Synthesis and insecticidal assessment of some innovative heterocycles incorporating a thiadiazole moiety against the cotton leafworm,: Spodoptera littoralis

Article abstract of DOI:10.1039/c7ra06087d

New 2-cyano-N-(5-ethyl-1,3,4-thiadiazol-2-yl)acetamide (1) was utilized as a versatile precursor for the synthesis of various heterocycles, such as pyrrole, pyridine, coumarin, thiazole, pyrido[2′,3′:3,4]pyrazolo[5,1-c]triazine, triazolo[5,1-c]triazine, aminopyrazole, thiophene, 1,3-dithiolane, triazolo[1,5-a]pyrimidine and benzo[d]imidazole derivatives. The newly synthesized compounds were identified by IR, MS, ¹H NMR, ¹³C NMR, DEPT, H-H COSY, HMBC, and HSQC. Representative compounds of the synthesized products were examined and estimated as insecticidal agents against the cotton leafworm, Spodoptera littoralis.

Full text of DOI:10.1039/c7ra06087d

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Synthesis and insecticidal assessment of some
innovative heterocycles incorporating a thiadiazole
moiety against the cotton leafworm, Spodoptera
littoralis†
Cite this: RSC Adv., 2017, 7, 39773
a
b
a
b
Ahmed A. Fadda, * M. Abd El Salam, Eman H. Tawfik, E. M. Anwar
and H. A. Etman
a
New 2-cyano-N-(5-ethyl-1,3,4-thiadiazol-2-yl)acetamide (1) was utilized as a versatile precursor for the
0
0
synthesis of various heterocycles, such as pyrrole, pyridine, coumarin, thiazole, pyrido[2 ,3 :3,4]pyrazolo
[
5,1-c]triazine, triazolo[5,1-c]triazine, aminopyrazole, thiophene, 1,3-dithiolane, triazolo[1,5-a]pyrimidine
Received 31st May 2017
Accepted 19th July 2017
1
and benzo[d]imidazole derivatives. The newly synthesized compounds were identified by IR, MS,
H
13
NMR, C NMR, DEPT, H–H COSY, HMBC, and HSQC. Representative compounds of the synthesized
products were examined and estimated as insecticidal agents against the cotton leafworm, Spodoptera
littoralis.
DOI: 10.1039/c7ra06087d
rsc.li/rsc-advances
which, in one or two steps, adds a highly functionalized
substituent or heterocyclic ring to the molecule. Cyanoaceta-
Introduction
13
In recent years, the development of heterocyclic agrochemicals mides are polyfunctional derivatives possessing both electro-
has become a main trend in research on pesticides because of philic and nucleophilic aspects. These chemical aspects have
their exible structure, low mammalian toxicity, and high been used to build up diverse heterocycles with diverse ring
1
14–26
activity. As an important class of heterocyclic compounds, 2,5- sizes,
which have wide spectrums of biological activity.
disubstituted 1,3,4-thiadiazoles are related with many types of
biological properties, probably by virtue of the –N]C–S– group,
Results and discussion
Chemistry
1
2
3
4
including acaricidal, insecticidal, herbicidal, antioxidant,
5
6
7
8
antibacterial, antidepressant, antidiabetic, antifungal, anti-
9
10
convulsant and anti-inammatory effects. In particular, many The synthetic procedures adopted to obtain the target
substituted 1,3,4-thiadiazole derivatives, including Schiff base compounds are depicted in Schemes 1–5. The new starting
derivatives, are of signicant interest because they possess compound, 2-cyano-N-(5-ethyl-1,3,4-thiadiazol-2-yl)acetamide
11
anticancer activities.
The thiadiazole moiety acts as (1), was prepared in dry benzene by treatment of 2-amino-5-
a “hydrogen binding domain” and “two-electron donor system”. ethyl-1,3,4-thiadiazole with 3-(3,5-dimethyl-1H-pyrazol-1-yl)-3-
Thiadiazoles are easily capable of crossing cellular membranes oxopropanenitrile as the cyanoacetylation reagent according
27
owing to their mesoionic nature and their better liposolubility, to the previously reported procedure (Scheme 1). The structure
attributed to the presence of a sulfur atom. 1,3,4-Thiadiazoles 1 was elucidated according to its spectral data. The IR spectrum
1
2
ꢀ1
are mesoionic systems, i.e. they are polyheteroatomic systems showed absorption bands at 3449 cm for the NH function,
ꢀ1
and contain a ve-membered heterocyclic ring associated with stretching absorption bands at 2749–2955 cm
for CH
conjugated p and p electrons and discrete regions of positive aliphatic, a sharp band at 2260 cm for the cyano group and
ꢀ
1
ꢀ
1
and negative charges.
