Design, synthesis and insecticidal activity of new 1,3,4-thiadiazole and 1,3,4-thiadiazolo[3,2-a]pyrimidine derivatives under solvent-free conditions

Article abstract of DOI:10.1080/00397911.2021.1945106

5-(3-Chlorophenyl)-1,3,4-thiadiazol-2-amine 2 was synthesized and employed to synthesize new 1,3,4-thiadiazole and 1,3,4-thiadiazolo[3,2-a]pyrimidine derivatives via reactions with variant electrophilic reagents under solvent-free conditions. The chemical structures of these novel compounds were elucidated scrupulously by aiding elemental data and spectroscopic techniques. The synthesized compounds were evaluated for the insecticidal activity against cotton leaf worm (Spodoptera littoralis). It was realized that the insecticidal activity of 1,3,4-thiadiazolo[3,2-a]pyrimidine derivatives emerged remarkable results comparable with 1,3,4-thiadiazole derivatives against cotton leafworm (Spodoptera littoralis).

Full text of DOI:10.1080/00397911.2021.1945106

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
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Design, synthesis and insecticidal activity of
new 1,3,4-thiadiazole and 1,3,4-thiadiazolo[3,2-
a]pyrimidine derivatives under solvent-free
conditions
Mahmoud F. Ismail, Hassan M. F. Madkour, Marwa S. Salem, Ali M. M.
Mohamed & Aly Fahmy Aly
To cite this article: Mahmoud F. Ismail, Hassan M. F. Madkour, Marwa S. Salem, Ali M. M.
Mohamed & Aly Fahmy Aly (2021): Design, synthesis and insecticidal activity of new 1,3,4-
thiadiazole and 1,3,4-thiadiazolo[3,2-a]pyrimidine derivatives under solvent-free conditions,
Synthetic Communications, DOI: 10.1080/00397911.2021.1945106
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https://doi.org/10.1080/00397911.2021.1945106
Design, synthesis and insecticidal activity of new
1
,3,4-thiadiazole and 1,3,4-thiadiazolo[3,2-a]pyrimidine
derivatives under solvent-free conditions
a
a
a
Mahmoud F. Ismail
, Hassan M. F. Madkour , Marwa S. Salem
,
a
b
Ali M. M. Mohamed , and Aly Fahmy Aly
a
Department of Chemistry, Faculty of Science, Ain Shams University, Cairo, Egypt Abbassia;
b
Central Agricultural Pesticide Lab., Pesticide Formulations Department, Agricultural research Center,
Giza, Egypt Dokky
ABSTRACT
ARTICLE HISTORY
5-(3-Chlorophenyl)-1,3,4-thiadiazol-2-amine 2 was synthesized and
Received 23 April 2021
employed to synthesize new 1,3,4-thiadiazole and 1,3,4-thiadia-
zolo[3,2-a]pyrimidine derivatives via reactions with variant electro-
philic reagents under solvent-free conditions. The chemical
structures of these novel compounds were elucidated scrupulously
by aiding elemental data and spectroscopic techniques. The synthe-
sized compounds were evaluated for the insecticidal activity against
cotton leaf worm (Spodoptera littoralis). It was realized that the
insecticidal activity of 1,3,4-thiadiazolo[3,2-a]pyrimidine derivatives
emerged remarkable results comparable with 1,3,4-thiadiazole deriv-
atives against cotton leafworm (Spodoptera littoralis).
KEYWORDS
1
,3,4-Thiadiazole; 1,3,4-
thiadiazolo[3,2-a]pyrimidine;
thiosemicarbazide;
m-chlorobenzoic acid;
insecticidal activity
GRAPHICAL ABSTRACT
CONTACT Mahmoud F. Ismail
fawzy2010@sci.asu.edu.eg
Department of Chemistry, Faculty of Science, Ain
Shams University, Cairo, Egypt Abbassia.
Supplemental data for this article can be accessed on the publisher’s website
ß 2021 Taylor & Francis Group, LLC

