Synthesis of highly functionalized thiazolo[3,2-: A] pyridine derivatives via a five-component cascade reaction based on nitroketene N, S-acetal

Article abstract of DOI:10.1039/d0ra03910a

A highly efficient and straightforward synthesis of N-fused heterocyclic compounds including 5-amino-7-(aryl)-8-nitro-N'-(1-(aryl)ethylidene)-3,7-dihydro-2H-thiazolo[3,2-a]pyridine-6-carbohydrazide derivatives is successfully achieved via a five-component cascade reaction utilizing cyanoacetohydrazide, various acetophenones, aromatic aldehydes, 1,1-bis(methylthio)-2-nitroethylene and cysteamine hydrochloride in ethanol at reflux conditions. The new approach involves domino N,S-acetal formation, Knoevenagel condensation, Michael reaction, imine-enamine tautomerization and N-cyclization sequences. The prominent advantages of this protocol include: facility of operation, available and economical starting materials, no need for toxic solvents, high yields and tolerance of a wide variety of functional groups.

Full text of DOI:10.1039/d0ra03910a

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Synthesis of highly functionalized thiazolo[3,2-a]
pyridine derivatives via a five-component cascade
reaction based on nitroketene N,S-acetal†
Cite this: RSC Adv., 2020, 10, 31039
*
Zohreh Sahhaf Razavi, Mohammad Bayat
and Hajar Hosseini
A highly efficient and straightforward synthesis of N-fused heterocyclic compounds including 5-amino-7-
(aryl)-8-nitro-N'-(1-(aryl)ethylidene)-3,7-dihydro-2H-thiazolo[3,2-a]pyridine-6-carbohydrazide derivatives
is successfully achieved via a five-component cascade reaction utilizing cyanoacetohydrazide, various
acetophenones, aromatic aldehydes, 1,1-bis(methylthio)-2-nitroethylene and cysteamine hydrochloride
in ethanol at reflux conditions. The new approach involves domino N,S-acetal formation, Knoevenagel
condensation, Michael reaction, imine–enamine tautomerization and N-cyclization sequences. The
prominent advantages of this protocol include: facility of operation, available and economical starting
materials, no need for toxic solvents, high yields and tolerance of a wide variety of functional groups.
Received 30th April 2020
Accepted 16th August 2020
DOI: 10.1039/d0ra03910a
rsc.li/rsc-advances
character. This feature of nitroketene N,S-acetals make them
highly useful to apply in the Michael addition, annulation and
multicomponent reactions.14 Today, multicomponent reactions
Introduction
The thiazolopyridine moiety is found in a wide spectrum of
biologically active compounds. Thiazolo[3,2-a]pyridines are an
important category with notable antibacterial and antifungal
activity1 and other considerable bioactivities including as
a beta-amyloid production inhibitor,2 potent CDK2-cyclin A
inhibitor,3 potential uterus stimulant,4 coronary dilator, anti-
hypertensives, and muscle relaxant.5 Also they are useful for
chemotherapy of various cancers, such as leukemia, lung
cancer, and melanoma.6–8 Some biologically active compounds
with this nucleus are presented in Fig. 1.9–11
(MCRs) have become a prominent strategy and are selected over
stepwise synthesis due to the following reasons: reduced
synthetic time, labor and cost, minimal utilization of toxic and
harmful chemicals, simple workup of products, high yields,
straight forward and simplicity of experimental procedures and
economic viability; therefore, MCRs are a powerful approach to
promotion of green chemistry by reducing the formation of
large quantities of waste.15–19
The ve-membered cyclic nitroketene N,S-acetal and
commercially available six-membered nithiazine have been
remarkably explored in the literature and their reactions with
different Michael acceptors are most expected. Here we report
the some synthesis of thiazolo[3,2-a]pyridine compounds per-
formed with cyclic ketene N,S-acetals (Scheme 1). In 2005,
Chakrabarti et al. described the reactions between diverse cyclic
N,S- and N,N-ketene acetals and itaconic anhydride (A).20 In
2010, Yan et al. reported one-pot synthesis of functionalized
bicyclic pyridines under solvent- and catalyst-free conditions
with triethoxymethane, ethyl 4,4,4-triuoro-3-oxobutanoate and
various ketene aminals (B).21 In 2011, Altug et al. developed the
synthesis of thiazolo[3,2-a]pyridines via a one-pot reaction
between 2-(nitromethylene)thiazolidine, aromatic aldehydes
and ethyl 2-cyanoacetate, malononitrile or 2-(phenylsulfonyl)
acetonitrile (C).22
Obviously, the synthesis of new classes of thiazolo[3,2-a]
pyridines may give a library of compounds as possible candi-
dates for various biological activities.
Cyclic ketene N,S-acetal structures are as such used as drugs
for the treatment of hypertension diseases and usually
employed as probes for nucleic acids to study the interaction
between G4 (G-quadruplex) and its ligands (Fig. 1, I–III).12 It's
interesting that the cyclic nitroketene N,S-acetal nithiazine IV
was the rst reported compound of neonicotinoid insecticides13
and is widely used as a common insecticide around the world
(Fig. 1). Synthetically, the cyclic nitroketene N,S-acetals have
a rigid structure and act as Michael donor 1,3-N,C di-
nucleophiles for the generation of nitrogen-containing hetero-
cyclic compounds. The ethylene motif has a polarized push–
pull type of alkene, therefore the one end expands an electro-
philic character, whereas the other end develops a nucleophilic
In 2018, our research group synthesized fused thiazolo[3,2-a]
pyridines utilizing the ve-membered cyclic nitroketene N,S-
acetal, dimedone and different aromatic aldehydes (D).23 Also
we reported the synthesis of indenone-fused thiazolo[3,2-a]
pyridines via a one-pot reaction between 2-(nitromethylene)
thiazolidine, aromatic aldehydes and 1,3-indandione (E).24 In
Department of Chemistry, Faculty of Science, Imam Khomeini International University,
Qazvin, Iran. E-mail: bayat_mo@yahoo.com; m.bayat@sci.ikiu.ac.ir
† Electronic supplementary information (ESI) available. See DOI:
10.1039/d0ra03910a
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Fig. 1 Selected examples of thiazolo[3,2-a]pyridines with biological and pharmacological activities and examples of drugs, insecticides and
probes having the ketene N,S-acetal structure.
