electrothermal (9100) apparatus and are uncor-
rected. The IR spectra were determined using KBr pellets on a Perkin Elmer 1430 spec-
trophotometer. The NMR spectra were recorded with a Varian Mercury VXR-300 NMR
1
spectrometer at 75 and 300 MHz (1 C and H NMR spectra, respectively) using DMSO-
d6 as solvent and results are expressed as d values. Mass spectra were taken on a
Shimadzu GCMS-QP 1000 Ex mass spectrometer at 70 eV. Elemental analyses were car-
ried out at the Microanalyses Center at Cairo University and were performed on Vario
EL III Elemental CHNS analyzer. Antimicrobial activity was performed at Chemistry
Department at Faculty of Science in Cairo University-Giza.
Preparation of compounds (3a–c)
General procedure
Conventional method A. Solution of 3-phenyl-4-thioxo-2-thiazolidinone 1 (0.01 mol) in
10 mL of glacial acetic acid and 4-formylphenyl benzoate, 4-formyl-2-methoxyphenyl
benzoate or salicylaldehyde 2a–c (0.01 mol) with fused sodium acetate (0.015 mol) was
refluxed for 2 h then left overnight at room temperature. The precipitated was filtered
off, washed with water and finally dried and recrystallized from ethanol–diox-
ane mixture.
Preparation of lemon juice. Fresh lemon was purchased from the local market. The
pieces were made using a knife and pressed in a fruit juicer to obtain the juice. Then
the juice was filtered through filter paper to remove solid material and clear portion of
juice was used as a catalyst.

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11
Green method B. Solution of 3-phenyl-4-thioxo-2-thiazolidinone 1 (0.01 mol) in 3 mL of
limon juice and 4-formylphenyl benzoate, 4-formyl-2-methoxyphenyl benzoate or salicy-
laldehyde 2a–c (0.01 mol) was stirred at room temperature. After reaction completion as
analyzed using TLC, the reaction mixture was quenched with cold water and stirred
continuously until free flowing solid was obtained. The resulting solid was filtered, dried
and recrystallization from ethanol-dioxane mixture.
4 -[(2-Oxo-3-phenyl-4-thioxothiazolidin-5-ylidene)methyl]phenyl benzoate (3a). Orange
1
crystals, yield =99%, m.p 220 ꢂC; ꢀmax/cmꢀ1 (KBr) 1717 (CO), 1584 (CO); H NMR
(DMSO-d6) d: 7.43–8.18 (m, 14H, Ar), 8.36 (s, 1H, CH); 13C NMR (DMSO)
d ¼ 120.3, 122.9, 128.1, 128.2, 128.3, 128.7, 129.1, 129.6, 131.1, 131.7, 133.9, 135.7,
136.0, 152.0, 163.9, 193.9; m/z ¼ 418 (Mþþ1, 5.43%), 417 (Mþ, 18.75%), 385 (0.25%),
357 (0.25%), 312 (1.84%), 297 (1.40%), 279 (0.53%), 223 (0.47%), 181 (0.36%), 149
(0.89%), 121 (2.30%) 109 (0.50%), 191 (0.16%), 183 (0.36), 151 (0.42%), 121 (0.66%),
105 (100%), 88 (0.86%), 77 (48.34%). Anal. Calcd for C23H15NO3S2: C, 66.17; H,
3.62; N, 3.35; S, 15.36. Found: C, 66.35; H, 3.43; N, 3.13; S, 15.18%.
Preparation of cycloadducts 5a–o
General procedure
Conventional method A. A mixture of 3a–c (0.01 mol) and N-arylmaleimides 4a–e
(0.01 mol) in glacial acetic acid (20 ml) was refluxed till decolourization took place, then
it was left overnight at room temperature. The solid obtained was filtered off, and
recrystallized from ethanol–dioxane mixture. The spectral data of compounds 5a–o are
shown below.
Green method B. A mixture of 3a–c (0.01 mol) in 3 ml of lemon juice was stirred and
left overnight at room temperature. After reaction completion as analyzed by TLC, the
reaction mixture was quenched with cold water and stirred continuously until free-flow-
ing solid was obtained. The resulting solid was filtered, dried and recrystallized from
ethanol–dioxane mixture.
4
-(6-(4-Methoxyphenyl)-2,5,7-trioxo-3-phenyl-2,3,4a,5,6,7,7a,8-octahydropyrrolo
[3’,4’:5,6]thiopyrano[2,3-d]thiazol-8-yl)phenyl benzoate (5c). Beige crystals,
yield ¼ 30%, m.p 220 ꢂC; ꢀmax/cmꢀ1 (KBr) 1728 (CO), 1682 (CO), 1598
1
(CO); H NMR (DMSO-d6) d: 3.82 (s, 3H, OCH3), 4.12 (dd, 1H, J ¼ 8.7,
6 Hz, H-6), 4.72 (d, 1H, J ¼ 6 Hz, H-5), 5.18 (d, 1H, J ¼ 8.7 Hz, H-7),
6.65–6.68 (m, 2H, Ar), 6.95–7.62 (m, 14H, Ar), 7.64–8.18 (m, 2H, Ar); 13C
NMR (DMSO) d ¼ 55.3, 108.3, 114.2, 114.3, 121.9, 122.9, 123.7, 127.8, 127.8,
128.7, 128.8, 129.0, 129.3, 129.4, 129.6, 130.4, 133.9, 134.2, 134.3, 150.2,
159.1, 164.4, 168.7, 173.5, 173.6; m/z ¼ 621 (Mþþ1, 1.25%), 620 (Mþ,
3.11%), 587 (1.76%), 560 (3.46%), 515 (0.3%), 417 (6.1%), 383 (3.1%), 296
(1.9%), 223 (0.34%), 203 (5.3%), 188 (1.8%), 134 (1.2%), 121 (2.0%), 105
(100%), 89 (0.9%), 77 (33.26%); Anal. Calcd for C34H24N2O6S2: C, 65.79; H,
3.90; N, 4.51; S, 10.33. Found: C, 65.97; H, 3.73; N, 4.73; S, 10.51%.