2
M. F. ISMAIL ET AL.
Introduction
The cotton leafworm (Spodoptera littoralis) (Boisd.) is a polyphagous insect that feeds
on leaves and is distributed worldwide. This insect is one of the major cotton pests that
cause serious harm to many important vegetables and field crops. The pest’s larvae can
[
1–3]
feed on about 90 economically important plant species belonging to 40 families.
There is a need for various insecticides with various modes of action, so scientists are
searching for alternative materials that are effective against this disease, safe for humans,
ecologically friendly, and consistent with targeted pest management (IPM) practices.
During the past years, substituted 1,3,4-thiadiazole derivatives have received significant
attention and have been increasingly investigated due to their broad spectrum of bio-
[
4–11]
[12]
logical activities.
ial,
Such ring system reported to possess antiviral,
antibacter-
[
13,14]
[15]
[16–21]
[22]
[23]
anti-inflammatory
COX-2 inhibitors,
anticancer,
anticonvulsant,
anti-depressant,
[
24]
[4,25–28]
[29]
[28]
insecticidal,
herbicidal
and acaricidal
activities.
Commercially, 1,3,4-thiadiazole motif is available in variant aspects such as Thiazafluron
and Tebuthiuron (pesticides).
It is worth noting that the applications of 1,3,4-thiadiazolo[3,2-a]pyrimidine skeleton
[
30–32]
have been prevalent in a wide range of areas, including antitumor,
antiviral
[
33]
[34,35]
[36,37]
agents,
antibacterial and antifungal,
agrochemicals and herbicides.
The literature survey revealed that the 1,3,4-thiadiazole moiety has been synthesized
[
25,26,38–41]
using variant methods.
In this regard, we utilized a methodology that depend-
ing on the reaction of an acid with thiosemicarbazide in the presence of phosphorus
[
25]
oxychloride.
By taking a closer look at the chemical structure of 2-amino-1,3,4-thiadiazole derivative,
it is evident that it possesses two neighboring nucleophilic sites as shown in Figure 1, sub-
sequently, we turned our attention to exploit the nucleophilicity of the two nitrogen atoms
of its compound to attack different electrophilic sites to construct novel 1,3,4-thiadiazole
and fused-thiadiazole compounds in order to evaluate their insecticidal activity against cot-
ton leafworm (Spodoptera littoralis) for the newly thiadiazole compounds.
Results and discussion
Chemistry
In the first efforts to obtain 5-(3-chlorophenyl)-1,3,4-thiadiazol-2-amine 2, the reaction
of m-chlorobenzoic acid with thiosemicarbazide in the ratio (1:1) in the presence of
[
42]
POCl , compound 1 was obtained instead of the desired product 2
practically.
3
Structurally, the unexpected product 1 was elucidated by spectroscopic analyses such as
1
IR, H NMR and mass spectra. Meanwhile, the requisite target compound 2 was
smoothly obtained in outstanding yield (85%) by the same methodology but with
changing the ratio between m-chlorobenzoic acid and thiosemicarbazide into (1:2). This
Figure 1. Tautmerism of 2-amino-1,3,4-thiadiazole derivative.

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Scheme 1. Synthesis of 1,3,4-thiadiazole derivatives 1 and 2.
problem may be explained on the basis of consumption of a part of thiosemicarbazide
by HCl, that evolved upon conversion of the acid to its acid chloride. So that, the for-
mation of compound 2 needs an extra quantity of thiosemicarbazide. (Scheme 1).
As a prove of the chemical structure of compounds 1 and 2, the IR spectrum of com-
ꢀ
1
pound 1 exhibited the presence of the stretching absorption band at 1673 cm compatible
1
with t
of the amide group. Moreover, the H NMR spectrum revealed the presence of
C¼O
a singlet peak (exchangeable with D O) at 13.31 ppm corresponding to one NH proton,
2
and six peaks compatible with the aromatic protons as two singlet peaks at 8.17 and
8.01 ppm and three doublet peaks at 8.06, 7.92 and 7.72 ppm corresponding to five protons
and one multiplet peak at 7.61–7.53 ppm corresponding to the remaining three protons.
13
Furthermore, the C NMR spectrum exhibited a peak at 163.2 ppm compatible with the
amide carbonyl carbon. On the other hand, the IR spectrum of compound 2 displayed
ꢀ
1
absorption bands at 3383 and 3299 cm compatible with NH group. Furthermore, the
2
1
H NMR spectrum of compound 2 manifested a singlet peak at 7.79ppm, two doublet
peaks at 7.89 and 7.07ppm corresponding to three aromatic protons and a multiplet peak
at 7.56–7.47ppm corresponding to one aromatic proton beside two protons exchangeable
13
with D O corresponding to NH protons. At the same time, the C NMR spectrum of
2
2
compound 2 is in keeping with the proposed chemical structure.
Further proof for the chemical structure of compound 1 was practically imple-
mented by synthesis of an authentic sample, through a reaction of compound 2 with
m-chlorobenzoyl chloride in the presence of pyridine. (Scheme 1)
Practically, we exploited the nucleophilic centers of compound 2 to synthesize a new
1,3,4-thiadiazole and fused-thiadiazole derivatives under solvent-free conditions, to dim-
inution utilizing the toxic solvent to preserve on the environment. At the same time, we
avoided using an eco-friendly solvent such as ethanol especially in this current stage,
because it is now very important in the medical field and sterilization after the world
was infected with the coronavirus disease (COVID-19).
Fusion of compound 2 with freshly distilled acetic anhydride and/or acetyl chloride
in the presence of pyridine afforded the monoacetyl derivative 3 (Scheme 2). This struc-
ꢀ
1
ture was supported by the appearance of an absorption band at 1694 cm (t
) in
C¼O
1
the IR spectrum. Moreover, the H NMR spectrum indicated the presence of a singlet