addition, we were able to produce the desired products using due to the ve-component nature of the dened reactions, great
cyanoacetamide, aromatic aldehydes and 2-(nitromethylene) efforts were made to obtain the desired products with high
thiazolidine (F).25 Moreover, in 2018, the reaction of cyanoace- purity. At rst ethanol was examined and the experimental
tohydrazide with aromatic aldehydes and 2-(nitromethylene) results showed when ethanol was used as solvent with trie-
thiazolidine/oxazolidine resulted in functionalized thiazolo/ thylamine at reux conditions, the yield of desired product 6a
oxazolo pyridine derivatives (G).26
Following our efforts to synthesize the new heterocyclic used (NEt3) is not working on the rate-limiting step. To prepare
compounds using cyanoacetohydrazide and based on previous 2-(nitromethylene)thiazolidine solution (from 1,1-
was 93% (Table 1, entry 1). It should be noted that the catalyst
works, we designed new reactions utilizing 2-(nitromethylene) bis(methylthio)-2-nitroethene and cysteamine hydrochloride,
thiazolidine as heterocyclic ketene aminal. In this article we which is mentioned in the Experimental section), it is necessary
report an efficient synthesis of highly functionalized 2H-thia- to use triethylamine to separate cysteamine from its salt.23,27 No
zolo[3,2-a]pyridine-6-carbohydrazide compounds via a one-pot reaction will occur without the use of triethylamine (entry 4).
ve-component domino reaction. To the best of our knowl- The use of other catalysts is related to the whole reaction.
edge, there is no report on the synthesis of these structures.
In order to increase the reaction rate, two types of catalysts
were used. With piperidine, the reaction efficiency decreased
slightly (entry 2) and with acetic acid, the product did not form
(entry 3). According to the investigations, it was determined that
in basic and acidic medium, other products are formed (two-,
three- and four-component products). The percentage of each
was different for various derivatives. In general, it was found
that the slightest change in the reaction conditions (even in
ethanol amount) leads to a decrease in the efficiency of the
desired product or oen its non-formation. In addition, we
observed the formation of a four-component by-product in two
cases, which are described in the general procedure section.
However, we also studied the effect of other solvents. The use of
water or acetonitrile did not result in the desired product (entry
5 and 7), and when the mixture of water and ethanol was used
(overall 1 : 1, v/v), the efficiency decreased (entry 6). With chlo-
roform, methanol and DMF, in reux conditions the desired
products were not formed (entry 8, 9 and 10).
Results and discussion
We have developed an efficient synthesis of new functionalized
thiazolo[3,2-a]pyridine structures 6 by using of cyanoacetohy-
drazide 1, acetophenone derivatives 2, aromatic aldehydes 3,
1,1-bis(methylthio)-2-nitroethene 4 and cysteamine hydrochlo-
ride 5 in the presence of triethylamine in ethanol at reux
conditions (Scheme 2).
Optimization of the conditions
Initially, cyanoacetohydrazide 1, 4-chloroacetophenone 2, 4-
chlorobenzaldehyde 3, 1,1-bis(methylthio)-2-nitroethene 4 and
cysteamine hydrochloride 5 were used as model substrates to
achieve the best yield.
In general, due to the variable reactivity of cyanoacetohy-
drazide (based on its specic structure) and on the other hand
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Scheme 1 Summary of previous works of thiazolo[3,2-a]pyridine synthesis.
Scheme 2 Synthetic scheme for the generation of products 6a–p.
With information obtained from optimization conditions 4 and cysteamine hydrochloride 5 as starting materials (Scheme
table, we could synthesize target compounds (E)-5-amino-7- 2).
(aryl)-8-nitro-N'-(1-(aryl)ethylidene)-3,7-dihydro-2H-thiazolo[3,2-
The reactions were completed aer 24 h to afford the cor-
a]pyridine-6-carbohydrazide 6a–p in good to high yields (70– responding heterocyclic structures. The results are summarized
95%) using cyanoacetohydrazide 1, acetophenone derivatives 2, in Table 2.
various aromatic aldehydes 3, 1,1-bis(methylthio)-2-nitroethene
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Table 1 Optimization conditions for the formation of 6aa
Entry
Solvent
Catalyst (mol%)
Time (h)
Temp (ꢁC)
Yield (%)
1
2
3
4
5
6
7
8
9
10
EtOH
EtOH
EtOH
EtOH
NEt3
Piperidine
AcOH
—
NEt3
NEt3
NEt3
NEt3
NEt3
NEt3
24
24
24
24
24
24
24
24
24
24
78
78
78
78
100
78
82
61
65
153
93
80
No reaction
No reaction
No reaction
40
No reaction
No reaction
No reaction
No reaction
H2O
H2O/EtOH (1 : 1, v/v)
CH3CN
CHCl3
MeOH
DMF
a
Reagents and conditions: cyanoacetohydrazide (1 mmol), 4-chloroacetophenone (1 mmol), 4-chlorobenzaldehyde (1 mmol), 1,1-bis(methylthio)-2-
nitroethene (1 mmol), cysteamine hydrochloride (1 mmol), solvent (20 mL), catalyst (1 mmol).
characteristic signals of four aliphatic carbons (CH3, CH and
two CH2 groups) were seen at d 13.8, 37.7, 27.6 and 50.8 ppm
respectively. Characteristic signal at d 81.8 ppm was related to
C]C–CO. The carbonyl group appeared at d 165.7 ppm (Fig. 2).
