An efficient synthesis of novel spiro[indole-3,8′-pyrano[2,3-d][1,3,4]thiadiazolo[3,2-a]pyrimidine derivatives via organobase-catalyzed three-component reaction of malononitrile, isatin and heterocyclic-1,3-diones

Article abstract of DOI:10.1080/17415993.2021.1944144

In this research, firstly, some derivatives of sulfur containing [1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one have been synthesized and then they were used for the synthesis of novel derivatives of 6′-amino-2,9′-dioxo-2′-phenyl-9′H-spiro[indoline-3,8′-pyrano[2,3-d][1,3,4]thiadiazolo[3,2-a]pyrimidine]-7′-carbonitriles via a one-pot three-component condensation reaction of 7-hydroxy-2-phenyl-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one derivatives, malononitrile and isatin compounds in the presence of DABCO as a organocatalyst and under solvent-free conditions. In this report, a new family of spiro-pyrano-thiadiazolo-pyrimidine derivatives have been synthesized in short reaction times (10–60 min) and good to excellent yields (80–96%). The structures of all synthesized products have been confirmed by IR, ¹H NMR, ¹³C NMR and mass spectrometry, and the structure of one selected product was characterized by single-crystal X-ray diffraction studies as well.

Full text of DOI:10.1080/17415993.2021.1944144

Journal of Sulfur Chemistry
ISSN: (Print) (Online) Journal homepage: https://www.tandfonline.com/loi/gsrp20
An efficient synthesis of novel spiro[indole-3,8′-
pyrano[2,3-d][1,3,4]thiadiazolo[3,2-a]pyrimidine
derivatives via organobase-catalyzed three-
component reaction of malononitrile, isatin and
heterocyclic-1,3-diones
Saedehsadat Hosseini, Abbas Ali Esmaeili, Amir Khojastehnezhad & Behrouz
Notash
To cite this article: Saedehsadat Hosseini, Abbas Ali Esmaeili, Amir Khojastehnezhad
& Behrouz Notash (2021): An efficient synthesis of novel spiro[indole-3,8′-pyrano[2,3-d]
[1,3,4]thiadiazolo[3,2-a]pyrimidine derivatives via organobase-catalyzed three-component
reaction of malononitrile, isatin and heterocyclic-1,3-diones, Journal of Sulfur Chemistry, DOI:
10.1080/17415993.2021.1944144
To link to this article: https://doi.org/10.1080/17415993.2021.1944144
Published online: 24 Jun 2021.
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JOURNAL OF SULFUR CHEMISTRY
https://doi.org/10.1080/17415993.2021.1944144
An efficient synthesis of novel spiro[indole-3,8ꢀ-pyrano[2,3-
d][1,3,4]thiadiazolo[3,2-a]pyrimidine derivatives via
organobase-catalyzed three-component reaction of
malononitrile, isatin and heterocyclic-1,3-diones
Saedehsadat Hosseinia, Abbas Ali Esmaeili a, Amir Khojastehnezhad a and
Behrouz Notashb
aDepartment of Chemistry, Faculty of Science, Ferdowsi University of Mashhad, Mashhad, Iran; bDepartment
of Inorganic Chemistry and Catalysis, Shahid Beheshti University, Tehran, Iran
ABSTRACT
ARTICLE HISTORY
Received 17 April 2021
Accepted 10 June 2021
In this research, firstly, some derivatives of sulfur containing
[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one have been synthesized and
then they were used for the synthesis of novel derivatives of 6ꢀ-
amino-2,9ꢀ-dioxo-2ꢀ-phenyl-9ꢀH-spiro[indoline-3,8ꢀ-pyrano[2,3-d]
[1,3,4]thiadiazolo[3,2-a]pyrimidine]-7ꢀ-carbonitriles via a one-pot
three-component condensation reaction of 7-hydroxy-2-phenyl-
5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one derivatives, malononi-
trile and isatin compounds in the presence of DABCO as a organocat-
alyst and under solvent-free conditions. In this report, a new family
of spiro-pyrano-thiadiazolo-pyrimidine derivatives have been syn-
thesized in short reaction times (10–60 min) and good to excellent
yields(80–96%). Thestructuresofallsynthesizedproductshavebeen
confirmed by IR, 1H NMR, 13C NMR and mass spectrometry, and the
structure of one selected product was characterized by single-crystal
X-ray diffraction studies as well.
KEYWORDS
7-hydroxy-2-phenyl-5H-
[1,3,4]thiadiazolo[3,2-
a]pyrimidin-5-one;
spirooxindole;
thiadiazolopyrimidine;
organobase-catalyzed;
multi-component reactions
CONTACT Abbas Ali Esmaeili
abesmaeili@um.ac.ir
Supplemental data for this article can be accessed here. https://doi.org/10.1080/17415993.2021.1944144
© 2021 Informa UK Limited, trading as Taylor & Francis Group

2
S. HOSSEINI ET AL.
1. Introduction
Recently, one of the main challenges in organic synthesis and medicinal chemistry is
the synthesis of novel heterocyclic systems with potential of biological activity [1–3].
Until now, different approaches have been developed for the synthesis of these valuable
compounds [4–7]. Among them, multicomponent reactions (MCRs) have emerged as a
powerful tool for the synthesis of a wide variety of biologically active heterocyclic com-
pounds and provide significant advantages over traditional methods such as high efficiency,
high selectivity, straightforward reaction design, mild reaction condition, environmental
friendliness and high atom economy [8–10]. These reactions in which several easily avail-
able starting materials combine into a single synthetic operation to form complex organic
structures that are widely used in chemicals and pharmaceuticals [11–17]. Also, during
the past decade, solvent-free reactions have been attracted widespread retention, because
they are in agreement with principle of green and sustainable chemistry [18–22]. Hence,
development and design of efficient and green approaches for synthesis of new biological
compounds is the endless task for chemists and pharmacists.
It is well known that spirooxindole compounds are considered as attractive synthetic
targets in organic chemistry due to the unique conformational and interesting three-
dimensional structural features that are existed in a couple of bioactive compounds as well
as naturally occurring substances [23–25]. In addition, these valuable materials have big
potential in synthetic medicinal chemistry owing to their privileged scaffolds and various
biological activities and pharmacological properties including antimalarial, antimicro-
bial, antifungal, antitubercular, antioxidant, and anticancer activities [26–29]. Besides, the
spiropyran heterocyclic compounds are a core of a wide variety of biologically active com-
pounds and extensively found in nature and show different physiological applications such
as anticancer [30], antimicrobial [31], antibacterial [32,33], and antifungal activities [34].
Representative examples of naturally obtained spirooxindoles are the NITD609 (antibac-
terial agent, Figure 1, I) [35], the MDM2-P53 interaction inhibitor (Figure 1, II) [36], and
MI-77301 (anticancer activity, Figure 1, III) [37].
On the other hand, the heterocyclic systems including pyrimidine ring display inter-
esting biological properties such as antimicrobial, antibacterial, antifungal, antiviral, anti-
cancer activities [38–44], and additionally, high biological activity was also discovered at
annulated derivatives of pyrimidine. On this basis, thiazolopyrimidine derivatives exhibit a
bunch range of biological and pharmaceutical activities such as antibacterial [45], antimi-
crobial [46], anti-inflammatory [47, 48], antihypertensive [49], antinociceptive [50], and
anticancer [51]. For example, the compounds IV and V have been used as anti-HIV-1
and anti-cancer drugs (Figure 1, IV an
d V) [52,53]. Thereby, based on these excellent and
diverse applications of spirooxindole and thiazolopyrimidine heterocyclic compounds, the
development and introduction of new approaches for the synthesis of these molecules is a
pressing need in modern chemistry [54,55].
Thus, in continuation of our extensive attempts for the synthesis of novel het-
erocyclic molecules from readily available starting materials [56–63] in this study,
firstly, some [1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one derivatives (3a-d) have been syn-
thesized based on heteroatom chemistry (Scheme 1) and then, they were employed for
the synthesis of novel 6ꢀ-amino-2,9ꢀ-dioxo-2ꢀ-phenyl-9ꢀH-spiro[indoline-3,8ꢀ-pyrano[2,3-
d][1,3,4]thiadiazolo[3,2-a]pyrimidine]-7ꢀ-carbonitrile derivatives (6a-q) via a one-pot

JOURNAL OF SULFUR CHEMISTRY
3
Figure 1. Selected biologically active compounds containing spirooxindole and thiazolopyrimidine
moiety.
Scheme 1. Synthesis of 7-hydroxy-2-phenyl-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one (3a-d).
Scheme 2. Synthesis of 6ꢀ-amino-2,9ꢀ-dioxo-2ꢀ-phenyl-9ꢀH-spiro[indoline-3,8ꢀ-pyrano[2,3-d][1,3,4]
thiadiazolo[3,2-a]pyrimidine]-7ꢀ-carbonitrile derivatives (6a-q).
three-component reaction of different 7-hydroxy-2-phenyl-5H-[1,3,4]thiadiazolo[3,2-
a]pyrimidin-5-one (3a-d), isatin derivatives (4a-k), and malononitrile (5) in the pres-
ence of DABCO under solvent-free conditions. To the best of our knowledge, this is
the first report for the synthesis of this kinds of products using 7-hydroxy-2-phenyl-
5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one as an effective heterocyclic 1,3-dicarbonyl
compound (Scheme 2).