4
M. F. ISMAIL ET AL.
Scheme 2. Synthetic Pathway of compounds 3–5.
Scheme 3. Synthetic Pathway of compounds 6–8.
peak exchangeable with D O at 12.66 ppm compatible with NH proton and another
2
13
singlet peak at 2.21 ppm compatible with CH protons. The C NMR spectrum also
3
elucidated the chemical structure of compound 3 by the appearance of two peaks at
160.1 and 22.3 ppm corresponding to the acetyl carbons.
Fusion of compound 2 with maleic anhydride in sand bath gave N-maleimide moiety
(Scheme 2). Similarly, and under the same conditions, the N-phthalimido moiety 5
4
was emanated from the reaction of compound 2 with phthalic anhydride. The chemical
structures of compounds 4 and 5 are in keeping with their spectroscopic and elemen-
tal analyses.
The reaction of 2-aminothiadiazole derivative 2 with cinnamoyl chloride in the pres-
ence of pyridine as a base-catalyzed furnished N-cinnamoyl derivative 6 (Scheme 3).

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1
The H-NMR spectrum of compound 6 clearly underscores the foreseeable structure for
it, where it displayed a broad singlet peak at 13.02 ppm fit with one NH proton, and
two doublet peaks at 7.81 and 7.00 ppm with J ¼ 15.6 Hz, both peaks fit with the two
13
olefinic trans protons (H and H ), respectively. Moreover, the C NMR spectrum
b
a
clarified this structure.
In like manner, p-toluenesulfonamide derivative 7 was commenced by fusion of
compound 2 with p-toluenesulphonyl chloride (Scheme 3). This structure was clearly
supported by elemental analysis besides spectral data. The IR spectrum of compound 7
ꢀ
1
emerged in the presence of two bands at 1332 and 1205 cm corresponding to the SO2
1
functional group. At the same time, the H NMR spectrum also emerged two singlet
peaks at 13.21 and 2.28 ppm matching with NH and CH protons, respectively, besides
3
two additional doublet peaks in the aromatic region at 7.47 and 7.10 ppm corresponding
1
3
to aryl protons of p-tolyl moiety. Also, C NMR spectrum of compound 7 revealed a
peak at 20.8 ppm corresponding to methyl carbon.
After reaction of compound 2 with different electrophilic centers such as C¼O and
O¼S¼O, now we estimate the nucleophilicity of compound 2 with other electrophilic
centers as C¼S, namely phenyl isothiocyanate under the solvent-free condition to afford
phenyl thiourea derivative 8 (Scheme 3).
The insertion of 3-iminoindolin-2-one moiety with compound 2 to give compound 9
was performed by fusion of compound 2 with isatin in the presence of drops of piperi-
dine (Scheme 4). The IR spectrum of compound 9 unequivocally ascertained its struc-
ꢀ
1
ture by the appearance of the absorption band at 1712 cm characteristic for C¼O of
indolinone moiety.
The reaction of compound 2 with variant aryl aldehydes, namely 4-methoxybenzalde-
hyde and 4-(dimethylamino)benzaldehyde afforded Schiff bases 10a,b, respectively. Both
Scheme 4. Synthetic Pathway of compounds 9–11.