The IR spectrum of 6a showed absorption bands at 3141 and
3284 cmꢀ1 due to NH and NH2 groups, strong absorption of
carbonyl group at 1626 and C–N band at 1237 cmꢀ1. Two
absorption bands due to nitro group appeared at 1514 and
Scope and limitations
This reaction was performed with ortho derivatives of benzal-
dehyde (2-chloro, 2-hydroxy and 2-nitro) under the same
conditions, which did not result in the product probably due to
steric effects. Also the use of acetophenone and 4-methox-
yacetophenone did not lead to the favorable products. The
reaction was also used with aliphatic ketones instead of aceto-
phenone derivatives and aliphatic aldehydes instead of
aromatic aldehydes which resulted in no product formation.
It was found that the major by-product of this reaction is a four-
component structure that was previously synthesized using two
equivalents of aldehyde26 which will prevent its formation by per-
forming the correct reaction steps (see Experimental section).
1302 cmꢀ1
.
Mechanism
A general plausible mechanism for the formation of thiazolo
[3,2-a]pyridine carbohydrazides is shown in Scheme 3. The
condensation of cyanoacetohydrazide 1 with acetophenone 2
Structure determination
The structures of all new compounds 6a–p were supported by leads to the hydrazide-hydrazone structures 7. On the basis of
1
means of IR, H NMR, 13C NMR spectroscopic and mass spec- well-established chemistry of 1,1-bis(methylthio)-2-nitroethene,
trometric data (see the ESI†).
on the other hand, addition of cysteamine hydrochloride 5 to
1
As a representative case the key signals of H and 13C NMR 1,1-bis(methylthio)-2-nitroethene 4 leads to the formation of
chemical shis of (E)-5-amino-7-(4-chlorophenyl)-N'-(1-(4-chlor- ketene N,S-acetal 9.23,27 The formation of b-nitrothiazolidine 9
ophenyl)ethylidene)-8-nitro-3,7-dihydro-2H-thiazolo[3,2-a]
pyridine-6-carbohydrazide 6a are presented in Fig. 2.
occurs in the presence of an equivalent amount of triethylamine
base for releasing cysteamine salt. Further, with adding alde-
The 1H NMR spectrum of 6a showed NH group at d 9.35 ppm. hyde 3, the Knoevenagel condensation affords intermediate 8.
The NH2 group appeared at d 8.15 ppm. The proton of CH at Then, Michael addition of nitroenamine 9 to adduct 8 leads to
pyridine ring was seen at d 5.66 ppm. Four protons of two the intermediate 10, which undergoes successive imine–
methylene groups appeared at d 4.22 to 4.38 ppm as two multi- enamine tautomerization followed by an intramolecular cycli-
plets. The signal at d 2.11 ppm was related to methyl group.
zation via nucleophilic addition of –NH to nitrile group. Finally,
The 1H-decoupled 13C NMR spectrum of 6a indicated 18 imine–enamine tautomerization leads to thiazolo[3,2-a]pyri-
distinct resonances in accordance to desired structure. The dine products 6 (Scheme 3).
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Table 2 Compounds 6a–pa
Entry
Aromatic aldehyde
Acetophenone derivative
Product
Yield (%)
Mp (ꢁC)
1
93
76
252–254
2
3
230–233
239–241
86
80
75
4
5
222–224
217–219
6
7
84
82
248–250
237–240
8
78
225–227
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Table 2 (Contd.)
Entry
Aromatic aldehyde
Acetophenone derivative
Product
Yield (%)
Mp (ꢁC)
9
80
203–205
10
11
78
90
234–236
218–220
12
95
244–246
13
14
85
87
242–245
244–246
15
75
253–255
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Table 2 (Contd.)
Entry
Aromatic aldehyde
Acetophenone derivative
Product
Yield (%)
Mp (ꢁC)
16
70
262–264
a
The reactions were performed using cyanoacetohydrazide (1 mmol), acetophenone derivatives (1 mmol), aromatic aldehydes (1 mmol), 1,1-
bis(methylthio)-2-nitroethene, (1 mmol), cysteamine hydrochloride (1 mmol), triethylamine (1 mmol), EtOH (20 mL).
constant (J) are reported in Hertz (Hz). Melting points were
measured with an electrothermal 9100 apparatus. Mass spectra
were recorded with an Agilent 5975C VL MSD with Triple-Axis
detector operating at an ionization potential of 70 eV. IR
spectra were measured with Bruker Tensor 27 spectrometer.
Elemental analyses for C, H and N were performed using
a PerkinElmer 2004 series [II] CHN elemental analyzer.