4
S. HOSSEINI ET AL.
2. Results and discussions
At the outset and to find the optimized reaction conditions, the three-component reac-
tion of heterocyclic-1,3-dione (3a), isatin (4a), and malononitrile (5) was selected as a
model reaction to synthesis of product 6a (Table 1). Then, in the first experiment, the
model reaction has been performed in the absence of catalyst under solvent-free condi-
tion at 100°C. The yield of the reaction was trace even after 24 h running the reaction
(Table 1, entry 1). Afterwards and in the second experiment, the model reaction was
examined in different catalysts including K2CO3, pipyridine, N,N-dimethylaminopyridine
(DMAP), 1,8-diazabicyclo[5.4.0]-undec-7-ene (DBU), diisopropylethylamine (DIPEA)
and 1,4-diazabicyclo[2.2.2]octane (DABCO) (Table 1, entries 2–7). The highest yield of
product 6a was obtained in the presence of DABCO as a Lewis basic catalyst (Table 1,
entry 7). After finding the best catalyst, in the next experiment, its amount has been opti-
mized (Table 1, entries 7–9). Surprisingly, the highest amount of product 6a was prepared
in the presence of 10 mol% of DABCO (93%) and the yields of the reaction were decreased
to 85 and 87% in the lower and upper amount of DABCO, respectively (Table 1, entries 8
and 9). Evaluation of the effect of solvent was the next experiment. As a result, the model
reaction was carried out in the presence of different polar and nonpolar solvents like H2O,
EtOH, MeOH, MeCN, THF and DMF, and more importantly solvent-free condition (Table
1, entries 1–15). Among these, the best condition was solvent-free in term of yield and time
of the reaction. The last experiment was the optimization of temperature. So, the model
reaction was tested in various temperatures including 80°C, 100°C and 120°C (Table 1,
entries 16 and 17). 100°C was the best temperature and with decrease the temperature to
Table 1. Optimization of reaction conditions for the synthesis of compound 6a.
Entry
Catalyst (mol%)
Condition
Temperature (°C)
Yield (%)a
Time (h)
1
2
3
4
5
6
7
8
–
Solvent-free
Solvent-free
Solvent-free
Solvent-free
Solvent-free
Solvent-free
Solvent-free
Solvent-free
Solvent-free
H2O
EtOH
MeOH
MeCN
THF
DMF
Solvent-free
Solvent-free
100
100
100
100
100
100
100
100
trace
86
47
89
57
85
93
85
87
52
84
85
86
82
84
82
93
24
5.0
2.0
4.0
2.0
K2CO3
Bipyridine
DMAP
DBU
DIPEA
DABCO (10)
DABCO (5)
DABCO (20)
DABCO (10)
DABCO (10)
DABCO (10)
DABCO (10)
DABCO (10)
DABCO (10)
DABCO (10)
DABCO (10)
3.0
25 (min)
25 (min)
25 (min)
3.0
1.0
2.0
7.0
1.0
1.0
25 (min)
25 (min)
9
100
10
11
12
13
14
15
16
17
reflux
reflux
reflux
reflux
reflux
80
80
120
aIsolated yield.

JOURNAL OF SULFUR CHEMISTRY
5
80°C, the yield of the reaction was reduced to 82 after 25 min running the reaction (Table
1, entry 16). Therefore, the optimized reaction condition for the synthesis of product 6a
was the use of 10 mol% DABCO under solvent-free condition at 100°C (Table 1, entry 7).
Thereupon, the scope of the reaction has been investigated for the synthesis of a number
of spiro-pyrano-thiadiazolo-pyrimidine derivatives (6a-q) via a one-pot three-component
condensation reaction of different 1,3-dicarbonyl compounds (3a-d), various isatin deriva-
tives (4a-k), and malononitrile (5) under solvent-free condition at 100°C (Table 2). All
Table 2. Synthesis of different 6ꢀ-amino-2,9ꢀ-dioxo-2ꢀ-phenyl-9ꢀH-spiro[indoline-3,8ꢀ-pyrano[2,3-
d][1,3,4]thiadiazolo[3,2-a]pyrimidine]-7ꢀ-carbonitrile derivatives 6a-q.a
aReaction condition: 7-hydroxy-2-phenyl-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one derivatives 3a-d (1.0 mmol), isatin
derivatives 4a-k (1.0 mmol), malononitrile 5 (1.2 mmol) and DUBCO (10 mol%) at 100°C under solvent-free condition

6
S. HOSSEINI ET AL.
Scheme 3. Proposed mechanism for the synthesis of spiro-pyrano-thiadiazolo-pyrimidine derivatives
in the presence of DABCO as a Lewis base catalyst.
isatin derivatives and heterocyclic1,3-diones with electron-withdrawing and electron-
donating groups gave the desired products with high yields (80–96%) in short reaction
times (10 to 60 min) (Table 2).
To better understanding the reaction mechanism and effect of DABCO as a Lewis base
catalyst on this reaction [64], a plausible mechanism has been proposed for the synthe-
sis of spiro-pyrano-thiadiazolo-pyrimidine derivatives (Scheme 2). As can be seen in this
scheme, in the first step, from the condensation reaction of isatin (4) and malononitrile
(5), the intermediate (A) was formed. On the other hand, the DABCO can act as a strong
nucleophile and attacks to heterocyclic-1,3dione (3) to produce the active intermediate
(B). Next, this active intermediate is ready to react with intermediate (A) via Michael
addition to generate the intermediate (C). Finally, after remove the DABCO and 6-exo-
dig-cyclization reaction of intermediate (C) and (D), respectively, the desired product (6)
was generated (Scheme 3).
An ORTEP diagram of 6c characterized by single crystal X-ray analysis (Figure 2). As
depicted in this figure, the chemical structure and the stereochemistry of product 6c con-
firmed successfully (CCDC 1527745): C30H20N6O3S: MW = 545. For more information
about X-ray crystallographic data of compound 6c, please see the supporting file.
3. Conclusion
In summary, in this study an efficient and fast procedure has been described for the
synthesis of novel derivatives of spiro-pyrano-thiadiazolo-pyrimidine through one-pot
three-component assembly of isatin derivatives, malononitrile, and some heterocyclic-1,3-
dione in the presence of DABCO as a catalyst and under solvent-free condition. Simple and
fast synthetic procedure, short reaction times, high to excellent isolated yields and carry
out the reactions without using any hazardous solvents are the most advantages of present
research.

JOURNAL OF SULFUR CHEMISTRY
7
Figure 2. ORTEP structures of compound 6c.
4. Experimental
4.1. Materials
All the starting materials have been purchased from Sigma-Aldrich and Merck companies
without any further purification. Melting points were recorded on an Electrothermal-type
9100 melting point apparatus and are uncorrected. The IR spectra were obtained on an
Avatar 370 FT-IR Thermo-Nicolet spectrometer. 1H and 13C NMR spectra were run on
BRUKER DRX-300 AVANCE spectrometer at 300 for 1H NMR, and 75 MHz for 13C NMR
DMSO-d6 was used as solvent. The mass spectra were scanned on a Varian Mat CH-7
at 70 eV. Elemental analysis was performed on a Thermo Finnigan Flash EA microanal-
yser. X-ray crystal structure data were collected on a Bruker D8 VENTURE PHOTON 100
CMOS diffractometer with graphite monochromated Cu Kα radiation at 296(2) K. Isatin
derivatives were prepared by known methods [65,66].
4.2. Typical procedure for the synthesis of heterocyclic-1,3dione (3)
In order to synthesis of compound 3, initially, the enamine 1 was prepared according to the
following procedure; 9.0 mL trifluoroacetic acid was added to a mixture of 3.0 g thiosemi-
carbazide and 3.06 g benzonitrile derivatives, and then the mixture was refluxed at 75°C for
6 h. After completion the reaction, the reaction was permitted to cool to room temperature
and next, 10 mL ammonium hydroxide solution was added droppingly and the mixture was
stirred constantly. The formed resulting precipitate was separated from the reaction mix-
ture by simple filtration and washed many times with hot EtOH and after recrystallization
with EtOH, it was dried in vacuum oven to afford the enamine 1 [67]. Afterwards, in order