6
M. F. ISMAIL ET AL.
1
Schiff bases were elucidated by the appearance of a singlet peak in H NMR spectra at
8.94 and 8.77 ppm corresponding to azo-methine protons.
Similarly, reaction of compound 2 with heteroaryl aldehyde exemplified by 1,3-diphenyl-
H-pyrazole-4-carbaldehyde afforded N-(5-(3-chlorophenyl)-1,3,4-thiadiazol-2-yl)-1-(1,3-
1
diphenyl-1H-pyrazol-4-yl)methanimine (11). Also, this Schiff base unambiguously was
1
determined by manifesting two singlet peaks in H NMR spectrum at 9.42, 8.91 ppm corre-
sponding to C –H
and azo-methine protons, respectively.
5
(pyrazole)
Among our endeavors in this work, reaction of 2-aminothiadiazole derivative 2 with
active methylene-containing reagents, for example, diethyl malonate, ethyl acetoacetate,
ethyl benzoyl acetate, acetylacetone, malononitrile and arylidene malononitrile, to con-
struct various fused-thiadiazole derivatives as shown in Scheme 5.
At this interesting point, the fusion of 2-aminothiadiazole derivative 2 with diethyl
malonate afforded thiadiazolo[3,2-a]pyrimidinone derivative 12 (Scheme 5). The IR
ꢀ
1
spectrum of compound 12 showed characteristic bands at 3425 and 1673 cm compat-
1
ible with OH and C¼O functionalities, respectively. Moreover, the H NMR spectrum
of compound 12 in DMSO-d solution manifested the presence of two singlet peaks at
6
1
2.99 (exchangeable with D O) and 3.91 ppm corresponding to OH proton for the enol
2
tautomer and CH protons for the keto tautomer. This means that it undergoes enol-
2
Scheme 5. Synthetic Pathway of compounds 12–17.

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keto isomerization (prototropy) and it is comprising of a diasteromeric mixture of enol-
keto tautomers (prototopic tautomers) in the ratio (69:31) as depicted in scheme 5.
The reaction of 2-aminothiadiazole derivative 2 with ethyl acetoacetate gave 7-methyl
thiadiazolo[3,2-a]pyrimidinone 13 in an excellent yield (81%). The structure of 13 was
interpreted depending on variant spectroscopic data and elemental analysis. For
1
example, the H NMR spectrum revealed two singlet peaks at 6.47 and 2.63 ppm corre-
sponding to C –H
and methyl protons, respectively.
(thiadiazolopyrimidinone)
6
Similarly,
2-(3-chlorophenyl)-7-phenyl-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one
(14) was commenced by fusion of 2-aminothiadiazole derivative 2 with ethyl benzoyla-
cetate in a sand bath.
The reaction of compound 2 with b-diketone, namely acetylacetone awarded thiadia-
zolopyrimidine derivative 15 as the sole product (Scheme 5). The predictable structure
of 15 was confirmed via the IR spectrum which exhibited the stretching absorption
ꢀ
1
1
band at 3387 cm compatible with the OH group. Moreover, the H NMR spectrum of
compound 15 manifested three singlet peaks at 6.88, 2.42 and 1.90 ppm compatible with
C –H
6
and two methyl protons, respectively, and the hydroxyl proton
(thiadiazolopyrimidinone)
appeared as a broad peak at a higher deshielded chemical shift due to the formation of
intramolecular chelation H-bonding in the five-membered ring as shown in scheme 5.
13
Moreover, the C NMR spectrum exhibited peaks at 93.1, 25.4 and 23.2 ppm compat-
3
ible with the saturated (Sp ) C–OH and two methyl carbons, respectively.
Noteworthy, the suggested mechanistic pathways for the formation of compounds
1
2–15 are illustrated with efficiency as shown in scheme 6.
In case of fusion of compound 2 with malononitrile absolutely gave 6-amino-2-(3-
chlorophenyl)imidazo[2,1-b][1,3,4]thiadiazole-5-carbonitrile (16). The IR spectrum dis-
ꢀ
1
played an absorption band at 2206 cm corresponding to the conjugated cyano group.
1
Furthermore, the H NMR spectrum showed a peak at 6.24 ppm (exchangeable with
D O) which is in keeping with NH protons.
2
2
Ultimately, the reaction of compound 2 with 2-(4-methoxybenzylidene)malononitrile
furnished thiadiazolopyrimidine derivative 17.
Insecticidal activity
Results and discussion
In a continuation of our previous studies on searching about bioactive compounds bear-
[
25,26]
ing 1,3,4-thiadiazole moiety,
,3,4-thiadiazole derivatives.
The data presented in Table 1 and illustrated by Figure 2 showed the insecticidal activity
we report here on the insecticidal activity of some
1
of the synthesized thiadiazolyl amine and imine derivatives. From this result, we concluded
that the Schiff base derivative 11 was the most potent compound against cotton leafworm
(Spodoptera littoralis) where its LC50 was (556.94 lg/mL) and the least potent compound
was the Schiff base derivative 10a which recorded LC50 of (735.97lg/mL). the other two
derivatives are arranged in the following order 2 and 10b where their LC50 were 576.71
and 605.47 lg/mL, respectively. LC50 of a compound under investigation is calculated from
Ldp curves in which the response percentages and the concentration of compounds in
ppm are represented in the vertical and horizontal axes, respectively.