General procedure of the synthesis of 5-amino-7-(aryl)-8-nitro-
N'-(1-(aryl)ethylidene)-3,7-dihydro-2H-thiazolo[3,2-a]pyridine-
6-carbohydrazide derivatives
A mixture of cysteamine hydrochloride (0.113 g, 1 mmol), 1,1-
Fig. 2 1H and 13C NMR chemical shifts of 6a.
bis(methylthio)-2-nitroethylene (0.165 g, 1 mmol), Et3N (140 mL,
1 mmol) and 10 mL EtOH in a 50 mL ask was reuxed for 5
hours. In another 50 mL ask the stoichiometric mixture of
Conclusion
cyanoacetohydrazide (1 mmol, 0.099 g) and acetophenone
derivative (1 mmol) in EtOH (10 mL) was reuxed for 3–5 hours
A green and efficient approach to easy synthesis of novel and
depending on the type of acetophenone. Aer these times, TLC
highly substituted fused 1,4-dihydropyridines, 5-amino-7-(aryl)-
shows the consumption of the starting components. Then,
8-nitro-N'-(1-(aryl)ethylidene)-3,7-dihydro-2H-thiazolo[3,2-a]
aromatic aldehyde (1 mmol) and the rst solution (HKA), were
pyridine-6-carbohydrazides, has been developed based on
added to the second mixture simultaneously. The progress of
a one-pot ve-component condensation via annulation of cyclic
the reaction was monitored by TLC using ethyl acetate/n-hexane
nitroketene N,S-acetal, b-nitrothiazolidine, and
a three-
(1 : 1). Aer completion of the reaction (24 hours), without the
need for chromatography or recrystallization, the precipitated
product was collected by ltration and washed with warm
ethanol to give the pure products 6a–p in excellent yield.
To achieve the pure products, it was necessary to complete
the reaction of cyanoacetohydrazide and acetophenone deriva-
tives in ethanol at reux conditions in sufficient time (3 hours
for 4-nitroacetophenone and 5 hours for 4-chloro and 4-bro-
moacetophenone), then with no need for product separation,
nitroenamine solution and aromatic aldehyde were added to
two-component hydrazone mixture at the same time. We found
component product of cyanoacetohydrazide, acetophenone
derivatives and different aromatic aldehydes. The reactions are
completed within 24 h in EtOH at reux conditions. The present
synthesis shows signicant properties such as high regiose-
lectivity, cascade one-pot methodology, high yields, simple
purication of products, and high atom economy.
Experimental
Materials
All commercially available reagents and other solvents were two distinct cases (6g and 6h) that led to a mixture of two
purchased from Aldrich and Merck chemical Co. and used products: the desired product and the product without partici-
without further purication. The NMR spectra were recorded pation of acetophenone derivative.26
1
with a Bruker DRX-300 AVANCE instrument (300 MHz for H
(E)-5-Amino-7-(4-chlorophenyl)-N'-(1-(4-chlorophenyl)ethyl-
and 75.4 MHz for 13C) with DMSO-d6 as solvent. Chemical shis idene)-8-nitro-3,7-dihydro-2H-thiazolo[3,2-a]pyridine-6-
are given in ppm (d) relative to internal TMS, and coupling carbohydrazide (6a). Yellow solid; yield: 0.468 g (93%); mp: 252–
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Scheme 3 Proposed mechanism for the formation of products 6.
254 ꢁC; IR (KBr) (nmax/cmꢀ1): 3284, 3141, 1626, 1514, 1452, 1302,
C
23H22ClN5O4S: C, 55.25; H, 4.44; N, 14.01. Found: C, 55.6; H,
1237, 1131, 850, 756; 1H NMR (300 MHz, DMSO): d 2.11 (3H, s, 4.7; N, 14.3.
CH3), 4.22–4.31 (2H, m, CH2), 4.36–4.38 (2H, m, CH2), 5.66
(E)-5-Amino-N'-(1-(4-chlorophenyl)ethylidene)-7-(4-uo-
(1H, s, CH), 7.32–7.39 (4H, m, ArH), 7.43 (2H, d, J ¼ 8.4 Hz, ArH), rophenyl)-8-nitro-3,7-dihydro-2H-thiazolo[3,2-a]pyridine-6-
7.75 (2H, d, J ¼ 8.4 Hz, ArH), 8.15 (2H, s, NH2), 9.35 (1H, s, NH); carbohydrazide (6c). Dark yellow solid; yield: 0.418 g (86%); mp:
13C{1H} NMR (125.6 MHz, DMSO): d 13.8 (CH3), 27.6 (CH2S), 239–241 ꢁC; 1H NMR (300 MHz, DMSO): d 2.08 (3H, s, CH3),
37.7 (CH), 50.8 (CH2N), 81.8 (C]C–CO), 123.3 (C–NO2), 124.3, 4.23–4.27 (2H, m, CH2), 4.35–4.39 (2H, m, CH2), 5.63 (1H, s,
127.7, 128.1, 128.2, 129.7, 131.3, 133.5, 137.1 (Ar), 143.3 (C]C– CH), 7.06–7.12 (2H, m, ArH), 7.39–7.43 (4H, m, ArH), 7.74 (2H,
S), 149.9 (C]N), 156.8 (C–NH2), 165.7 (C]O); anal. calcd for d, J ¼ 8.4 Hz, ArH), 8.14 (2H, s, NH2), 9.30 (1H, s, NH); 13C{1H}
C
22H19Cl2N5O3S: C, 52.39; H, 3.80; N, 13.88. Found: C, 52.7; H, NMR (125.6 MHz, DMSO): d 13.7 (CH3), 27.6 (CH2S), 37.5 (CH),
3.5; N, 13.7.