a strong sharp band at 1702 cm for the amidic carbonyl
1
The synthetic approaches adopted to obtain the newly function. Its H NMR spectrum (DMSO-d ) indicated the exis-
6
synthesized compounds depend on regioselective attack on the tence of a triplet signal at dH 1.29 ppm due to protons of the
cyanoacetamido moiety of the precursor 1 by different reagents,
a
Chemistry Department, Faculty of Science, Mansoura University, 35516 Mansoura,
Egypt. E-mail: afadda50@yahoo.com
b
Plant Protection Research Institute, ARC, Dokki, Giza, Egypt
†
Electronic supplementary information (ESI) available. See DOI:
0.1039/c7ra06087d
1
Scheme 1 Synthesis of starting compound 1.
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methyl group, a quartet signal at d
H
3.01 ppm attributed to triethylamine furnished the pyrrole derivative 4. The proposed
methylene protons and two singlet signals at dH 4.06 and d
structure was in agreement with the analytical and spectral
H
1
3
1
1
2.73 ppm ascribed to CH protons and NH proton. Its C NMR data. Therefore, the H NMR spectrum of the yielded product
2
and DEPT spectra (DMSO-d ) indicated the presence of a methyl exhibited three singlet signals at dH 7.02, 7.06 and 7.91 ppm
6
carbon at d
and d 26.49 ppm in addition to a cyano carbon at d
15.57 ppm, two quaternary carbons at d 158.44 and d
62.69 ppm, and a carbonyl carbon at d
C C
14.19 ppm and two methylene carbons at d 23.16 corresponding to the pyrrolone proton H-4, pyrimidinone H-3
C
C
C
and NH proton, respectively, in addition to a broad singlet
1
1
C
signal at d
H
8.63 ppm due to NH
2
protons, two triplets at d
, two quartets at d
, and a multiplet at d
7.43 ppm assigned to aromatic protons. The IR spectrum
Thus, cyclocondensation of compound 1 with 2-hydroxy-1- revealed the presence of two CO groups stretching at 1666 and
H
1.26
2.95
H
7.20–
C
166.49 ppm. The MS and 1.41 ppm corresponding to two CH
3
H
+
exhibited a molecular ion peak (M ) at m/z 196 assigned to the and 3.19 ppm assignable to two CH
molecular formula C H N OS.
2
7
8 4
ꢀ1
ꢀ1
naphthaldehyde in hot ethanol containing piperidine as 1700 cm , an NH group at 3142 and 3331 cm and an NH
a basic catalyst furnished the coumarin derivative 2. The reac- absorption band at 3408 cm . The mass spectrum displayed
tion of 1 with 1,3-dicarbonyl compounds was studied for the a molecular ion peak at m/z 492 ascribed to the molecular
2
ꢀ
1
purpose of establishment of pyridine derivatives with effective formula
22 20 8 2 2
C H N O S . Furthermore, Gewald reaction of
biological activities. Therefore, it reacted with acetylacetone to compound 1 with both phenyl isothiocyanate and elemental
afford the pyridine derivative 3. The previous product's structure sulfur in warm ethanol using triethylamine as a basic catalyst
was established according to its spectral data. The IR spectrum yielded the thiazole derivative 5. The proposed structure was in
ꢀ
1
1
exhibited three absorption bands at 3447, 2221 and 1676 cm
agreement with the elemental analysis, IR and MS (Scheme 2).
Recently, diazotized heterocyclic amines have been reported
due to OH, CN and CO function groups, respectively. The H
NMR spectrum indicated the appearance of three new singlets at as a perfect building block for the synthesis of bridged-head
29
H
d 2.11, 2.42 and 6.56 ppm attributed to two methyl protons and nitrogen heterocyclic systems. Consequently, coupling of
1
3
the pyridinone H-5. In addition, its C NMR spectrum indicated compound 1 with both 4,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-
the presence of two new methyl carbons at d 20.31 and d 3-diazonium chloride and 1H-1,2,4-triazol-3-diazonium chlo-
0.99 ppm and one aromatic carbon at d 100.38 ppm. The ride in pyridine at 0–5 C furnished the corresponding
C
C
30
ꢁ
2
C
structure of the pyridine derivative 3 was also established by 2D hydrazono compounds 6 and 8. When compounds 6 and 8 were
NMR, such as H–H COSY, HSQC and HMBC. The mass spectrum heated under reux in acetic acid, they cyclized to N-(5-ethyl-
+
exhibited a molecular ion peak (M ) at m/z 260, which agreed 1,3,4-thiadiazol-2-yl)-4-imino-8,10-dimethyl-4,6-dihydropyrido
0 0
12 4
with the molecular formula C12H N OS (Scheme 2).