8
M. F. ISMAIL ET AL.
Scheme 6. The suggested mechanistic Pathways to compounds 12–15.
Table 1. The insecticidal activity of newly synthesized thiadiazolyl amine and imine derivatives.
Concentration in ppm
Toxicity
Compound
250
500
750
1000
1250
LC50
LC90
index
Slope
2
26.73
29.84
34.35
28.90
45.78
42.49
46.53
47.02
57.74
50.37
53.87
58.19
65.87
55.97
59.01
65.78
71.73
60.24
62.90
71.27
576.71
735.97
605.47
556.94
3235.37
10064.51
10178.47
3526.81
23.809
18.654
22.652
24.654
1.711
1.128
1.046
1.599
1
1
1
0a
0b
1
On considering the toxicity lines slope, we noticed that the slope decreases in the fol-
lowing order 1.711, 1.599, 1.128 and 1.046 for thiadiazoles 2, 11, 10a and 10b, respect-
ively. This order revealed that the homologous response of treated strain of cotton

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leafworm (Spodoptera littoralis) showed variation in its response toward the tested com-
pounds to be in the following order 2 > 11 > 10a > 10b.
The tabulated data in Table 2 and exhibited by Figure 3 represented the insecticidal
activity of the newly synthesized 1,3,4-thiadiazolo[3,2-a]pyrimidine and imidazo[2,1-
b][1,3,4]thiadiazole derivatives against cotton leafworm (Spodoptera littoralis). From this
table, we showed that this class of compounds is the most potent derivatives among all
the tested compounds, where they recorded the least values of LC . Also, we deduced
50
that the thiadiazolopyrimidine derivatives 14 and 17 were the most potent synthesized
compounds all over the tested compounds, where their LC50 were 137.28 and 144.34 lg/
mL, respectively. Table 2 also showed that imidazothiadiazole derivative 16 has more
insecticidal activity than the other thiadiazolopyrimidine derivative 15 and the recorded
LC50 of both was 147.37 and 185.92 lg/mL on the sequence.
In contrast to the previous results and according to the slope value of the toxicity
lines we concluded that the response of cotton leafworm (Spodoptera littoralis) was in
the following order 16 > 17 > 15 > 14 where the slopes were 2.708. 2.509. 1.621 and
0.980, respectively.
The result tabulated in Table 3 and exhibited by Figure 4 represented the insecticidal
activity of the newly synthesized thiadiazolyl amide derivatives against cotton leafworm
Spodoptera littoralis). From the results, we obtained that thiadiazolyl cinnamamide deriva-
(
tive 6 has more potential activity than both thiadiazolyl acetamide 3 and thiadiazolyl ben-
zamide 1 since the recorded LC50 were 361.51, 520.50 and 548.11 lg/mL, respectively.
Figure 2. Ldp line of the newly synthesized thiadiazolyl amine and imine derivatives.
Table 2. The insecticidal activity of newly synthesized synthesized thiadiazolopyrimidine and carbon-
itrile derivatives.
Concentration in ppm
Toxicity
Compound
250
500
750
1000
1250
LC50
LC90
index
Slope
1
1
1
1
4
5
6
7
60.07
58.26
73.16
72.47
70.89
75.69
92.39
91.15
76.50
83.69
97.17
96.31
80.12
88.18
98.71
98.18
82.64
91.01
99.40
99.05
137.28
185.92
147.37
144.34
2789.06
1148.16
439.67
469.39
100.00
73.90
93.09
95.33
0.980
1.621
2.708
2.502