(E)-5-Amino-N'-(1-(4-chlorophenyl)ethylidene)-7-(3-methox-
yphenyl)-8-nitro-3,7-dihydro-2H-thiazolo[3,2-a]pyridine-6-
50.8 (CH2N), 82.1 (C]C–CO), 114.8, 114.9 (Ar), 123.4 (C–NO2),
127.7, 128.2, 129.7, 129.8, 133.5, 137.1, 149.7 (Ar), 140.6 (C]C–
S), 149.9 (C]N), 156.6 (C–NH2), 159.9, 161.7 (Ar), 165.7 (C]O);
carbohydrazide (6b). Yellow solid; yield: 0.379 g (76%); mp: 230– anal. calcd for C22H19ClFN5O3S: C, 54.15; H, 3.92; N, 14.35.
233 ꢁC; IR (KBr) (nmax/cmꢀ1): 3486, 3400, 3327, 2909, 1658, 1519, Found: C, 54.3; H, 3.6; N, 14.1.
1458, 1375, 1254, 785; 1H NMR (300 MHz, DMSO): d 2.10 (3H, s,
(E)-5-Amino-N'-(1-(4-chlorophenyl)ethylidene)-7-(4-methox-
CH3), 3.69 (3H, s, OCH3), 4.21–4.30 (2H, m, CH2), 4.38–4.41 (2H, yphenyl)-8-nitro-3,7-dihydro-2H-thiazolo[3,2-a]pyridine-6-
m, CH2), 5.57 (1H, s, CH), 6.77 (1H, d, J ¼ 7.8 Hz, ArH), 6.91–6.94 carbohydrazide (6d). Orange solid; yield: 0.399 g (80%); mp:
(2H, m, ArH), 7.20 (1H, t, J ¼ 7.5 Hz, ArH), 7.43 (2H, d, J ¼ 222–224 ꢁC; IR (KBr) (nmax/cmꢀ1): 3272, 3128, 1626, 1484, 1442,
8.4 Hz, ArH), 7.75 (2H, d, J ¼ 8.4 Hz, ArH), 8.14 (2H, s, NH2), 9.22 1303, 1233, 1129, 1013, 825; 1H NMR (300 MHz, DMSO): d 2.10
(1H, s, NH); 13C{1H} NMR (125.6 MHz, DMSO): d 13.6 (CH3), 27.6 (3H, s, CH3), 3.68 (3H, s, OCH3), 4.22–4.28 (2H, m, CH2), 4.35–
(CH2S), 38.2 (CH), 50.7 (CH2N), 54.9 (OCH3), 82.0 (C]C–CO), 4.40 (2H, m, CH2), 5.51 (1H, s, CH), 6.83 (2H, d, J ¼ 8.7 Hz, ArH),
111.4, 114.4, 120.0 (Ar), 123.5 (C–NO2), 127.7, 128.2, 129.4, 7.28 (2H, d, J ¼ 8.7 Hz, ArH), 7.43 (2H, d, J ¼ 8.4 Hz, ArH), 7.75
133.5, 137.1 (Ar), 145.8 (C]C–S), 149.0 (Ar), 150.0 (C]N), 156.5 (2H, d, J ¼ 8.4 Hz, ArH), 8.12 (2H, s, NH2), 9.17 (1H, s, NH); 13
C
(C–NH2), 159.0 (CAr–OMe), 165.3 (C]O); anal. calcd for {1H} NMR (75.4 MHz, DMSO): d 13.7 (CH3), 26.9 (CH2S), 38.9
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(CH), 50.8 (CH2N), 55.0 (OCH3), 82.4 (C]C–CO), 113.7 (Ar), 9 Hz, ArH), 8.22 (2H, d, J ¼ 9 Hz, ArH), 8.24 (2H, s, NH2), 9.39
124.0 (C–NO2), 127.8, 128.3, 129.0, 133.7, 136.3, 136.8 (Ar), 141.5 (1H, s, NH); 13C{1H} NMR (125.6 MHz, DMSO): d 13.6 (CH3), 27.6
(C]C–S), 149.0 (C]N), 150.0 (C–NH2), 158.2 (CAr–OMe), 165.6 (CH2S), 38.1 (CH), 50.7 (CH2N), 54.9 (OCH3), 81.9 (C]C–CO),
(C]O); m/z (%) ¼ 474 (0.1), 439,2 353,2 305,18 288 (100), 257 (94), 111.5, 114.3, 120.0 (Ar), 123.4 (C–NO2), 127.0, 129.4, 131.6, 144.4
218,17 186,24 167 (31), 138 (79), 117,10 103 (77), 77 (43), 61 (38); (Ar), 145.8 (C]C–S), 147.1 (C]N), 150.3 (C–NH2), 156.6 (CAr–
anal. calcd for C23H22ClN5O4S: C, 55.25; H, 4.44; N, 14.01.
(E)-5-Amino-N'-(1-(4-chlorophenyl)ethylidene)-7-(3,4-dime-
thoxyphenyl)-8-nitro-3,7-dihydro-2H-thiazolo[3,2-a]pyridine-6-
OMe), 159.0 (C]O); anal. calcd for C23H22N6O6S: C, 54.11; H,
4.34; N, 16.46.