[2 ,3 :3,4]pyrazolo[5,1-c][1,2,4]triazine-3-carboxamide (7) and N-
Recently, the reaction of a-halocarbonyl compounds with the (5-ethyl-1,3,4-thiadiazol-2-yl)-4-imino-4,6-dihydro-[1,2,4]triazolo
cyanoacetamide moiety has been reported as a simple, new and [5,1-c][1,2,4]triazine-3-carboxamide (9), respectively. The nucle-
effective synthetic route for the production of pyrrole deriva- ophilic properties of the ring nitrogen enabled attack on the
28
tives. Hence, it was fascinating to study the reaction of 1 with cyano group in order to synthesize compounds 7 and 9. The IR
phenacyl bromide. Cyclocondensation of 1 with phenacyl spectrum of 7 exhibited three absorption bands at 3449, 3433,
ꢀ
1
bromide in hot ethanol containing a catalytic amount of and 3406 cm due to three NH groups besides one carbonyl
ꢀ
1
1
absorption band at 1646 cm . The H NMR spectrum displayed
two D O-exchangeable singlets at d 12.33 and 12.82 ppm due
to two NH protons, and additionally three singlets at d 2.47,
.79 and 6.98 ppm were characterized for two methyl protons of
the pyridine ring and one aromatic proton of the pyridine ring,
respectively. In addition, a triplet and a quartet were found at d
.31 and 3.02 ppm, characteristic of the side chain ethyl group.
Its mass spectrum indicated a molecular ion peak at m/z 369
2
H
H
2
H
1
+
(
M ), which agreed with its molecular formula of C H N OS.
15 15 9
Compound 9's structure was conrmed on the basis of spectral
data. Its IR spectrum exhibited the lack of an absorption band
attributed to the cyano function. Three NH absorption bands
ꢀ
1
appeared at 3128, 3331 and 3440 cm , while a strong absorp-
ꢀ
1
tion appeared at 1661 cm for the amidic carbonyl group. The
1
H NMR spectrum (DMSO-d ) indicated the absence of a singlet
6
signal assignable to methylene protons, whereas a singlet signal
was found at dH 8.58 ppm due to the aromatic proton of the
triazole ring, as well as two singlets at d
characteristic of NHCO and ]NH protons, while the side chain
CH CH protons appeared at d 1.30 ppm as a triplet and at d
H
11.84 and 14.37 ppm
2
3
H
H
Scheme 2 Synthesis of coumarin, pyridine, pyrrole, thiazole, triazolo
0
0
3.02 ppm as a quartet. Moreover, the mass spectrum for the
[
5,1-c]triazine
pyrido[2 ,3 :3,4]pyrazolo[5,1-c]triazine
and
azo
compound derivatives.
triazolo[5,1-c]triazine structure 9 displayed a molecular ion
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peak (M ) at m/z 291 corresponding to the molecular formula
C H N OS (Scheme 2).
9
9 9
Due to its highly biological activity, next, the reactivity of the
active methylene group existing in compound 1 towards various
diazonium salts was also studied. Thus, diazocoupling reaction
of compound 1 with antipyrine diazonium chloride, sulfathia-
zole diazonium chloride and sulfamethazine diazonium chlo-
ꢁ
ride in pyridine at 0–5 C afforded the hydrazone derivatives
1
1
0a–c. IR, H NMR and MS results were in agreement with the
proposed structures. Thus, the IR spectrum of 10b exhibited an
Scheme 3 Reaction of compound 1 with phenyl isothiocyanate.
ꢀ
1
absorption band at 2231 cm attributed to the cyano function,
ꢀ1
while absorption bands at 3130, 3226 and 3469 cm were
ascribed to three NH groups, in addition to a strong absorption
ꢀ1
1
band at 1665 cm for the carbonyl group. Its H NMR spectrum
DMSO-d ) provided two olenic protons, H-5 and H-4, of the
thiazole ring, which appeared as doublets at d 6.84 and
.26 ppm that were coupled to each other with a coupling
constant J ¼ 4 Hz, while the aromatic protons appeared at d
(
6
H
7
H
0
0
7
.80 and 7.97 ppm as doublets in an AA XX system, J ¼ 8 Hz, in
addition to three singlet signals at dH 12.37, 12.38 and
2.81 ppm ascribed to ]N–NH, NHSO and NHCO, respectively.
Moreover, the methyl protons were appeared as triplet signals at
1.30 ppm, while the methylene protons appeared as quartet
signal at d 3.01 ppm. Moreover, the mass spectrum of
1
2
d
H
H
compound 10b displayed a molecular ion peak at m/z 462
ascribed to the molecular formula C H N O S (Scheme 2).