1
0
M. F. ISMAIL ET AL.
Figure 3. Ldp line of the newly synthesized thiadiazolopyrimidine and imidazothiadiazole derivatives.
Table 3. The insecticidal activity of newly synthesized thiadiazolyl amide derivatives.
Concentration in ppm
Toxicity
Compound
250
500
750
1000
1250
LC50
LC90
index
Slope
1
3
6
31.25
28.73
43.98
47.73
48.78
55.29
57.74
61.02
61.78
64.59
69.14
66.18
69.61
74.88
69.47
548.11
520.50
361.51
4292.61
2776.58
8206.58
25.049
26.281
37.976
1.434
1.763
0.945
Figure 4. Ldp line of the newly synthesized thiadiazolyl amide derivatives.
The strain homogeneity has a great effect on the insecticidal activity results, this fact
could be clear on studying the slope values of the toxicity which declared that, the
treated strain of cotton leafworm (Spodoptera littoralis) showed a high response toward
thiadiazolyl acetamide 3 followed by thiadiazolyl benzamide 1 and finally thiadiazolyl
cinnamamide 6 as shown from the slope values 1.763, 1.434 and 0.945 on a sequence.

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On concerning the data presented in Table 4 and illustrated by Figure 5 which repre-
sented the insecticidal activity of the newly synthesized thiadiazole derivatives contain-
ing pyrrolone moiety against cotton leafworm (Spodoptera littoralis). We showed that as
the concentration of the tested compound increases the mortality percent increases.
Also, we deduced that compound 5 was the most active compound against the treated
pest, where it recorded LC50 of 275.47 lg/mL followed by compounds 9 and 4, where
they recorded LC50 values of 332.78 and 410.14 lg/mL, respectively.
The slope of the toxicity revealed the overall response of the treated pest against the
tested thiadiazole derivatives where it showed the homologous response in the order
4
> 9 > 5, where the slopes were 2.398, 1.667 and 1.084 on rank order.
Table 5 and Figure 6 exhibited the insecticidal activity of thiadiazole derivatives con-
taining (¼S) against cotton leaf worms (Spodoptera littoralis). This data showed that p-
toluene sulfonamide derivative 7 was more potent than phenyl thiourea derivative 8 as
given from the LC50 values 466.72 and 513.68 lg/mL, respectively.
On the other hand, the order of homologous response is somewhat different to be com-
pound 8 > 7 as a result of the slope values which are 1.666 and 1.158 on the sequence.
Table 4. The insecticidal activity of newly synthesized thiadiazole derivatives containing pyrro-
lone moiety.
Concentration in ppm
Toxicity
Compound
250
500
750
1000
1250
LC50
LC90
index
Slope
4
5
9
30.30
48.18
41.80
58.18
60.07
61.59
73.52
68.14
72.18
82.33
72.82
78.71
87.71
76.18
83.09
410.14
275.47
332.78
1403.8
4187.14
1955.16
33.471
48.951
41.263
2.398
1.084
1.667
Figure 5. Ldp line of the newly synthesized thiadiazole derivatives containing pyrrolone moiety.
Table 5. The insecticidal activity of newly synthesized thiadiazole derivatives containing (¼S).
Concentration in ppm
Toxicity
Compound
250
500
750
1000
1250
LC50
LC90
index
Slope
7
8
37.68
30.12
51.38
49.22
59.43
60.79
64.93
68.51
69.01
74.01
466.72
513.68
5963.92
3020.12
29.422
26.728
1.158
1.666