8
S. HOSSEINI ET AL.
to synthesis of heterocyclic-1,3-dione, the prepared enamine 1 (5.0 mmol) was added to
a solution of bis(2,4,6-trichlorophenyl) malonate 2 (5.0 mmol) in 10 mL acetone and this
mixture was stirred at room temperature for 3 h. After completion the reaction the result-
ing precipitate has been separated from the reaction mixture by simple filtration and finally
it was recrystallized with the mixture of chloroform/ethanol (10:10 mL) to afford the final
product of heterocyclic-1,3-dione (3).
Spectral data for compound (3):
White powder; Mp: 274–277°C, 0.2 g, yield 81%; Rf (1:1 n-hexane/EtOAc) 0.68; IR (KBr)
1
(υmax/cm–1): 3076, 2869, 2745, 2657, 2568, 2504 (OH), 1661.38 (1C=O); H NMR
(300.84 MHz, DMSO-d6): δ (ppm): 5.44 (1H, s, CH), 7.58–7.67 (3H, m, CHarom), 7.93 (2H,
d, 3JH,H = 6.016 Hz, CHarom), 11.95 (1H, br, s, OH); 13C NMR (75.65 MHz, DMSO-d6):
δ (ppm): 86.10 (CH– C=O), 127.64, 128.72, 130.03 (5CHarom of phenyl), 133.07 (Carom),
157.93 (N=C–N), 157.24 (N–C =O), 168.39 (N–C–OH), 162.35 (N=C–S); MS: (m/z,
%), 245 (M+, 28), 242, (100), 202 (99), 120 (88), 104 (87), 77 (92), 69 (95), 51 (87), 39 (49),
29 (87).
4.3. Typical procedure for the spiro-pyrano-thiadiazolo-pyrimidine derivatives
4a-q
A mixture of heterocyclic-1,3-diones 3a-d (1.0 mmol), isatin derivatives 4a-k (1.0 mmol)
and malononitrile 5 (1.2 mmol) was stirred under solvent-free condition at 100°C for 10 to
60 min. The progress of the reaction was monitored by TLC. After finalization of the reac-
tion, the reaction mixture was cooled to room temperature and thereafter the precipitated
product was separated from the reaction mixture by simple filtration and washed three
times with EtOH (20 mL). The obtained crude products were more purified by crystalliza-
tion (EtOH) to afford the final product 6a-q. The structures of all synthesized products have
been confirmed by IR, 1H NMR, 13C NMR, mass spectrometry, CHN analysis, and also a
structure of one selected product has been characterized by single-crystal X-ray diffraction
studies as well.
The chemical structure of all prepared products have been characterized with mass, FT-
IR, 1H NMR, 13C NMR, and CHN analysis (see Supporting Information). For example, the
1H NMR spectrum of product (6a) exhibited two doublet and two triplet with four protons
for the protons related to isatin ring at δ = 687–7.22, a singlet with two protons for NH2 at
δ = 7.49, one multiplet (3H) and one doublet (2H) for the protons related to phenyl ring
of thiadiazolopyrimidine moiety at δ = 7.60–792, and finally a singlet with one proton for
NH at δ = 10.66. Moreover, the FT-IR was another analysis to approve the structures of all
synthesized products. In this regard, the IR absorption peak at 3429 cm−1 is assigned to the
NH group, the peak at 2197 cm−1 is belongs to CN moiety and the peaks at 1723 and 1698
are attributed to the C=O functional groups. In addition, the carbon NMR spectrum of 6a
showed 20 distinct C NMR signal particularly carbonyls at δ = 158.9 and 177.8 ppm and
cyanide at δ = 117.8 ppm. Besides, the mass spectrometry of all synthesized compounds
exhibited the molecular ion peaks at relevant m/z values.
Spectral data for compound (6a):
Gray powder; Mp: 300°C, 0.41 g, yield 93%; Rf (1:3 n-hexane/EtOAc) 0.42; FT-IR (KBr)
(υmax/cm−1): 3649, 3429, 3313, 3289, 3186, 2197 (CN), 1723, 1698 (2 C=O); 1H NMR

JOURNAL OF SULFUR CHEMISTRY
9
(300.84 MHz, DMSO-d6): δ (ppm): 10.66 (s, 1H, NH), 7.92 (d, 2H, 3JHH = 6.9 Hz, HAr),
3
7.71-7.60 (m, 3H, HAr), 7.49 (s, 2H, NH2), 7.22 (t, 1H, JHH = 7.4 Hz, HAr), 7.10 (d,
1H, 3JHH = 7.2 Hz, HAr), 6.94 (t, 1H, 3JHH = 7.5 Hz, HAr), 6.87 (d, 1H, 3JHH = 7.5 Hz,
HAr); 13C NMR (75.65 MHz, DMSO-d6): δ (ppm): 48.7 (Cspiro), 57.0 (=C-CN), 96.5
(=C-C=O), 109.8 (CHAr), 117.8 (CN), 122.3, 124.4, 127.8, 128.3, 129.1, 130.1 (8 CHAr),
133.5, 133.7, 142.7 (3 CAr), 154.8 (N-C =N), 158.9 (C=O), 159.6 (=C-NH2), 159.9 (N-
N=C), 161.9 (CO-C=C-O), 177.8 (C=Oisa); MS: (m/z, %), 441 (M+, 21), 194 (100), 28
(99), 202 (97), 77 (78), 167 (74), 243 (73), 103 (72), 139 (62), 334 (42), Anal. Calcd for
C22H12N5O3S(440.43): C,60.00; H, 2.75; N,19.08%. Found: C, 60.28; H, 3.03; N, 18.95%.
Spectral data for compound (6b):
Milky powder; Mp: 300°C, 0.42 g, yield 94%; Rf (1:3 n-hexane/EtOAc) 0.37; FT-IR
(KBr)(υmax/cm−1): 3426, 3358, 3325, 3293, 3248, 3198, 3023, 2194 (CN), 1731, 1690 (2
1
C=O); H NMR (300.84 MHz, DMSO-d6): δ (ppm): 10.65 (s, 1H, NH), 7.82 (d, 2H,
3JHH = 7.8 Hz, HAr), 7.48–7.43 (m, 4H, HAr, NH2), 7.21 (t, 1H, 3JHH = 7.7 Hz, HAr), 7.10
(d, 1H, 3JHH = 7.5 Hz, HAr), 6.93 (t, 1H, 3JHH = 7.5 Hz, HAr), 6.86 (d, 1H,3JHH = 7.8 Hz,
HAr), 2.41 (s, 3H, CH3); 13C NMR (75.65 MHz, DMSO-d6): δ (ppm): 21.6 (CH3), 48.7
(Cspiro), 57.0 (=C-CN), 96.4(=C-C=O), 109.7 (CHAr), 117.7 (CN), 122.3, 124.4, 125.6,
127.7, 129.0 (7 CHAr), 130.7, 133.7, 142.7, 144.0 (4 CAr), 154.8 (N-C=N), 158.8 (C=O),
159.6 (=CNH2), 159.8 (N-N=C), 161.8 (CO-C=C-O), 177.8 (C=O isa); MS: (m/z, %),
453 (M+, 5), 206 (100), 28 (97), 116 (57),192 (57), 133 (46), 331 (43), 215 (33), 65 (20),
Anal. Calcd for C23H14N6O3S (365.06): C, 60.79; H, 3.11; N,18.49%. Found: C, 60.62; H,
2.94; N, 18.65%.
Spectral data for compound (6c):
White powder; Mp: 300°C, 0.51 g, yield 94%; Rf = 0.53 (1:3 n-hexane/EtOAc); FT-IR
(KBr)(υmax/cm−1): 3485, 3381, 3183, 3060, 3036, 2917, 2200 (CN), 1710, 1654 (2 C=O),
1H NMR (300 MHz, DMSO-d6): δ (ppm): 7.83 (d, 2H,3JHH = 8.1 Hz, HAr), 7.58–7.52
(m, 4H, HAr, NH2), 7.44 (d, 2H, 3JHH = 8.1 Hz, HAr), 7.38–7.29 (m, 3H, HAr), 7.23–7.19
3
3
(m, 2H, HAr), 7.00 (t, 1H, JHH = 7.5 Hz, HAr), 6.79 (d, 1H, JHH = 7.5 Hz, HAr), 5.04
(1H, d,2JHH = 16.2 Hz, PhCHAHB), 4.94 (1H, d,2JHH = 15.9 Hz, PhCHAHB), 2.41 (s, 3H,
CH3);13C NMR (75 MHz, DMSO-d6): δ (ppm): 21.6 (CH3), 44.0 (Cspiro), 48.5 (CH2), 56.7
(=C-CN), 96.3 (=C-C=O), 109.4 (CN), 117.8, 123.2, 124.3, 125.6, 127.6, 127.7, 127.8,
128.9, 129.1 (13CHAr), 130.7, 132.9, 136.5, 143.3 (4 CAr), 144.1 (N-C=N), 154.9 (C=O),
158.9 (CAr), 159.7 (=CNH2), 160.0 (N-N=C), 162.0 (CO-C=C-O), 176.5 (C=Oisa);
MS: (m/z, %), 544 (M+, 19), 90 (100), 280 (78), 64 (75), 253 (72), 451 (72), 39 (71), 215 (70),
116 (51), 133 (39). Anal. Calcd for C30H20N6O3S (544.59): C, 66.17; H, 3.70; N, 15.43%.
Found: C, 66.30; H, 3.54; N, 15.25%.
Spectral data for compound (6d):
White powder; Mp: 300°C, 0.42 g, yield 89%; Rf (1:3 n-hexane/EtOAc) 0.47; FT-IR
(KBr)(υmax/cm−1): 3497, 3377, 3186, 3052, 3031, 2974, 2880, 2202 (CN), 1714, 1657 (2
C=O), 1H NMR (300 MHz, DMSO-d6): δ (ppm): 7.79 (d, 2H,3JHH = 7.8 Hz, HAr), 7.55
3
3
(s, 2H, NH2), 7.42 (d, 2H, JHH = 7.8 Hz, HAr), 7.33 (t, 1H, JHH = 7.7 Hz, HAr), 7.16
3
(d, 1H, JHH = 7.5 Hz, HAr), 7.10-7.00 (m, 2H, HAr), 3.23 (s, 3H, N-CH3), 2.40 (s, 3H,
CH3); 13C NMR (75 MHz, DMSO-d6): δ (ppm): 21.6 (CH3), 27.0 (N-CH3), 48.3 (Cspiro),
56.5 (=C-CN), 96.4 (=C-C=O), 108.7 (CHAr), 117.6 (CN), 123.0, 124.1, 125.6, 127.7,
129.3 (7 CHAr), 130.7, 132.9, 144.1, 144.3 (CAr), 154.7 (N-C=N), 158.7 (C=O), 159.6