1
6
14 8 3 3
The reactivity of the methylene group in the cyanoacetamide
derivative 1 towards isothiocyanate was examined. Thus, treat- Scheme 4 Synthesis of arylidene, aminopyrazole and 2-pyridone
derivatives.
ment of 1 with phenyl isothiocyanate in DMF including potas-
sium hydroxide at room temperature furnished the non-isolable
thiocarbamoyl salt 11, which underwent heterocyclization upon
reaction with a-halocarbonyl compounds chloroacetyl chloride, NMR and 2D NMR, such as H–H COSY, HSQC and HMBC. Its
+
chloroacetone and phenacyl chloride to give the corresponding mass spectrum displayed a molecular ion peak (M ) at m/z 369,
thiazole derivatives 12, 13a and 13b, respectively (Scheme 3). which agreed with the molecular formula C17
The structure of 12 was characterized by the appearance of spectrum of 13b indicated an absorption band at 3446 cm for
15 5 2
H N OS . The IR
ꢀ
1
ꢀ
1
a singlet signal equivalent to two protons at d 4.02 ppm in the the NH group, a sharp band at 2187 cm for the cyano function
H
1
ꢀ1
H NMR spectrum, which represent the C5 protons of the and a strong sharp band at 1626 cm for the carbonyl function.
1
thiazolidinone moiety. In addition, a multiplet signal equiva- The H NMR spectrum (DMSO-d
6
) revealed the presence of two
7.19 and 14.49 ppm assignable to the
aromatic protons. The IR spectrum revealed the presence of olenic proton of the thiazole ring and the NH proton, and
lent to ve protons at d
H
7.38–7.52 ppm was ascribed to the singlet signals at d
H
ꢀ1
a new absorption band at 1747 cm due to the carbonyl group a multiplet signal at d
7.21–7.61 ppm assigned to aromatic
H
at C4 of the thiazole ring. According to the MS of compound 12, protons, in addition of triplet and quartet signals at d
H
1.30 and
the m/z was 371 corresponding to its molecular formula 2.96 ppm due to the ethyl group. The mass spectrum exhibited
C H N O S . The IR spectrum of 13a exhibited stretching a molecular ion peak at m/z 431 attributed to the molecular
1
6
13 5 2 2
ꢀ
1
frequencies at 3486, 2184 and 1626 cm for the NH, CN and CO formula C22
17 5 2
H N OS .
1
frequencies, respectively. The H NMR spectrum exhibited two
Moreover, the reaction of the intermediate 11 with chlor-
and oacetonitrile furnished (E)-2-(4-amino-3-phenylthiazol-2(3H)-
olenic protons of the thiazole ring, a multiplet signal at d
ylidene)-2-cyano-N-(5-ethyl-1,3,4-thiadiazol-2-yl)acetamide (14).
.48–7.60 ppm related to aromatic protons, in addition to IR and MS results are compatible with the proposed structure
a triplet at d 1.28 ppm and a quartet at d 2.91 ppm assignable (Scheme 3).
singlet signals at d
H 3
1.88 and 7.01 ppm due to the CH
H
7
H
H
1
3
to the side chain ethyl group. The C NMR spectrum was
assigned by signals at dC 13.11 and 13.98 ppm for the two dimethyl sulfate furnished the novel ketene N,S-acetal 15. The
methyl carbons, a signal at d
22.71 ppm due to the methylene structure of 15 was identied by spectral data. The IR spectrum
carbon, a signal at d
106.89 ppm related to the methine carbon, displayed absorption bands at 3448, 3313 and 2227 cm due to
a signal at d 115.16 ascribed to cyano carbon, and signals at d
two NH groups and the nitrile function, respectively, in addition
28.73–130.51 ppm assigned to aromatic carbons. The structure to a carbonyl absorption band at 1638 cm . Its mass spectrum
of the thiazole derivative 13a was also established by DEPT
Treatment of the thiocarbamoyl salt intermediate 11 with
C
ꢀ
1
C
C
C
ꢀ
1
1
1
3
+
C
exhibited a molecular ion peak at m/z 345 (M ), which agrees
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1
15 5 2
with its molecular formula C15H N OS . Its H NMR spectrum 1 in ethanol in the presence of piperidine, it afforded 2-pyridone
displayed three singlet signals at dH 2.85, 9.80 and 9.83 ppm derivatives 19a–d. The structures 18a–d and 19a–d were
assignable to SCH , NHPh and NHCO, respectively, a multiplet conrmed on the basis of spectral data.