(E)-5-Amino-7-(3-chlorophenyl)-8-nitro-N'-(1-(4-nitrophenyl)
carbohydrazide (6e). Yellow solid; yield: 0.397 g (75%); mp: 217– ethylidene)-3,7-dihydro-2H-thiazolo[3,2-a]pyridine-6-
219 ꢁC; 1H NMR (300 MHz, DMSO): d 2.10 (3H, s, CH3), 3.67 carbohydrazide (6k). Orange solid; yield: 0.462 g (90%); mp:
(3H, s, OCH3), 3.68 (3H, s, OCH3), 4.24–4.36 (4H, m, 2CH2), 5.51 218–220 ꢁC; IR (KBr) (nmax/cmꢀ1): 3408, 3297, 1639, 1573, 1508,
1
(1H, s, CH), 6.85 (2H, s, ArH), 7.00 (1H, s, ArH), 7.43 (2H, d, J ¼ 1447, 1387, 1241, 1134, 853, 772; H NMR (300 MHz, DMSO):
8.4 Hz, ArH), 7.75 (2H, d, J ¼ 8.4 Hz, ArH), 8.13 (2H, s, NH2), 9.14 d 2.21 (3H, s, CH3), 4.22–4.31 (2H, m, CH2), 4.35–4.45 (2H, m,
(1H, s, NH); anal. calcd for C24H24ClN5O5S: C, 54.39; H, 4.56; N, CH2), 5.71 (1H, s, CH), 7.25–7.42 (4H, m, ArH), 7.99 (2H, d, J ¼
13.21.
9 Hz, ArH), 8.22 (2H, d, J ¼ 9 Hz, ArH), 8.28 (2H, s, NH2), 9.49
(1H, s, NH); 13C{1H} NMR (125.6 MHz, DMSO): d 13.7 (CH3), 27.6
(CH2S), 37.9 (CH), 50.8 (CH2N), 81.4 (C]C–CO), 123.0 (C–NO2),
(E)-5-Amino-N'-(1-(4-chlorophenyl)ethylidene)-8-nitro-7-
phenyl-3,7-dihydro-2H-thiazolo[3,2-a]pyridine-6-
carbohydrazide (6f). Dark yellow solid; yield: 0.393 g (84%); mp: 123.4, 126.6, 126.8, 127.0, 127.7, 130.2, 132.6 (Ar), 144.4 (C]C–
248–250 ꢁC; 1H NMR (300 MHz, DMSO): d 2.10 (3H, s, CH3), S), 146.7, 147.2 (Ar), 148.1 (C]N), 150.3 (CAr–NO2), 157.0 (C–
4.21–4.31 (2H, m, CH2), 4.36–4.44 (2H, m, CH2), 5.59 (1H, s, NH2), 165.7 (C]O); m/z (%) ¼ 509 (0.02), 471 (0.5), 432 (0.2), 387
CH), 7.17–7.41 (5H, m, ArH), 7.42 (2H, d, J ¼ 8.7 Hz, ArH), 7.74 (0.1), 326 (48), 311 (100), 292 (78), 261 (59), 222,25 179 (46), 149
(2H, d, J ¼ 8.7 Hz, ArH), 8.13 (2H, s, NH2), 9.25 (1H, s, NH); anal. (42), 117 (95), 103 (41), 77 (70), 61 (78); anal. calcd for C22H19-
calcd for C22H20ClN5O3S: C, 56.23; H, 4.29; N, 14.90.
(E)-5-Amino-7-(3-chlorophenyl)-N'-(1-(4-chlorophenyl)ethyl-
idene)-8-nitro-3,7-dihydro-2H-thiazolo[3,2-a]pyridine-6-
ClN6O5S: C, 51.31; H, 3.72; N, 16.32.
(E)-5-Amino-7-(4-chlorophenyl)-8-nitro-N'-(1-(4-nitrophenyl)
ethylidene)-3,7-dihydro-2H-thiazolo[3,2-a]pyridine-6-
carbohydrazide (6g). Orange solid; yield: 0.413 g (82%); mp: carbohydrazide (6l). Light orange solid; yield: 0.488 g (95%); mp:
237–240 ꢁC; 1H NMR (300 MHz, DMSO): d 2.11 (3H, s, CH3), 244–246 C; IR (KBr) (nmax/cmꢀ1): 3278, 3147, 1632, 1585, 1516,
ꢁ
4.20–4.30 (2H, m, CH2), 4.36–4.42 (2H, m, CH2), 5.71 (1H, s, 1454, 1306, 1238, 1134, 851, 749; 1H NMR (300 MHz, DMSO):
CH), 7.22–7.77 (8H, m, ArH), 8.16 (2H, s, NH2), 9.34 (1H, s, NH); d 2.21 (3H, s, CH3), 4.25–4.32 (2H, m, CH2), 4.36–4.42 (2H, m,
anal. calcd for C22H19Cl2N5O3S: C, 52.39; H, 3.80; N, 13.88.
(E)-5-Amino-N'-(1-(4-chlorophenyl)ethylidene)-7-(3-uo-
rophenyl)-8-nitro-3,7-dihydro-2H-thiazolo[3,2-a]pyridine-6-
CH2), 5.70 (1H, s, CH), 7.33 (2H, d, J ¼ 8.4 Hz, ArH), 7.38 (2H, d, J
¼ 8.7 Hz, ArH), 7.98 (2H, d, J ¼ 9 Hz, ArH), 8.20 (2H, d, J ¼ 9 Hz,
ArH), 8.24 (2H, s, NH2), 9.50 (1H, s, NH); 13C{1H} NMR (75.4 MHz,
carbohydrazide (6h). Yellow solid; yield: 0.379 g (78%); mp: 225– DMSO): d 14.2 (CH3), 28.1 (CH2S), 38.0 (CH), 50.9 (CH2N), 81.8
1
ꢁ
227 C; H NMR (300 MHz, DMSO): d 2.11 (3H, s, CH3), 4.20– (C]C–CO), 123.9 (C–NO2), 127.5, 128.6, 130.1, 139.4, 143.8, 144.9
4.30 (2H, m, CH2), 4.36–4.42 (2H, m, CH2), 5.72 (1H, s, CH), (C]C–S), 147.6, 147.9 (Ar), 148.5 (C]N), 151.0 (CAr–NO2), 157.7
6.95–7.74 (8H, m, ArH), 8.15 (2H, s, NH2), 9.34 (1H, s, NH); anal. (C–NH2), 166.5 (C]O); m/z (%) ¼ 509 (0.01), 453 (0.4), 410 (0.2),
calcd for C22H19ClFN5O3S: C, 54.15; H, 3.92; N, 14.35.