10
S. HOSSEINI ET AL.
(=CNH2), 160.0 (N-N=C), 161.9 (CO-C=C-O), 176.3 (C=O isa); MS: (m/z, %), 468
(M+, 12), 206 (100), 220 (93), 28 (90), 152 (74), 255 (73), 116(56), 90(50), 133(42), 467(37),
Anal. Calcd for C24H16N6O3S (468.48): C, 61.53; H, 3.44; N, 17.94%. Found: C, 61.62; H,
3.24; N, 18.15%.
Spectral data for compound (6e):
White powder; Mp: 300°C, 0.45 g, yield 94%; Rf (1:3 n-hexane/EtOAc) 0.48; FT-IR
(KBr)(υmax/cm−1): 3489, 33.77, 3190, 3064, 3032, 2984, 2937, 2880, 2199 (CN), 1709, 1656
(2 C=O); 1H NMR (300.84 MHz, DMSO-d6): δ (ppm): 7.80 (d, 2H,3JHH = 7.8 Hz, HAr),
7.53 (s, 2H, NH2), 7.41 (d, 2H, 3JHH = 7.8 Hz, HAr), 7.32 (t, 1H, 3JHH = 7.5 Hz, HAr), 7.17
(d, 1H, 3JHH = 7.2 Hz, HAr), 7.12 (d, 1H, 3JHH = 7.8 Hz, HAr), 7.01 (t, 1H, 3JHH = 7.4 Hz,
HAr), 3.80 (q, 2H, 3JHH = 13.8 Hz,3JHH = 6.9 Hz,CH2-CH3), 2.39 (s, 3H, CH3), 1.24 (t,
3H,3JHH = 6.9 Hz, CH2-CH3); 13C NMR (75.65 MHz, DMSO-d6): δ (ppm): 17.5 (CH2-
CH3), 26.3 (CH3), 39.8 (CH2), 53.0 (Cspiro), 61.4 (=C-CN), 101.1 (=C-C=O), 113.5
(CN), 122.3, 127.6, 129.0, 130.3, 132.5, 134.0 (8 CHAr), 135.4, 137.9, 147.9 (3CAr), 148.9
(N-C=N), 159.5 (C=O), 163.5 (CAr), 164.3 (=CNH2), 164.7 (CO-C=C-O), 166.6 (N-
N=C), 180.5 (C=O isa); MS: (m/z, %), 483 (M+, 52), 206 (100), 221 (72), 454 (69), 29 (68),
426 (42), 117 (38), 179 (36), 91 (29), 256 (15), Anal. Calcd for C25H18N6O3S (482.51): C,
62.23; H, 3.76; N, 17.42%. Found: C, 62.12; H, 3.94; N, 17.65%.
Spectral data for compound (6f):
Gray powder; Mp: 298°C, 0.39 g, yield 87%; Rf (1:3 n-hexane/EtOAc) 0.34; FT-IR
(KBr)(υmax/cm−1): 3649, 3427, 3317, 3289, 3187, 2913, 2860, 2200 (CN), 1724, 1699
1
(2 C=O); H NMR (300.84 MHz, DMSO-d6): δ (ppm): 10.56 (s, 1H, NH), 7.92 (d,
3
2H, JHH = 6.6 Hz, HAr), 7.71-7.60 (m, 3H, HAr), 7.48 (s, 2H, NH2), 7.02 (d, 2H,
3JHH = 6.0 Hz, HAr), 6.93 (s, 1H, HAr), 6.76 (d, 1H,3JHH = 7.8 Hz, HAr), 2.21 (s, 3H,
CH3); 13C NMR (75.65 MHz, DMSO-d6): δ (ppm): 21.1 (CH3), 48.7 (Cspiro), 57.2 (=C-
CN), 96.6 (=C-C=O), 109.5 (CN), 117.8, 124.9, 127.8, 128.4, 129.3, 130.2 (8 CHAr),
131.1, 133.5, 133.8, 140.3 (4CAr), 154.8 (N-C=N), 158.8 (C=O), 159.6 (=CNH2), 159.8
(N-N=C), 161.9 (CO-C=C-O), 177.7 (C=O isa); MS: (m/z, %), 455 (M+, 6), 176 (100),
207 (97), 243 (74), 28 (72), 153 (72), 126 (72), 102 (72), 66 (72), 44 (62), Anal. Calcd for
C23H14N6O3S (454.46):C, 60.70; H, 3.11; N, 18.49%. Found: C, 60.62; H, 2.94; N, 18.36%.
Spectral data for compound (6g):
White powder; Mp: 297°C, 0.45 g, yield 94%; Rf (1:3 n-hexane/EtOAc) 0.60; FT-IR
(KBr)(υmax/cm−1): 3457, 3325, 3183, 3052, 2987, 2933, 2880, 2199 (CN), 1704, 1656
1
(2 C=O); H NMR (300 MHz, DMSO-d6): δ (ppm): 7.74-7.70 (m, 2H, HAr), 7.52-
3
3
7.48 (m, 4H, HAr, NH2), 7.32 (t, 1H, JHH = 7.4 Hz, HAr), 7.17 (d, 1H, JHH = 6.3 Hz,
HAr), 7.11 (d, 1H, 3JHH = 7.82 Hz, HAr), 7.01 (t, 1H, 3JHH = 7.4 Hz, HAr), 3.80 (q, 2H,
3JHH = 14.1 Hz,3JHH = 6.9 Hz, CH2-CH3), 2.40 (s, 3H, CH3), 1.24 (t, 3H,3JHH = 6.9 Hz,
CH2-CH3); 13C NMR (75 MHz, DMSO-d6): δ (ppm): 12.7 (CH2-CH3), 21.2 (CH3), 35.0
(CH2), 48.2 (Cspiro), 56.7 (=C-CN), 96.4 (=C-C=O), 108.7 (CN), 117.5, 122.8, 124.3,
125.0, 128.1, 128.3, 129.3, 130.0, (8 CHAr), 133.1, 134.2, (2CAr), 139.8 (N-C=N), 143.2
(CAr), 154.8 (C=O), 158.8 (CAr), 159.7 (=CNH2), 159.9 (CO-C=C-O), 161.9 (N-
N=C), 175.8 (C=O isa); MS: (m/z, %), 483 (M+, 23), 29 (99), 190 (97), 206 (74), 118
(81), 74 (80), 216 (68), 256 (60), 91 (51), 134 (50), Anal. Calcd for C25H18N6O3S (482.51):
C, 62.23; H, 3.76; N, 17.42%. Found: C, 62.32; H, 3.58; N, 17.15%.