1
2
M. F. ISMAIL ET AL.
Figure 6. Ldp line of the newly synthesized thiadiazole derivatives containing (¼S).
On studying the results of the toxicity index, we declared that the thiadiazolopyrimidine
and imidazothiadiazole possess the highest insecticidal activity toward cotton leafworm
(Spodoptera) followed by thiadiazole derivatives containing pyrrolone moiety and the least
insecticidal activity showed with thiadiazolyl amine and imine derivatives. The order of the
insecticidal activity for synthesized thiadiazole derivatives with respect to toxicity index was
as follows 14 > 17 > 16 > 15 > 5 > 9> 6 > 4 > 7 > 8 > 3 > 1> 11 > 2 > 10b > 10a.
This order may be attributed to the presence of substituent or ring system as thiadiazolo-
pyrimidine, imidazothiadiazole and pyrrolone rings, carbonyl group (C¼O) and cyano
group (CN) which act to stabilize the strong aromaticity of the ring, which also provides
great in vivo stability to this five-membered ring system and low toxicity for higher verte-
brates, including human beings which also, potentiates the ¼ N–C–S moiety of the thiadia-
zole ring where It is supposed that 1,3,4-thiadiazole derivatives exhibit various biological
[43–46]
activities due to the presence of this ¼ N–C–S moiety.
Conclusion
In conclusion, various mixed-heterocyclic compounds incorporating 1,3,4-thiadiazole
and 1,3,4-thiadiazolo[3,2-a]pyrimidine derivatives were synthesized under solvent-free
conditions. The synthesized compounds were evaluated for their insecticidal activity
against cotton leaf worms (Spodoptera littoralis). The results indicated that 1,3,4-thiadia-
zolo[3,2-a]pyrimidine derivatives displayed remarkable results more than 1,3,4-thiadia-
zole derivatives against cotton leafworm (Spodoptera littoralis).
Full experimental details and spectroscopic data for all synthesized compounds could
be found via the “Supplementary Content” section of this article’s webpage.
Experimental
All reactions were followed by thin-layer chromatography (TLC) (Kieselgel 60 F254
,
Merck, Darmstadt, Germany) and under UV lamp (Thomas Scientific, Swedesboro,

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New Jersey, USA) (254 nm) spots were seen. The melting points of the newly synthe-
sized compounds were measured by Mel-Temp II melting point apparatus and are
uncorrected. IR spectra were recorded in KBr disk on Nicolet iS10 FT-IR spectrometer
1
13
(
Thermo Scientific, Waltham, USA). The H-NMR (at 300 MHz) and C-NMR (at
75 MHz) spectra were implemented on a Varian Gemini spectrometer (International
Equipment Trading Ltd., Mundelein, Illinois, USA) in DMSO-d as a solvent by using
6
tetramethylsilane (TMS) as a reference at Faculty of Science, Cairo University, Giza,
Egypt. Elemental analysis was performed on Perkin-Elmer 2400 CHN elemental ana-
lyzer (PerkinElmer, Inc., Waltham, USA). The mass spectrum was performed on
Shimadzu GC-MS QP1000EX apparatus (Shimadzu, Kyoto, Japan) at the Faculty of
Science, El-Azhar University, Cairo, Egypt. Evaluation of the insecticidal activity was
implemented at Central Agricultural Pesticide Lab., Pesticide Formulations Department,
Agricultural Research Center, Giza, Egypt.
3
-Chloro-N-(5-(3-chlorophenyl)-1,3,4-thiadiazol-2-yl)benzamide 1
Method a
A mixture of m-chlorobenzoic acid (1.56 g, 0.01 mol) and phosphorus oxychloride (15 ml)
was refluxed for 15 min, then thiosemicarbazide (0.91 g, 0.01 mol) was added, afterward
the reflux was persistent for 3 h, then the reaction mixture was cooled and 5 ml of water
was added drop by drop and then the reflux was persistent for 45 min. After cooling, the
reaction mixture was poured onto cooled water containing pieces of ice, then the mixture
was neutralized by NaOH (40%) solution. The deposited solid was filtered off and washed
well with water, dried and recrystallized from ethanol to give 1, yield: 65%.
Method B
A mixture of 2-aminothiadiazole derivative 2 (2.11 g, 0.01 mol) and m-chlorobenzoyl
ꢁ
chloride (1.28 ml) in pyridine (0.5 ml) was fused in the sand bath at 120 C for 2 h.
After cooling, the product was collected, dried and recrystallized from dioxane to give
1
, yield: 68%.
ꢁ
1: As yellow crystals; m.p.:248–250 C. Anal. Calcd. for C H Cl N OS (350.22): C,
15
9
2 3
5
ꢀ
1.44; H, 2.59; N, 12.00; S, 9.15. Found: C, 51.41; H, 2.55; N, 12.11; S, 9.12. FTIR (KBr,
ꢀ
1
.þ
1
/cm ): 3133 (NH), 1673 (C¼O). MS m/z (%): 349 (M ; 11.18). H-NMR (300 MHz,
DMSO-d ) d (ppm): 13.31 (s, 1H, NH, exchangeable with D O), 8.17 (s, 1H, Ar–H),
6
2
8
.06 (d, 1H, Ar–H, J ¼ 8.0 Hz), 8.01 (s, 1H, Ar–H), 7.92 (d, 1H, Ar–H, J ¼ 7.6 Hz), 7.72
13
(d, 1H, Ar–H, J ¼ 7.6 Hz), 7.61–7.53 (m, 3H, Ar–H). C-NMR (75 MHz, DMSO-d ) d
6
(ppm): 169.1, 163.2, 154.7, 134.1, 133.8, 132.9, 132.4, 131.9, 131.3, 131.0, 129.2, 127.8,
126.3, 125.4, 125.0.
[42]
5
-(3-Chlorophenyl)-1,3,4-thiadiazol-2-amine 2 . A mixture of m-chlorobenzoic acid
(1.56 g, 0.01 mol) and phosphorus oxychloride (15 ml) was refluxed for 15 min, then thiose-
micarbazide (1.8 g, 0.02 mol) was added, afterward, the reflux was persistent for 3 h, then
the reaction mixture was cooled and 8 ml of water was added drop by drop and then the
reflux was persistent for 3 h. After cooling, the reaction mixture was poured onto cooled
water containing pieces of ice, then the mixture was neutralized by NaOH (40%) solution.