(E)-5-Amino-7-(3,4-dimethoxyphenyl)-8-nitro-N'-(1-(4-nitro-
phenyl)ethylidene)-3,7-dihydro-2H-thiazolo[3,2-a]pyridine-6-
carbohydrazide (6i). Light yellow solid; yield: 0.432 g (80%); mp:
368 (0.8), 326,18 311 (46), 292 (100), 261 (69), 222,20 205,10 179 (40),
149 (55), 117 (38), 103 (53), 77 (90), 61 (70); anal. calcd for C22-
H19ClN6O5S: C, 51.31; H, 3.72; N, 16.32.
(E)-5-Amino-7-(3-uorophenyl)-8-nitro-N'-(1-(4-nitrophenyl)
213–215 ꢁC; 1H NMR (300 MHz, DMSO): d 2.17 (3H, s, CH3), 3.68 ethylidene)-3,7-dihydro-2H-thiazolo[3,2-a]pyridine-6-
(3H, s, OCH3), 3.70 (3H, s, OCH3), 4.22–4.35 (2H, m, CH2), 4.36– carbohydrazide (6m). Yellow solid; yield: 0.423 g (85%); mp:
4.45 (2H, m, CH2), 5.55 (1H, s, CH), 6.86 (2H, s, ArH), 7.00 (1H, s, 242–245 ꢁC; IR (KBr) (nmax/cmꢀ1): 3279, 3145, 1630, 1581, 1516,
ArH), 7.98 (2H, d, J ¼ 9 Hz, ArH), 8.22 (2H, d, J ¼ 9 Hz, ArH), 8.24 1441, 1301, 1235, 1184, 1009, 851, 750; 1H NMR (300 MHz,
(2H, s, NH2), 9.30 (1H, s, NH); 13C{1H} NMR (125.6 MHz, DMSO): d 2.21 (3H, s, CH3), 4.22–4.31 (2H, m, CH2), 4.35–4.45
DMSO): d 14.1 (CH3), 28.1 (CH2S), 31.1 (CH), 51.2 (CH2N), 55.9 (2H, m, CH2), 5.71 (1H, s, CH), 7.25–7.42 (4H, m, ArH), 7.99 (2H,
(OCH3), 55.9 (OCH3), 82.5 (C]C–CO), 112.5, 112.6, 120.4 (Ar), d, J ¼ 9 Hz, ArH), 8.22 (2H, d, J ¼ 9 Hz, ArH), 8.28 (2H, s, NH2),
123.9 (C–NO2), 124.0, 127.4, 137.2 (Ar), 144.9 (C]C–S), 147.6 9.49 (1H, s, NH); 13C{1H} NMR (125.6 MHz, DMSO): d 13.7 (CH3),
(C]N), 148.3 (CAr–OMe), 148.6 (CAr–OMe), 150.8 (C–NH2), 156.7 27.7 (CH2S), 37.9 (CH), 50.8 (CH2N), 81.6 (C]C–CO), 113.7 (d,
(C]O); anal. calcd for C24H24N6O7S: C, 53.33; H, 4.48; N, 15.55. 2JCF ¼ 21 Hz, CH of Ar), 114.6 (d, 2JCF ¼ 21 Hz, CH of Ar), 123.2
(E)-5-Amino-7-(3-methoxyphenyl)-8-nitro-N'-(1-(4-nitro-
phenyl)ethylidene)-3,7-dihydro-2H-thiazolo[3,2-a]pyridine-6-
(C–NO2), 123.5, 124.0, 127.0 (Ar), 130.1 (d, 3JCF ¼ 8 Hz, CH of Ar),
144.4 (C]C–S), 147.2, 147.2 (Ar), 148.1 (C]N), 150.4 (CAr–NO2),
carbohydrazide (6j). Yellowish orange solid; yield: 0.397 g 157.0 (C–NH2), 162.0 (d, 1JCF ¼ 242 Hz, C–F), 165.8 (C]O); m/z
(78%); mp: 234–236 ꢁC; 1H NMR (300 MHz, DMSO): d 2.19 (%) ¼ 495 (0.02), 455 (0.4), 438 (0.2), 394 (0.1), 351 (0.5), 326,7
(3H, s, CH3), 3.70 (3H, s, OCH3), 4.22–4.28 (2H, m, CH2), 4.37– 311,12 293,19 276 (34), 245 (36), 222,3 206,15 179,17 149 (38), 117
4.42 (2H, m, CH2), 5.61 (1H, s, CH), 6.77 (1H, d, J ¼ 7.8 Hz, ArH), (40), 103 (47), 77 (100), 61 (97); anal. calcd for C22H19FN6O5S: C,
6.92 (2H, m, ArH), 7.21 (1H, t, J ¼ 7.8 Hz, ArH), 7.98 (2H, d, J ¼ 53.01; H, 3.84; N, 16.86.
This journal is © The Royal Society of Chemistry 2020
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Paper
7 M. S. A. El-Gaby, A. G. Al-Sehemi, Y. A. Mohamed and
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K. Kim, Bioorg. Med. Chem., 2008, 16, 284.