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11
Spectral data for compound (6h):
Milky powder; Mp: 293°C, 0.43 g, yield 96%; Rf (1:3 n-hexane/EtOAc) 0.43; FT-IR
1
(KBr)(υmax/cm–1): 3649, 3501, 3444, 3375, 3187, 2199 (CN), 1725, 1651 (2 C=O); H
NMR (300 MHz, DMSO-d6): δ (ppm): 10.65 (s, 1H, NH),7.74-7.71 (m, 2H, HAr), 7.51-
7.49 (m, 4H, HAr, NH2), 7.22 (t, 1H, 3JHH = 7.7 Hz, HAr), 7.10 (d, 1H, 3JHH = 7.22 Hz,
3
3
HAr), 6.94 (t, 1H, JHH = 7.4 Hz, HAr), 6.87 (d, 1H, JHH = 7.5 Hz, HAr), 2.40 (s, 3H,
CH3); 13C NMR (75 MHz, DMSO-d6): δ (ppm): 21.2 (CH3), 48.7 (Cspiro), 57.0 (=C-CN),
96.5 (=C-C=O), 109.7 (CHAr), 117.7 (CN), 122.3, 124.4, 125.0, 128.2, 128.3, 129.1, 130.1
(7CHAr), 133.7, 134.2, 139.8 (3CAr), 142.8 (N-C=N), 154.8 (CAr), 158.8 (C=O), 159.7
(=CNH2), 159.8 (N-N=C), 161.9 (CO-C=C-O), 177.8 (C=O isa); MS: (m/z, %), 454
(M+, 2), 29 (100), 194 (80), 66 (57), 39 (56), 90 (50), 134 (47), 116 (33), 216 (31), 167 (31),
Anal. Calcd for C23H14N6O3S (454.46): C, 60.79; H, 3.11; N, 18.49%. Found: C, 60.82; H,
3.38; N, 18.31%.
Spectral data for compound (6i):
Milky powder; Mp: 281°C, 0.46 g, yield 95%; Rf (1:3 n-hexane/EtOAc) 0.59; FT-IR
(KBr)(υmax/cm−1): 3489, 3369, 3187, 3015, 2962, 2917, 2872, 2201 (CN), 1716, 1703 (2
1
C=O); H NMR (300.84 MHz, DMSO-d6): δ (ppm): 7.79-7.70 (m, 2H, HAr), 7.53-7.49
3
(m, 4H, HAr, NH2), 7.13 (d, 1H, JHH = 6.3 Hz, HAr), 6.99-6.95 (m, 2H, HAr), 3.20 (s,
3H, N-CH3), 2.40 (s, 3H, CH3), 2.24 (s, 3H,CH3); 13C NMR (75.65 MHz, DMSO-d6): δ
(ppm): 21.1 (CH3), 21.2 (CH3), 26.9 (N-CH3), 48.4 (Cspiro), 56.6 (=C-CN), 96.6 (=C-
C=O), 108.4 (CN), 117.7, 124.8, 125.0, 128.2, 128.3 (5 CHAr), 129.5 (CAr), 130.1, 132.0
(2 CHAr), 134.2, 139.8 (2CAr), 142.0 (N-C=N), 154.8, 158.7 (2 CAr), 159.7 (C=O), 159.9
(=CNH2), 160.0 (N-N=C), 162.0 (CO-C=C-O), 176.2 (C=O isa); MS: (m/z, %), 482
(M+, 21), 29 (100), 232 (100), 257 (51), 217 (50), 167 (36), 190 (25), 118 (22), 91 (18), 66
(15), 44 (13). Anal. Calcd for C25H18N6O3S (482.51): C, 62.23; H, 3.76; N, 19.42%. Found:
C, 62.42; H, 3.88; N, 19.15%
Spectral data for compound (6j):
Gray powder; Mp: 300°C, 0.47 g, yield 88%; Rf (1:3 n-hexane/EtOAc) 0.55; FT-IR
(KBr)(υmax/cm−1): 3481, 3448, 3352, 3268, 3183, 3068, 2198 (CN), 1743, 1724 (2 C=O);
1H NMR (300.84 MHz, DMSO-d6): δ (ppm): 10.81 (s, 1H, NH), 7.74-7.72 (m, 2H,
HAr), 7.58 (s, 2H, NH2), 7.54-7.49 (m, 2H, HAr), 7.42-7.35 (m, 2H, HAr), 6.84 (d, 1H,
3JHH = 8.1 Hz, HAr), 2.40 (s, 3H,CH3); 13C NMR (75.65 MHz, DMSO-d6): δ (ppm): 21.2
(CH3), 49.0 (Cspiro), 56.2 (=C-CN), 95.9 (=C-C=O), 111.7 (CHAr), 114.0 (CAr), 117.6
(CN), 125.0, 127.3, 128.2, 128.3, 130.1, 131.8 (6 CHAr), 134.2, 136.0 (2 CAr), 139.8 (N-
C=N), 142.1, 155.0 (2 CAr), 158.9 (C=O), 159.7 (=CNH2), 160.0 (CO-C=C-O), 162.1
(N-N=C),177.5 (C=O isa); MS: (m/z, %), 534 (M+, 3), 114 (100), 138 (90), 272 (85),
69 (83), 216 (82), 91 (80), 29 (80), 245 (78), 165 (76), Anal. Calcd for C23H13BrN6O3S
(533.36): C, 51.79; H, 2.46; N, 15.76%. Found: C, 51.82; H, 2.38; N, 15.55%.
Spectral data for compound (6k):
Gray powder; Mp: 300°C, 0.43 g, yield 89%; Rf (1:3 n-hexane/EtOAc) 0.47; FT-IR
1
(KBr)(υmax/cm−1): 3436, 3330, 3186, 3076, 3019, 2207 (CN), 1730, 1701 (2 C=O); H
NMR (300 MHz, DMSO-d6): δ (ppm): 10.80 (s, 1H, NH), 7.81 (d, 2H,3JHH = 7.8 Hz, HAr),
7.58 (s, 2H, NH2), 7.43 (d, 2H,3JHH = 7.8 Hz, HAr), 7.29-7.23 (m, 2H, HAr), 6.89 (d, 1H,
3JHH = 8.4 Hz, HAr), 2.40 (s, 3H, CH3); 13C NMR (75 MHz, DMSO-d6): δ (ppm): 21.6
(CH3), 49.0 (Cspiro), 56.2 (=C-CN), 95.9 (=C-C=O), 111.1 (CHAr), 117.6 (CN), 124.7