1
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M. F. ISMAIL ET AL.
The deposited solid was filtered off and washed well with water, dried and recrystallized
ꢁ
ꢁ
[42]
from ethanol to give 2 as yellow crystals; m.p.:175–177 C (Lit. m.p.: 212v214 C) , yield:
8
4
1
7
7
5%. Anal. Calcd. for C H ClN S (211.67): C, 45.40; H, 2.86; N, 19.85; S, 15.15. Found: C,
8 6 3
ꢀ
1
5.38; H, 2.83; N, 19.89; S, 15.22. FTIR (KBr, ꢀ/cm ): 3383, 3299 (NH ), 1664 (C ¼ N),
2
.þ
1
618 (C ¼ C). MS m/z (%): 211.34 (M ;18.70). H-NMR (300 MHz, DMSO-d ) d (ppm):
6
.89 (d, 1H, Ar–H, J¼ 6.6 Hz), 7.79 (s, 1H, Ar–H), 7.07 (d, 1H, Ar–H, J ¼ 6.9 Hz),
13
.56–7.47 (m, 3H, ((1H, Ar–H) þ (2H, NH , exchangeable with D O)). C-NMR
2
2
(75 MHz, DMSO-d ) d (ppm): 169.0, 154.7, 133.7, 132.8, 130.9, 129.1, 125.4, 125.0.
6
Insecticidal activity
Materials and methods
Susceptible strain insect
In the current research, the cotton leafworm strain was taken from field colonies and
reared in the central laboratory for agricultural pesticides. This strain was collected
ꢁ
from the province of Sharkia. The strain was held at 25 ± 2 C and 65 ± 5 percent rela-
tive humidity away from any chemical pressure under laboratory conditions.
Chemical used
The newly synthesized 1,3,4-thiadiazole and fused thiadiazole derivatives.
Method of bioassay technique
The effects on 4 instar larvae of cotton leafworm (Spodoptera littoralis) of the synthe-
sized thiadiazole derivatives were determined to simulate the actual treatments under
[
47]
field conditions using the leaf dipping technique.
A stock solution of each chemical
was freshly prepared. Subsequent water dilution was made to achieve serial concentra-
tions of 250, 500, 750, 1000 and 1250 ppm. Fresh castor bean leaves were dipped in
each concentration for ten seconds then left to dry. The treated leaves were transferred
to petri-dishes and ten larvae were placed in each one then it was covered. Leaf disks
immersed in distilled water as control treatment. On drying, the leaf disks were placed
in individual Petri dishes (9-cm diameter). Each treatment (concentration) was repli-
th
cated 3 times, including water solvent control. Ten of the 4 instar larvae were placed
on each leaf disk (replication), and thus the total number of tested larvae per concentra-
tion was 30. Mortalities were recorded 24 h after insecticide treatment. Mortality data
,
[48]
were corrected using Abbott s formula
and subjected to statistical analysis by the
[
49]
method of Finney.
toxicity index calculated according to the Yun-Pei Sun equation.
Toxicity index ¼ LC of most potent compound=LC of tested compound ꢂ 100
The LC50 and toxicity index were also estimated. Noteworthy, the
[
50]
5
0
50
ORCID
Mahmoud F. Ismail
Marwa S. Salem
http://orcid.org/0000-0002-9243-6236
http://orcid.org/0000-0001-7237-6451

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