3
signal at d 7.10–7.49 ppm related to the aromatic protons, and
Treatment of compound 1 with carbon disulde in DMF,
containing potassium hydroxide, at room temperature afforded
H
a triplet signal at d
.04 ppm corresponding to CH
spectrum was identied by signals at d
characterized to the two methyl carbons, a signal at d
H H
1.30 ppm and a quartet signal at d
1
3
3
2
CH
3
protons. The C NMR the intermediate enaminonitrile 20, which underwent hetero-
11.87 and 17.45 ppm cyclization upon treatment with a-halocarbonyl compounds,
C
C
C
such as phenacyl bromide, chloroacetyl chloride, to give the
corresponding ketene S,S-dithiolane derivatives or thiophene
2
1
1
1
4.38 ppm ascribed to the methylene carbon, a signal at d
14.58 ppm assigned to the cyano carbon, signals at d 123.6– derivatives (Scheme 5). Thus, the in situ stirring reaction of the
C
28.41 ppm assigned to aromatic carbons, and a signal at dC non-isolable intermediate 20 with phenacyl bromide or chlor-
63.68 ppm attributed to the amidic carbonyl carbon atom. The oacetyl chloride in the presence of a protic solvent such as
structure of the ketene N,S-acetal 15 was also characterized by ethanol afforded the 1,3-dithiolane derivatives 21 and 23,
1
3
DEPT C NMR and 2D NMR, such as H–H COSY, HSQC and respectively. On the other hand, when the intermediate enam-
HMBC (Scheme 3). inonitrile 20 was reuxed with phenacyl bromide in DMF only
Next, the synthetic potency and applicability of cyanoaceta- as an aprotic solvent and in the presence of a catalytic amount
mide derivative 1 were investigated to develop a facile and of triethylamine, a thiophene derivative 22 was obtained. The
convenient route to some novel pyrazole and pyridine derivatives spectral data of the isolated products was in complete agree-
31,32
with an anticipated wide spectrum of bioresponses.
Thus, the ment with structures 21, 22 and 23. The IR spectrum of
Knoevenagel condensation of 1 with aromatic aldehydes, namely compound 22 indicated the lack of an absorption band
piperonal, vanilline, and 4-N,N-dimethylbenzaldehyde, in assigned to a conjugated C^N function and showed absorption
ꢀ1
reuxing ethanol using piperidine as a basic catalyst afforded bands at 3413, 3345, 3296, 2622, 1718 and 1645 cm assignable
the corresponding arylidene derivatives 16a–c. Treatment of 16c to NH, NH , SH, PhCO, and amidic C]O functions, respec-
2
1
with hydrazine hydrate in boiling ethanol yielded 3-amino-5-(4- tively. The H NMR spectrum (DMSO-d
6
) displayed a broad
, and a multiplet
(
dimethylamino)phenyl)-N-(5-ethyl-1,3,4-thiadiazol-2-yl)-1H- singlet signal at d 8.35 ppm assignable to NH
H
2
pyrazole-4-carboxamide (17). Michael addition of hydrazine signal in the dH 7.43–7.60 ppm region that is distinctive for
hydrate to a,b-unsaturated nitrile 16c led to the formation of aromatic protons, besides triplet and quartet signals at dH 1.31
compound 17 via in situ intramolecular 1,5-dipolar cyclization and 2.95 ppm, respectively, corresponding to the side chain
through the nucleophilic addition of the amino group to the ethyl group. Its mass spectrum exhibited a molecular ion peak
cyano function to afford dihydropyrazole, which underwent at m/z 390, corresponding to molecular formula C16
H
14
N
4
O
2
S
3
.
1
3
auto oxidation to furnish the target pyrazole. The assignment of The C NMR spectrum was characterized by a signal at d
C
1
structures 16a–c and 17 was supported by spectral data. The H 12.37 ppm ascribed to the methyl carbons, a signal at d
C
6 C
NMR (DMSO-d ) spectra of structures 16a–c exhibited, in 23.29 ppm ascribed to methylene carbon, a signal at d 126.83–
general, a singlet signal at dH 8.082–8.353 ppm attributable to 130.71 ppm attributed to aromatic carbons, and signals at dC
vinylic protons. Furthermore, the IR spectrum of compound 17 167.14 and 185.86 ppm corresponding to the two carbonyl
revealed the absence of a cyano function and instead, the carbon atoms. The structure of the thiophene derivative 22 was
ꢀ1
13
appearance of a new absorption band at 3280 and 3152 cm
assigned to an NH group.
One-pot reactions of the cyanoacetamide derivative 1 with
also characterized by DEPT C NMR and 2D NMR, such as H–H
2
COSY, HSQC and HMBC.
The ketene S,S-dithioacetal 24 was prepared by reaction of 1
ethyl cyanoacetate and different aromatic aldehydes, namely with carbon disulde in the presence of potassium hydroxide in
benzaldehyde, p-nitrobenzaldehyde, p-chlorobenzaldehyde and DMF, followed by alkylation with dimethyl sulfate (Scheme 5).