12
S. HOSSEINI ET AL.
(CHAr), 125.6 (CAr), 126.3, 127.7, 129.0 (5 CHAr), 130.7, 135.7, 141.7, 144.1 (4 CAr), 154.9
(N-C=N), 158.9 (C=O), 159.6 (=CNH2), 160.0 (N-N=C), 162.0 (CO-C=C-O), 177.6
(C=O isa); MS: (m/z, %), 489 (M+, 28), 227 (100), 29 (75), 257 (68), 216 (56), 190 (35),
368 (33), 118 (22), 461 (20), 66 (18), Anal. Calcd for C23H13ClN6O3S (488.90): C, 56.50;
H, 2.68; N, 17.19%. Found: C, 56.72; H, 2.36; N, 17.07%.
Spectral data for compound (6l):
Brick powder; Mp: 280 °C, 0.42 g, yield 86%; Rf (1:3 n-hexane/EtOAc) 0.46; FT-IR
(KBr)(υmax/cm−1): 3534, 3444, 3324, 3193, 2200 (CN), 1737, 1697 (2 C=O); 1H NMR
(300 MHz, DMSO-d6): δ (ppm): 11.43 (s, 1H, NH),8.23 (dd, 1H, 3JHH = 8.4 Hz,3JHH
=
3
2.4 Hz, HAr), 8.13 (d, 1H, JHH = 2.4 Hz, HAr), 7.94-7.91 (m, 2H, HAr), 7.71-7.60 (m,
3
4H, HAr, NH2), 7.11 (d, 1H, JHH = 8.4 Hz, HAr); 13C NMR (75 MHz, DMSO-d6): δ
(ppm):48.9 (Cspiro), 55.5 (=C-CN), 95.5 (=C-C=O), 110.0(CHAr), 117.5 (CN), 120.4,
126.6, 127.8, 128.3, 130.2 (7 CHAr), 133.6, 134.6 (2 CAr), 143.0 (N-C=N), 149.3 (CAr),
155.1 (C=O), 159.1 (CAr), 159.8 (=CNH2), 160.2 (N-N=C), 162.4 (CO-C=C-O), 178.5
(C=O isa); MS: (m/z, %), 486 (M+, 5), 29 (100), 196 (74), 97 (28), 202 (26), 243 (26), 131
(18), 468 (17), 208 (14), 66 (12), Anal. Calcd for C22H11N7O5S (485.43): C, 54.43; H, 2.28;
N, 20.20%. Found: C, 54.62; H, 2.44; N, 19.95%.
Spectral data for compound (6m):
White powder; Mp: 300°C, 0.49 g, yield 91%; Rf (1:3 n-hexane/EtOAc) 0.63; FT-IR
(KBr)(υmax/cm−1): 3322, 3293, 3252, 3178, 2987, 2946, 2876, 2198(CN), 1710, 1659
1
3
(2 C=O); H NMR (300.84 MHz, DMSO-d6): δ (ppm): 7.96 (d, 2H, JHH = 8.7 Hz,
HAr), 7.71 (d, 2H, JHH = 8.4 Hz, HAr), 7.62 (d, 2H, NH2), 7.35 (dd,3JHH = 2.1 Hz,
3
3JHH = 8.1 Hz,1H, HAr), 7.32 (d, 1H, 3JHH = 2.4 Hz, HAr), 7.17 (d, 1H, 3JHH = 8.4 Hz,
HAr), 3.79 (q, 3JHH = 13.8 Hz, 3JHH = 6.6 Hz, 2H,CH2), 1.21 (t, 3H,3JHH = 6.9 Hz, CH3);
13C NMR (75.65 MHz, DMSO-d6): δ (ppm): 12.6 (CH3), 35.2 (CH2), 48.4 (Cspiro), 55.9
(=C-CN), 95.9 (=C-C=O), 110.3 (CN), 117.4, 124.6, 126.9, 127.2 (6 CHAr), 129.1 (CAr),
129.6 (CHAr), 130.3, 135.0, 138.3 (3CAr), 142.1 (N-C=N), 154.9 (C=O), 158.6 (CAr),
158.9 (=CNH2), 160.0 (CO-C=C-O), 162.2 (N-N=C), 175.6 (C=O isa); MS: (m/z, %),
537 (M+, 41), 29 (92), 511 (89), 115 (31), 235 (26), 209 (20), 254 (18), 44 (11), 482 (11).
Anal. Calcd for C24H14Cl2N6O3S (537.37): C, 53.64; H, 2.63; N, 15.64%. Found: C, 53.82;
H, 2.38; N, 15.75%
Spectral data for compound (6n):
Gray powder; Mp: 300°C, 0.44 g, yield 87%; Rf (1:3 n-hexane/EtOAc) 0.30; FT-IR
(KBr)(υmax/cm−1): 3489, 3377, 3299, 3186, 3027, 2945, 2847, 2202 (CN), 1725, 1657
1
(2 C=O); H NMR (300.84 MHz, DMSO-d6): δ (ppm): 10.47 (s, 1H, NH),7.96 (d,
3
3
2H, JHH = 8.7 Hz, HAr), 7.72 (d, 2H, JHH = 8.7 Hz, HAr), 7.48 (d, 2H, NH2), 7.76
(d, 2H, JHH = 7.5 Hz, HAr), 3.67 (s, 2H,CH3); 13C NMR (75.65 MHz, DMSO-d6): δ
3
(ppm): 49.2 (Cspiro), 55.9 (CH3), 57.1 (=C-CN), 96.5 (=C-C=O), 110.1, 111.2 (2
CHAr), 113.8 (CN), 117.7, 127.3, 129.6 (5 CHAr), 130.3, 134.9, 136.0, 138.3 (4 CAr),
154.8 (N-C=N), 155.6 (C=O), 158.5 (=CNH2), 158.9 (CAr), 159.8 (N-N=C), 161.9
(CO-C=C-O), 177.6 (C=O isa); MS: (m/z, %), 505 (M+, 11), 223 (100), 29 (99),
208 (83), 236 (30), 153 (30), 136 (25), 276 (24), 66 (23), 322 (8). Anal. Calcd for
C23H13ClN6O4S (504.90): C, 54.71; H, 2.60; N, 16.65%. Found: C, 54.82; H, 2.39;
N, 16.39%

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13
Spectral data for compound (6o):
Gray powder; Mp: 300°C, 0.39 g, yield 82%; Rf (1:3 n-hexane/EtOAc) 0.43; FT-IR
1
(KBr)(υmax/cm–1): 3440, 3329, 3191, 3076, 3019, 2202 (CN), 1727, 1702 (2 C=O); H
NMR (300.84 MHz, DMSO-d6): δ (ppm): 10.81 (s, 1H, NH), 7.91 (d, 2H, 3JHH = 6.9 Hz,
HAr), 7.70-7.58 (m, 5H, HAr, NH2), 7.29-7.26 (m, 2H, HAr), 6.90 (d, 1H,3JHH = 8.1 Hz,
HAr); 13C NMR (75.65 MHz, DMSO-d6): δ (ppm): 49.0 (Cspiro), 56.3 (=C-CN), 96.0 (=C-
C=O), 111.2 (CHAr), 117.7 (CN), 124.7 (CHAr), 126.3 (CAr), 127.8, 128.3, 129.0, 130.2
(6 CHAr), 133.6, 135.7, 141.7 (3 CAr), 155.0 (N-C=N), 159.0 (C=O), 159.7 (=CNH2),
160.0 (N-N=C), 162.1 (CO-C=C-O), 177.6 (C=O isa); MS: (m/z, %), 475 (M+, 2), 29
(98), 44 (85), 66 (73), 227 (67), 36 (61), 103 (56), 201 (55), 77 (54), 121 (43), Anal. Calcd
for C22H11ClN6O3S (474.88): C, 55.64; H, 2.33; N, 17.70%. Found: C, 55.72; H, 2.14; N,
17.95%.
Spectral data for compound (6p):
Karami powder; Mp: 300°C, 0.45 g, yield 85%; Rf (1:3 n-hexane/EtOAc) 0.65; FT-
IR (KBr)(υmax/cm−1): 3464, 3329, 3174, 3064, 3027, 2913, 2202 (CN), 1705, 1653
1
(2 C=O); H NMR (300.84 MHz, DMSO-d6): δ (ppm): 7.93 (d, 2H,3JHH = 6.9 Hz,
3
HAr), 7.71–7.57 (m, 4H, HAr, NH2), 7.51 (d, 2H, JHH = 6.9 Hz, HAr), 7.37-7.26
3
(m, 3H, HAr), 7.23-7.19 (m, 2H, HAr), 7.01 (t, 1H, JHH = 7.3 Hz, HAr), 6.78
3
(d, 1H, JHH = 7.8 Hz, HAr), 5.05 (1H, d,2JHH = 16.2 Hz, phCHAHB), 4.95 (1H,
d,2JHH = 16.2 Hz, phCHAHB); 13C NMR (75.65 MHz, DMSO-d6): δ (ppm): 44.0 (Cspiro),
48.5 (CH2),56.7 (=C-CN), 96.3 (=C-C=O), 109.4 (CN), 117.8, 123.2, 124.3, 127.6,
127.7, 127.9, 128.3, 128.9, 129.2, 130.2 (14 CHAr), 132.9, 133.6, 136.5 (3 CAr), 143.3
(N-C=N), 154.9 (C=O), 158.9 (CAr), 159.7 (=CNH2), 160.0 (N-N=C), 162.1 (CO-
C=C-O), 176.6 (C=O isa); MS: (m/z, %), 531 (M+, 10), 90(100), 281 (85), 242
(78), 202 (78), 175 (78), 102 (78), 51 (78), 28 (77), 120 (63). Anal. Calcd for
C29H18N6O3S (530.56): C, 65.65; H, 3.42; N, 15.84%. Found: C, 65.62; H, 3.24;
N, 15.95%.
Spectral data for compound (6q):
Karami powder; Mp: 300°C, 0.41 g, yield 80%; Rf (1:3 n-hexane/EtOAc) 0.46;
FT-IR (KBr)(υmax/cm−1): 3599, 3468, 3339, 3239, 3192, 3031, 2831, 2201 (CN),
1737, 1702 (2 C=O); 1H NMR (300.84 MHz, DMSO-d6): δ (ppm): 10.82 (s, 1H,
3
NH), 7.91 (d, 2H, JHH = 6.9 Hz, HAr), 7.70–7.58 (m, 5H, HAr, NH2), 7.41 (dd,
3
3
1H, JHH = 1.8 Hz,3JHH = 8.1 Hz, HAr), 7.36 (d, 1H, JHH = 1.8 Hz, HAr), 6.85 (d,
1H,3JHH = 8.1 Hz, HAr); 13C NMR (75.65 MHz, DMSO-d6): δ (ppm): 49.0 (Cspiro), 56.3
(=C-CN), 96.0 (=C-C=O), 111.7 (CHAr), 114.1 (CAr), 117.7 (CN), 127.4, 127.8, 128.3,
130.2, 131.8 (7 CHAr), 133.6, 136.0 (2 CAr), 142.1 (N-C=N), 155.0 (CAr), 159.0 (C=O),
159.7 (=CNH2), 160.0 (N-N=C), 162.1 (CO-C=C-O), 177.5 (C=O isa); MS: (m/z, %),
519 (M+, 6),28 (100), 102 (75), 76 (56), 202 (54), 44 (42), 120 (38), 271 (37), 242 (37), 138
(32), Anal. Calcd for C22H11BrN6O3S (519.33): C, 50.88; H, 2.14; N, 16.18%. Found: C,
50.62; H, 2.41; N, 15.95%.
Disclosure statement
No potential conflict of interest was reported by the author(s).