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N. HANAFY METWALLY ET AL.
Preparation of cycloadducts 7a–d, 8
General procedure
To each of 3a-b (0.01 mol) in glacial acetic acid (20 mL) was added acrylonitrile 6a or
ethyl acrylate 6b (0.01 mol). The mixture was refluxed till decolorization took place,
then it was left overnight at room temperature. The solid was filtered off and recrystal-
lized from ethanol–dioxane mixture.
4
-(6-Cyano-2-oxo-3-phenyl-3,5,6,7-tetrahydro-2H-thiopyrano[2,3-d]thiazol-7-yl)phenyl
benzoate (7a). Beige crystals, yield =50%, m.p 180 ꢂC; ꢀmax/cmꢀ1 (KBr) 2240
1
(CN), 1745 (CO), 1625 (CO); H NMR (DMSO-d6) d: 3.75–3.81 (m, 2H, H-5), 4.0
(t, 1H, J ¼ 5.4 Hz, H-6), 4.5 (d, 1H, J ¼ 5.4 Hz, H-7), 7.39–8.16 (m, 14H, Ar); 13C
NMR (DMSO) d ¼ 103.4, 118.0, 121.7, 122.0, 124.1, 128.0, 128.7, 129.2, 129.5,
130.2, 133.8, 135.5, 150.3, 164.2, 168.3; m/z ¼ 471 (Mþþ1, 2.7%), 470 (Mþ, 8.7%),
417 (7.1%), 357 (1.0%), 295 (7.5%), 279 (2.1%), 251 (1.4%), 191 (2.1%), 159
(1.5%), 132 (2.6%), 105 (100%), 88 (4.3%), 77 (39.2%); Anal. Calcd for
C26H18N2O3S2: C, 66.36; H, 3.86; N, 5.95; S, 13.63. Found: C, 66.20; H, 3.67; N,
6.18; S, 13.81%.
3
-Phenyl-3,5,5a,11b-tetrahydro-2H,6H-chromeno[4’,3’:4,5]thiopyrano[2,3-d]thiazole-2,6-
dione (8). Beige crystals, yield =83%, m.p 234–236 ꢂC; ꢀmax/cmꢀ1 (KBr) 3447 (NH2),
1
1767 (CO), 1671 (CO); H NMR (DMSO-d6) d: 3.47 (d, 2H, J¼ 3.6 Hz, H-5), 4.03 (m,
1H, H-6), 4.46 (d, 1H, J¼ 6.0 Hz, H-7), 7.16–7.53 (m, 9H, Ar); Anal. Calcd for
C19H13NO3S2: C, 62.11; H, 3.57; N, 3.81; S, 17.45, Found: C, 62.29; H, 3.40; N, 3.61;
S, 17.64%.
General procedure of 9a,b and 10
A solution of equimolecular amounts (0.01 mol) of 3a–c, malononitrile in ethanol (100 mL)
and few drops of triethylamine was refluxed for 1 h, then left at room temperature. The
solid product so obtained was filtered off and crystallized from acetic acid.
4 -(5-Amino-6-cyano-2-oxo-3-phenyl-3,7-dihydro-2H-thiopyrano[2,3-d]thiazol-7-yl)-2-
methoxyphenyl benzoate (9b)
Beige crystals, yield =39%, m.p 200 ꢂC; ꢀmax/cmꢀ1 (KBr) 3452 (NH2), 2243 (CN), 1680
1
(CO), 1595 (CO); H NMR (DMSO-d6) d: 3.80 (s, 3H, OCH3), 4.46 (s, 1H, H-7),
6.92–8.14 (m, 15H, Ar and NH2); 13C NMR (DMSO) d ¼ 55.8, 72.1, 105.7, 111.8, 117.3,
118.5, 119.2, 123.3, 128.1, 128.6, 128.8, 129.6, 129.66, 129.7, 133.6, 133.8, 138.7, 141.2,
150.9, 151.2; Anal. Calcd for C27H19N3O4S2: C, 63.14; H, 3.73; N, 8.18; S, 12.48, Found:
C, 63.33; H, 3.56; N, 8.41; S, 12.31%.

R
SYNTHETIC COMMUNICATIONSV
13
5 -Amino-3-phenyl-3,11b-dihydro-2H,6H-chromeno[4',3':4,5]thiopyrano[2,3-d]thiazole-
2,6-dione (10)
Beige crystals, yield =43%, m.p 280 ꢂC; ꢀmax/cmꢀ1 (KBr) 3447 (NH2), 1767 (CO), 1671
1
(CO); H NMR (DMSO-d6) d: 4.40 (s, 1H, H-7), 7.08–7.61 (m, 11H, Ar and NH2);
Anal. Calcd for C19H12N2O3S2: C, 59.99; H, 3.18; N, 7.36; S, 16.85. Found: C, 59.81; H,
3.35; N, 7.59; S, 16.68%.
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