4
-N,N-dimethylbenzaldehyde (1 : 1 : 1 molar ratio), in reuxing The structure of 24 was established on the basis of the spectral
1
13
13
ethanol containing a catalytic amount of piperidine yielded the data ( H NMR, C NMR, DEPT C NMR and 2D NMR, such as
-pyridone derivatives 18a–d, respectively. On the other hand, H–H COSY, HSQC and HMBC).
2
the 2-pyridone derivatives 18a–d, were also acquired via reac-
tion of cyanoacetamide 1 with arylidene ethyl cyanoacetate in
hot ethanol under reux containing piperidine as the catalyst.
In addition, pyridin-2-ones 18d and 19d were also obtained via
the reaction of the arylidene derivative 16c with ethyl cyanoa-
cetate and malononitrile, respectively, in ethanol in the pres-
ence of piperidine as the catalyst. Another route for the
synthesis of 2-pyridone derivatives was the one-pot reaction of
the cyanoacetamide derivative 1 with malononitrile and the
same mentioned aromatic aldehydes (1 : 1 : 1 molar ratio) fol-
lowed by reuxing in ethanol containing a few drops of piper-
idine to furnished 19a–d. Moreover, when arylidene
malononitrile was reuxed with the cyanoacetamide derivative Scheme 5 Reaction of compound 1 with carbon disulfide.
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Polarized cyanoketene S,S-acetals are utilized as a key insecticidal activity, such as in the fused heterocyclic
intermediate for the synthesis of a wide-ranging variety of fused compounds 7and 9. Furthermore, compound 10a possesses
heterocycles. Thus, further reaction of 24 with 3-amino-1H- a toxic effect, which may be due to the presence of a pyrazolone
1,2,4-triazole in reuxing pyridine afforded triazolo[1,5-a] moiety and a cyano group, thus suggesting that the compounds
pyrimidine 25. Compound 25 was also elucidated by the spec- from the present series with electron withdrawing groups can
tral data. Moreover, compound 24 was also used as a versatile serve as important gateways for the design and development of
starting material for the synthesis of fused heterocyclic new insecticidal agents with potent activity and minimal toxicity.
compounds by treatment with bifunctional nucleophilic
reagents. Thus, heating of 24 with o-phenylenediamine in
pyridine afforded benzo[d]imidazole derivative 26. The IR
Experimental
Instruments
spectrum of 26 exhibited absorption bands at 3451, 3303, and
ꢀ1
ꢀ1
3
130 cm for three NH stretching modes, a band at 2219 cm
All melting points were recorded using a Gallenkamp melting
for the cyano function, and a strong absorption band for the point apparatus in degrees centigrade and are uncorrected. The
ꢀ
1
1
amidic carbonyl group at 1679 cm . The H NMR spectrum IR spectra (KBr) were determined on a Mattson 5000 FTIR
revealed no signal for SCH protons, while a multiplet signal at spectrophotometer at the Faculty of Science, Mansoura
7.47–7.64 ppm was assigned to aromatic protons, two singlet University. NMR spectra ( H, C, DEPT, H–H COSY, HSQC and
signals at d 7.93 ppm and d 8.35 ppm appeared for 2NH and HMBC) were acquired using a Bruker WP 400 MHz, 500 MHz,
3
1
13
d
H
H
H
NHCO protons, respectively, beside a triplet at dH 1.35 ppm 300 MHz and 125 MHz at the Faculty of Pharmacy, Beni-Suef
attributed to CH3 protons, and a quartet at dH 3.06 ppm University with DMSO-d as the solvent, utilizing TMS as an
6
assigned to CH protons. Its mass spectrum exhibited a molec- internal standard reference, and chemical shis are expressed
2
ular ion peak at m/z 312, attributed to the molecular formula as d ppm. Mass spectra were measured using a Finnegan MAT
C
14
H
12
N
6
OS (Scheme 5).