14
S. HOSSEINI ET AL.
Funding
The Research Council of Ferdowsi University of Mashhad is acknowledged for financial support
[grant no. 3/41699].
ORCID
Abbas Ali Esmaeili http://orcid.org/0000-0002-1650-0224
Amir Khojastehnezhad http://orcid.org/0000-0002-9078-7323
References
[1] de Souza MVN. Synthesis and biological activity of natural thiazoles: an important class of
heterocyclic compounds. J Sulfur Chem. 2005;26:429–449.
[2] Negri G, Kascheres C, Kascheres AJ. Recent development in preparation reactivity and
biological activity of enaminoketones and enaminothiones and their utilization to prepare
heterocyclic compounds. J Heterocycl Chem. 2004;41:461–491.
[3] Al-Mulla A. A review: biological importance of heterocyclic compounds. Der Pharma Chem.
2017;9:141–147.
[4] Bur SK, Padwa A. The Pummerer reaction: methodology and strategy for the synthesis of
heterocyclic compounds. Chem Rev. 2004;104:2401–2432.
[5] Heravi MM, Sadjadi S. Recent advances in the application of the Sonogashira method in the
synthesis of heterocyclic compounds. Tetrahedron. 2009;65:7761–7775.
[6] Varma RS. Solvent-free synthesis of heterocyclic compounds using microwaves. J Heterocycl
Chem. 1999;36:1565–1571.
[7] Eftekhari-Sis B, Zirak M, Akbari A. Arylglyoxals in synthesis of heterocyclic compounds.
Chem Rev. 2013;113:2958–3043.
[8] Zhu J, Bienaymé H. Multicomponent reactions. Lyon, French: Wiley; 2006.
[9] de Graaff C, Ruijter E, Orru RV. Recent developments in asymmetric multicomponent reac-
tions. Chem Soc Rev. 2012;41:3969–4009.
[10] Cioc RC, Ruijter E, Orru RV. Multicomponent reactions: advanced tools for sustainable organic
synthesis. Green Chem. 2014;16:2958–2975.
[11] Domling A, Wang W, Wang K. Chemistry and biology of multicomponent reactions. Chem
Rev. 2012;112:3083–3135.
[12] Zarganes-Tzitzikas T, Dömling A. Modern multicomponent reactions for better drug synthe-
ses. Org Chem Front. 2014;1:834–837.
[13] Insuasty D, Castillo J, Becerra D, et al. Synthesis of biologically active molecules through
multicomponent reactions. Molecules. 2020;25:505.
[14] Orru RV, Ruijter E. Synthesis of heterocycles via multicomponent reactions II. London:
Springer Science & Business Media; 2010.
[15] Slobbe P, Ruijter E, Orru RV. Recent applications of multicomponent reactions in medicinal
chemistry. MedChemComm. 2012;3:1189–1218.
[16] Sunderhaus JD, Dockendorff C, Martin SF. Applications of multicomponent reactions for the
synthesis of diverse heterocyclic scaffolds. Org Lett. 2007;9:4223–4226.
[17] Rotstein BH, Zaretsky S, Rai V, et al. Small heterocycles in multicomponent reactions. Chem
Rev. 2014;114:8323–8359.
[18] Eshghi H, Khojastehnezhad A, Moeinpour F, et al. Nanomagnetic organic–inorganic hybrid
(Fe@ Si-Gu-Prs): a novel magnetically Green catalyst for the synthesis of tetrahydropyridine
derivatives at room temperature under solvent-free conditions. Tetrahedron. 2015;71:436–444.
[19] Maleki B, Eshghi H, Khojastehnezhad A, et al. Silica coated magnetic NiFe2O4 nanoparticle
supported phosphomolybdic acid; synthesis, preparation and its application as a heterogeneous
and recyclable catalyst for the one-pot synthesis of tri-and tetra-substituted imidazoles under
solvent free conditions. RSC Adv. 2015;5:64850–64857.

JOURNAL OF SULFUR CHEMISTRY
15
[20] Khojastehnezhad A, Moeinpou F, Vafaei M. Molybdenum oxide supported on silica
(MoO3/SiO2): An efficient and reusable catalyst for the synthesis of 1, 8-dioxodecahydroacri
dines under solvent-free conditions. J Mex Chem Soc. 2015;59:29–35.
[21] Davoodnia A, Khojastehnezhad A. Carbon-based solid acid catalyzed synthesis of polyhydro-
quinoline derivatives via Hantzsch reaction under solvent-free conditions. J Chil Chem Soc.
2012;57:1385–1387.
[22] Khojastehnezhad A, Davoodnia A, Bakavoli M, et al. Silica gel-supported polyphosphoric
acid (PPA/SiO2): an efficient and reusable heterogeneous catalyst for facile synthesis of 14-
aryl-14H-dibenzo [a, j] xanthenes under solvent-free conditions. Chin J Chem. 2011;29:
297–302.
[23] Yu B, Yu D-Q, Liu H-M. Spirooxindoles: promising scaffolds for anticancer agents. Eur J Med
Chem. 2015;97:673–698.
[24] Barakat A, Islam MS, Ghawas HM, et al. Substituted spirooxindole derivatives as potent
anticancer agents through inhibition of phosphodiesterase 1. RSC Adv. 2018;8:14335–14346.
[25] Babu SA, Padmavathi R, Aslam NA, et al. Recent developments on the synthesis and
applications of natural products-inspired spirooxindole frameworks. Stud Nat Prod Chem.
2015;46:227–339.
[26] Haddad S, Boudriga S, Akhaja TN, et al. A strategic approach to the synthesis of functional-
ized spirooxindole pyrrolidine derivatives: in vitro antibacterial, antifungal, antimalarial and
antitubercular studies. New J Chem. 2015;39:520–528.
[27] Islam MS, Ghawas HM, El-Senduny FF, et al. Synthesis of new thiazolo-pyrrolidine–(spirooxin
dole) tethered to 3-acylindole as anticancer agents. Bioorg Chem. 2019;82:423–430.
[28] Yang J, Liu X-W, Wang D-D, et al. Diversity-oriented one-pot multicomponent synthesis of
spirooxindole derivatives and their biological evaluation for anticancer activities. Tetrahedron.
2016;72:8523–8536.
[29] El-Hashash MA, Rizk SA. One-pot synthesis of novel spirooxindoles as antibacterial and
antioxidant agents. J Heterocycl Chem. 2017;54:1776–1784.
[30] Barman S, Das J, Biswas S, et al. A spiropyran–coumarin platform: an environment sen-
sitive photoresponsive drug delivery system for efficient cancer therapy. J Mater Chem.
2017;5:3940–3944.
[31] Poojari S KSJK, Naik S. Synthesis and antimicrobial studies of New spiropyran quina-
zolinone derivatives with amide, urea, and sulfonamide moieties. J Heterocycl Chem.
2017;54:3527–3537.
[32] Chen L, Zhu Y, Yang D, et al. Synthesis and antibacterial activities of antibacterial peptides with
a spiropyran fluorescence probe. Sci Rep. 2014;4:1–7.
[33] Kumla D, Sousa E, Marengo A, et al. 1, 3-Dioxepine and spiropyran derivatives of viomellein
and other dimeric naphthopyranones from cultures of Aspergillus elegans KUFA0015 and their
antibacterial activity. Phytochemistry. 2021;181:112575.
[34] Moosavi-Zare AR, Zolfigol MA, Noroozizadeh E, et al. Synthesis and characterization of acetic
acid functionalized poly (4-vinylpyridinium) salt as new catalyst for the synthesis of spiropyran
derivatives and their biological activity. J Mol Catal. 2016;425:217–228.
[35] van Pelt-Koops J, Pett H, Graumans W, et al. The spiroindolone drug candidate NITD609
potently inhibits gametocytogenesis and blocks Plasmodium falciparum transmission to
anopheles mosquito vector. Antimicrob Agents Chemother. 2012;56:3544–3548.
[36] Ding K, Lu Y, Nikolovska-Coleska Z, et al. Structure-based design of spiro-oxindoles as
potent, specific small-molecule inhibitors of the MDM2− p53 interaction. J Med Chem.
2006;49:3432–3435.
[37] Lu J, McEachern D, Li S, et al. Reactivation of p53 by mdm2 inhibitor mi-77301 for the
treatment of endocrine-resistant breast cancer. Mol Cancer Ther. 2016;15:2887–2893.
[38] Holla BS, Mahalinga M, Karthikeyan MS, et al. Synthesis of some novel pyrazolo [3, 4-d] pyrim-
idine derivatives as potential antimicrobial agents. Bioorg Med Chem. 2006;14:2040–2047.
[39] Sharma P, Rane N, Gurram V. Synthesis and QSAR studies of pyrimido [4, 5-d]
pyrimidine-2, 5-dione derivatives as potential antimicrobial agents. Bioorg Med Chem Lett.
2004;14:4185–4190.