(E)-5-Amino-8-nitro-N'-(1-(4-nitrophenyl)ethylidene)-7-
phenyl-3,7-dihydro-2H-thiazolo[3,2-a]pyridine-6-
carbohydrazide (6n). Yellow solid; yield: 0.417 g (87%); mp: 244–
1
ꢁ
246 C; H NMR (300 MHz, DMSO): d 2.19 (3H, s, CH3), 4.22–
4.32 (2H, m, CH2), 4.37–4.43 (2H, m, CH2), 5.63 (1H, s, CH),
7.15–7.39 (5H, m, ArH), 7.98 (2H, d, J ¼ 9 Hz, ArH), 8.22 (2H, d, J
¼ 9 Hz, ArH), 8.24 (2H, s, NH2), 9.42 (1H, s, NH); 13C{1H} NMR
(125.6 MHz, DMSO): d 13.6 (CH3), 27.6 (CH2S), 38.2 (CH), 50.7
(CH2N), 82.1 (C]C–CO), 123.4 (C–NO2), 123.8, 126.8, 126.9,
127.8, 128.2, 144.3 (Ar), 144.4 (C]C–S), 147.1 (Ar), 147.4 (C]N),
150.3 (CAr–NO2), 156.5 (C–NH2), 165.6 (C]O); m/z (%) ¼ 480
(0.03) [M]+, 437,1 392 (0.2), 345,1 326,16 311,27 275 (54), 258 (100),
227 (80), 179,22 149 (41), 117 (30), 103 (48), 77 (71), 61 (45); anal.
calcd for C22H20N6O5S: C, 54.99; H, 4.20; N, 17.49.
11 G. A. El-Hag Ali, A. Khalil, A. H. A. Ahmed and M. S. A. El-
Gaby, Acta Chim. Slov., 2002, 49, 365.
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Chem., 2009, 17, 585; (b) A. K. Jain, A. Vaidya,
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Ed., 2013, 52, 9464; (b) M. Tomizawa and J. E. Casida, J.
Agric. Food Chem., 2011, 59, 2883.
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I. Yavari, N. Zahedi, L. Baoosi and S. Skoulika, Mol.
Diversity, 2018, 22, 11.
(E)-5-Amino-N'-(1-(4-bromophenyl)ethylidene)-7-(4-methox-
yphenyl)-8-nitro-3,7-dihydro-2H-thiazolo[3,2-a]pyridine-6-
carbohydrazide (6o). Yellow solid; yield: 0.408 g (75%); mp: 253–
1
255 ꢁC; H NMR (300 MHz, DMSO): d 2.09 (3H, s, CH3), 3.68
(3H, s, OCH3), 4.23–4.28 (2H, m, CH2), 4.35–4.39 (2H, m, CH2),
5.50 (1H, s, CH), 6.82 (2H, d, J ¼ 8.1 Hz, ArH), 7.27 (2H, d, J ¼
8.1 Hz, ArH), 7.56 (2H, d, J ¼ 8.1 Hz, ArH), 7.67 (2H, d, J ¼
8.4 Hz, ArH), 8.11 (2H, s, NH2), 9.16 (1H, s, NH); anal. calcd for
C
23H22BrN5O4S: C, 50.74; H, 4.07; N, 12.86.
(E)-5-Amino-N'-(1-(4-bromophenyl)ethylidene)-7-(4-chlor-
15 L. M. Ramos, M. O. Rodrigues and B. A. D. Neto, Org. Biomol.
Chem., 2019, 17, 7260.
16 I. A. Ibarra, A. Islas-Jacome and E. Gonzalez-Zamora, Org.
Biomol. Chem., 2018, 16, 1402.
17 G. Mari, M. Verboni, L. D. Crescentini, G. Favi,
S. Santeusanio and F. Mantellini, Org. Chem. Front., 2018,
5, 2108.
ophenyl)-8-nitro-3,7-dihydro-2H-thiazolo[3,2-a]pyridine-6-
carbohydrazide (6p). Yellow solid; yield: 0.383 g (70%); mp: 262–
1
ꢁ
264 C; H NMR (300 MHz, DMSO): d 2.10 (3H, s, CH3), 4.24–
4.29 (2H, m, CH2), 4.32–4.38 (2H, m, CH2), 5.65 (1H, s, CH),
7.34–7.37 (4H, m, ArH), 7.56 (2H, d, J ¼ 8.1 Hz, ArH), 7.66 (2H, d,
J ¼ 9 Hz, ArH), 8.14 (2H, s, NH2), 9.34 (1H, s, NH); anal. calcd for
C
22H19BrClN5O3S: C, 48.14; H, 3.49; N, 12.76. Found: C, 48.5; H,
18 (a) X. Chang, X. Zhang and Z. Chen, Org. Biomol. Chem.,
2018, 16, 4279; (b) S. Yu, R. Hua, X. Fu, G. Liu, D. Zhang,
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F. C. Gozzo, C. C. Gatto and B. A. D. Neto, J. Org. Chem.,
2018, 83, 4044.
3.2; N, 12.6.
Conflicts of interest
The authors declare no competing nancial interest.
Acknowledgements
Financial support of this research from Imam Khomeini
International University, Iran is gratefully acknowledged.
20 S. Chakrabarti, K. Panda, N. C. Misra, H. Ila and H. Junjappa,
Synlett, 2005, 1437.
21 S.-J. Yan, Y.-L. Chen, L. Liu, N.-Q. He and J. Lin, Green Chem.,
2010, 12, 2043.
Notes and references
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31048 | RSC Adv., 2020, 10, 31039–31048
This journal is © The Royal Society of Chemistry 2020