212 instrument at the Faculty of Science, Cairo University, and
the Regional Center for Mycology & Biotechnology, Al-Azhar
University. Elemental analyses were performed at the Micro-
analytical Unit, Faculty of Science, Cairo University. TLC (silica
Insecticidal activity
Toxicity test for the cotton leafworm, Spodoptera littoralis. gel, aluminium sheets 60 F254, Merck) was carried out aer all
The insecticidal activities of the newly synthesized tested the reactions.
nd
compounds against the 2 instar larvae of the cotton leafworm,
S. littoralis (Boisd.), of the laboratory strain are shown in
Table 1. The bioassay results revealed that all tested compounds
possess strong to weak insecticidal activity aer 7 days of
treatment with median lethal concentration (LC50) values that
ranged from 627.94 to 64.12 ppm. The efficacy of the different
tested compounds was measured by comparing the tested
compounds (based on LC50 value) with the most effective
compound (the lowest LC50 value) according to the toxicity
index. Regarding the determined LC50 and LC90 values, 1,3,4-
thiadiazole derivatives 10b, 10c, 7, 10a and 9 showed the most
potent toxic effects with LC50 values of 64.12, 69.17, 75.51, 91.45
and 101.30 ppm, respectively, and toxicity indices of 100, 92.69,
Synthesis of 2-cyano-N-(5-ethyl-1,3,4-thiadiazol-2-yl)acetamide
1)
(
A solution of 2-amino-5-ethyl-1,3,4-thiadiazole (5.16 g, 0.04 mol)
in dry benzene (30 mL) was added to a solution of 3-(3,5-
dimethyl-1H-pyrazol-1-yl)-3-oxopropanenitrile (6.52 g, 0.04 mol)
in the same solvent (15 mL) and the reaction mixture was
reuxed for 3 h. Aer cooling, the solid precipitate was isolated
by ltration and puried via recrystallization from ethanol to
ꢁ
afford 1. White crystals; mp 230–232 C; yield 90%; IR (KBr)
ꢀ
1
1
n/cm : 3449 (NH), 2260 (CN), 1702 (CO); H NMR (400 MHz,
DMSO-d ): d ppm 1.29 (t, 3H, CH ), 3.01 (q, 2H, CH ), 4.06 (s,
6
H
3
2
1
3
2
H, CH ), 12.73 (s, 1H, NHCO). C NMR (400 MHz, DMSO-d6):
2
84.91, 70.11 and 63.29%, respectively. It is interesting to note
C
d ppm 14.19, 23.16, 26.49, 115.57, 158.44, 162.7, 166.49. MS m/
that the insecticidal activities of the tested compounds against
+
+
z (%): 197 (M + 1, 83.33), 196 (M , 69.23), 181 (89.74), 155
94.87), 139 (100), 110 (94.87), 71 (93.59), 61 (91.03). Anal. for
OS (196.23): calcd: C, 42.85; H, 4.11; N, 28.55%; found:
nd
the 2 instar larvae of S. littoralis (Boisd.) aer 7 days of
(
treatment obey the following smooth order: 10b > 10c > 7 > 10a >
7 8 4
C H N
9 > 5 > 18c > 18b > 17 > 19c > 22 > 12 > 16a > 4 > 19d > 18d > 25 >
18a > 19b > 13b > 14 > 19a > 26 > 3 > 2 > 16c > 23 > 21 > 15 > 13a >
24 > 1.
C, 42.92; H, 4.05; N, 28.43%.
Synthesis of N-(5-ethyl-1,3,4-thiadiazol-2-yl)-3-imino-3H-benzo
Structure–activity relationship. The structure–activity rela-
tionship revealed that 1,3,4-thiadiazole derivatives 10b and 10c
[
f]chromene-2-carboxamide (2)
were the most potent toxic compounds and exhibited interesting To a solution of compound 1 (0.4 g, 0.002 mol) in absolute
biological activities, and thus emerged as potential leads for ethanol (25 mL) in the presence of piperidine (0.5 mL), 2-
33
further development as insecticides candidates. This may be hydroxy-1-naphthaldehyde (0.35 g, 0.002 mol) was added. The
due to the presence of a sulfonamide group in addition to reaction mixture was reuxed for 3 h and then le to cool. The
a cyano group in their structures, beside the other common formed precipitate was ltered off, puried by washing with