16
S. HOSSEINI ET AL.
[40] Holý A, Votruba I, Masojídková M, et al. 6-[2-(Phosphonomethoxy) alkoxy] pyrimidines with
antiviral activity. J Med Chem. 2002;45:1918–1929.
[41] Hocková D, Holý A, Masojídková M, et al. 5-Substituted-2, 4-diamino-6-[2-(phosphonome
thoxy) ethoxy] pyrimidines acyclic nucleoside phosphonate analogues with antiviral activity. J
Med Chem. 2003;46:5064–5073.
[42] Amr A-GE, Mohamed AM, Mohamed SF, et al. Anticancer activities of some newly synthesized
pyridine, pyrane, and pyrimidine derivatives. Bioorg Med Chem. 2006;14:5481–5488.
[43] Matsumoto J, Minami S. Pyrido [2, 3-d] pyrimidine antibacterial agents. 3. 8-alkyl-and 8-vinyl-
5, 8-dihydro-5-oxo-2-(1-piperazinyl) pyrido [2, 3-d] pyrimidine-6-carboxylic acids and their
derivatives. J Med Chem. 1975;18:74–79.
[44] Rival Y, Grassy G, Taudou A, et al. Antifungal activity in vitro of some imidazo [1, 2-a]
pyrimidine derivatives. Eur J Med Chem. 1991;26:13–18.
[45] Coburn R, Glennon R. Mesoionic purinone analogs IV: synthesis and in vitro antibacte-
rial properties of mesoionic thiazolo [3, 2-a] pyrimidin-5, 7-diones and mesoionic 1, 3,
4-thiadiazolo [3, 2-a] pyrimidin-5, 7-diones. J Pharm Sci. 1973;62:1785–1789.
[46] Sayed HH, Shamroukh AH, Rashad AE. Synthesis and biological evaluation of some pyrimi-
dine, pyrimido [2, 1-b][1, 3] thiazine and thiazolo [3, 2-a] pyrimidine derivatives. Acta Pharm.
2006;56:231–244.
[47] Tozkoparan B, Ertan M, Krebs B, et al. Condensed heterocyclic compounds: synthesis and
antiinflammatory activity of novel thiazolo [3, 2-a] pyrimidines. Arch Pharm Med Chem.
1998;331:201–206.
[48] Tozkoparan B, Ertan M, Kelicen P, et al. Synthesis and anti-inflammatory activities of some
thiazolo [3, 2-a] pyrimidine derivatives. Il Farmaco. 1999;54:588–593.
[49] Jeanneau-Nicolle E, Benoit-Guyod M, Namil A, et al. New thiazolo [3, 2-a] pyrimi-
dine derivatives, synthesis and structure-activity relationships. Eur J Med Chem. 1992;27:
115–120.
[50] Selvam TP, Karthik V, Kumar PV, et al. Design, synthesis, antinociceptive, and anti-
inflammatory properties of thiazolopyrimidine derivatives. Toxicol Environ Chem. 2012;94:
1247–1258.
[51] Abu-Hashem AA, Youssef MM, Hussein HA. Synthesis, antioxidant, antituomer activities
of some new thiazolopyrimidines, pyrrolothiazolopyrimidines and triazolopyrrolothiazolopy-
rimidines derivatives. J Chin Chem Soc. 2011;58:41–48.
[52] Danel K, Pedersen EB, Nielsen C. Synthesis and anti-HIV-1 activity of novel 2, 3-dihydro-7
H-thiazolo [3, 2-a] pyrimidin-7-ones. J Med Chem. 1998;41:191–198.
[53] Fatima S, Sharma A, Saxena R, et al. One pot efficient diversity oriented synthesis of polyfunc-
tional styryl thiazolopyrimidines and their bio-evaluation as antimalarial and anti-HIV agents.
Eur J Med Chem. 2012;55:195–204.
[54] Saatluo BE, Baradarani MM, Różycka-Sokołowska E, et al. Spiro [4H-2, 3-dihydropyran-3,
3ꢀ-oxindoles] derived from 1, 2, 3, 4-tetrahydroquinoline. J Heterocycl Chem. 2018;55:226–
239.
[55] Vahedi H, Baradarani MM, Rashidi A, et al. Spiro [4H-pyran-3, 3ꢀ-oxindoles] derived from 1,
2, 3, 4-tetrahydroquinoline. J Heterocycl Chem. 2015;52:1208–1211.
[56] Esmaeili AA, Vesalipoor H, Hosseinabadi R, et al. An efficient diastereoselective synthesis
of spiro pyrido [2, 1-b][1, 3] oxazines via a novel pyridine-based three-component reaction.
Tetrahedron Lett. 2011;52:4865–4867.
[57] Esmaeili AA, Zendegani H. Three-component reactions involving zwitterionic intermedi-
ates for the construction of heterocyclic systems: one pot synthesis of highly functionalized
γ -iminolactones. Tetrahedron. 2005;61:4031–4034.
[58] Zangouei M, Esmaeili AA, Mague JT. One-pot three component isocyanide-based reaction:
synthesis of novel tetracyclic fused furo [2ꢀ, 3ꢀ: 4, 5] pyrimido [2, 1-b][1, 3] benzothiazole.
Tetrahedron. 2017;73:2894–2900.
[59] Khojastehnezhad A, Maleki B, Karrabi B, et al. Synthesis of highly functionalized piperidines
using polyphosphoric acid supported on silica-coated magnetic nanoparticles. Org Prep
Proced Int. 2017;49:338–345.

JOURNAL OF SULFUR CHEMISTRY
17
[60] Hosseininasab N, Davoodnia A, Rostami-Charati F, et al. Synthesis of New pyrimido [4ꢀ, 5ꢀ: 3,
4] pyrazolo [1, 2-b] phthalazine-4, 7, 12-triones: derivatives of a new heterocyclic ring system.
J Heterocycl Chem. 2018;55:161–165.
[61] Allameh S, Davoodnia A, Khojastehnezhad A. An efficient and eco-friendly synthesis of 14-
aryl-14H-dibenzo [a, j] xanthenes using H4 [SiW12O40] as a heterogeneous and reusable
catalyst under solvent-free conditions. Chin Chem Lett. 2012;23:17–20.
[62] Javid A, Khojastehnezhad A, Eshghi H, et al. Synthesis of pyranopyrazoles using a magnetically
separable modified preyssler heteropoly acid. Org Prep Proc Int. 2016;48:377–384.
[63] Moeinpour F, Khojastehnezhad A. An efficient One-Pot synthesis of 1, 8-dioxodecahydroacri
dines using silica-supported polyphosphoric Acid (PPA-SiO2) under solvent-free conditions.
J Chem. 2012;9:504–509.
[64] Bugaenko DI, Karchava AV, Yurovskaya MA. The versatility of DABCO: synthetic applications
of its basic, nucleophilic, and catalytic properties part 1. Catalysis of Morita–Baylis–Hillman
and Knoevenagel reactions. Chem Heterocycl Com. 2020,56(2).
[65] Almeida MR, Leitão GG, Silva BV, et al. Counter-current chromatography separation of isatin
derivatives using the Sandmeyer methodology. J Braz Chem Soc. 2010;21:764–769.
[66] Silva BV, Esteves PM, Pinto AC. Chlorination of isatins with trichloroisocyanuric acid. J Braz
Chem Soc. 2011;22:257–263.
[67] Akhavan M, Esmaeili AA, Zangouei M, et al. Convenient one-pot access to novel densely
functionalized pyrano [2, 3-d][1, 3, 4] thiadiazolo [3, 2-a] pyrimidines via three component
reaction. Res Chem Int. 2017;43:4683–4696.