features of all compounds. Moreover, the results of the insecti- ethanol, and then dried and recrystallized from ethanol to
ꢁ
cidal activity clearly demonstrated that the presence of electron furnish 2. Pale yellow crystals; mp 253–255 C; yield 85%; IR
ꢀ
1
1
withdrawing groups/atoms is essential for enhancing (KBr) n/cm : 3435, 3322 (2NH), 1733 (CO). H NMR (400 MHz,
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nd
Table 1 Insecticidal activity of the newly synthesized compounds against the 2 instar larvae of the cotton leafworm, S. littoralis (Boisd.), after 7
a
days of treatment
LC50 (ppm) and condence
LC90 (ppm) and condence
Toxicity index
Tested compounds
limits at 95%
limits at 95%
Slope
% at LC50 value
1
1
7
1
9
5
1
1
1
1
2
1
1
4
1
1
2
1
1
1
1
1
2
3
2
1
2
2
1
1
2
1
0b
0c
64.12, 47.12, 87.01
69.17, 53.80, 87.48
75.51, 59.44, 95.05
259.07, 163.95, 666.16
225.01, 164.53, 366.87
235.22, 173.25 377.15
288.78, 210.83 493.24
422.79, 295.71, 725.63
454.49, 323.96, 774.83
2.113 ꢂ 0.417
2.502 ꢂ 0.351
2.597 ꢂ 0.355
2.566 ꢂ 0.429
2.065 ꢂ 0.267
2.154 ꢂ 0.317
2.049 ꢂ 0.288
1.767 ꢂ 0.231
2.250 ꢂ 0.319
2.197 ꢂ 0.322
2.362 ꢂ 0.279
2.267 ꢂ 0.326
2.231 ꢂ 0.323
2.336 ꢂ 0.291
1.908 ꢂ 0.222
2.357 ꢂ 0.298
2.127 ꢂ 0.241
2.391 ꢂ 0.302
2.186 ꢂ 0.275
2.772 ꢂ 0.391
2.125 ꢂ 0.284
2.181 ꢂ 0.266
2.145 ꢂ 0.264
1.846 ꢂ 0.211
2.539 ꢂ 0.295
2.178 ꢂ 0.269
2.188 ꢂ 0.269
2.091 ꢂ 0.264
2.293 ꢂ 0.280
2.297 ꢂ 0.309
2.693 ꢂ 0.347
2.756 ꢂ 0.333
100
92.69
84.91
70.11
63.29
55.52
27.23
26.61
24.44
22.05
21.79
21.44
19.95
19.19
18.58
18.35
17.07
16.81
16.55
16.44
16.22
14.97
14.30
13.44
13.32
13.24
13.22
13.01
12.29
11.64
11.34
10.21
0a
91.45, 67.78, 116.76
101.30, 76.88, 131.68
115.48, 84.07, 150.36
235.41, 178.96, 309.27
240.91, 181.73, 311.86
262.31, 194.03, 334.36
290.72, 215.83, 371.94
294.26, 231.53, 369.04
298.94, 224.51, 380.06
321.34, 242.23, 408.97
334.04, 256.08, 416.27
344.93, 264.73, 439.91
349.27, 268.69, 434.98
375.58, 294.25, 470.43
381.33, 296.33, 472.43
387.34, 294.35, 485.22
389.93, 308.90, 482.03
395.26, 300.87, 497.92
428.20, 330.22, 531.29
448.32, 346.01, 556.57
476.84, 370.61, 601.48
481.22, 383.88, 582.89
484.28, 377.30, 598.21
484.93, 378.15, 598.60
492.62, 381.52, 611.87
521.67, 412.29, 638.29
550.83, 436.27, 682.24
564.99, 457.82, 683.14
627.94, 513.81, 747.33
8c
8b
7
9c
2
993.61, 673.32, 1853.32
1279.72, 870.94, 2322.95
973.84, 719.65, 1548.13
1114.06, 806.06, 1860.78
1026.68, 762.93, 1571.35
1098.63, 802.36, 1798.5
1206.54, 872.60, 2018.38
1181.66, 904.50, 1731.51
1619.94, 1158.03, 2627.91
1221.88, 931.20, 1810.47
1504.17, 1112.55, 2304.69
1310.07, 999.64, 1941.12
1494.55, 1129.37, 2243.94
1130.61, 855.53, 1745.80
1584.55, 1162.05, 2541.15
1656.80, 1261.38, 2451.76
1774.75, 1340.77, 2669.08
2359.00, 1688.68, 3822.99
1538.40, 1215.39, 2137.24
1877.49, 1418.89, 2829.16
1868.67, 1414.22, 2808.55
2020.45, 1503.41, 3137.98
1889.44, 1445.06, 2792.62
1990.66, 1462.13, 3221.37
1690.21, 1306.90, 2486.15
1831.85, 1459.39, 2542.52
2
6a
9d
8d
5
8a
9b
3b
4
9a
6
6c
3
1
5
3a
4
a
Toxicity index is dened as the ratio of the most effective compound's LC50 value to the other tested compound's LC50 value multiplied by 100.
DMSO-d ): d ppm 1.20 (t, 3H, CH ), 2.80 (q, 2H, CH ), 7.65–8.66 1.37 (t, 3H, CH ), 2.11 (s, 3H, CH ), 2.42 (s, 3H, CH ), 3.19 (q, 2H,
6
H
3
2
3
3
3
1
3
13
(
m, 6H, Ar-H), 9.81 (s, 1H, CH]). C NMR (400 MHz, DMSO- CH ), 6.56 (s, 1H, pyridine H-5). C NMR (400 MHz, DMSO-d6):
2
d ): d ppm 13.8, 23.11, 100.79, 112.33, 115.02, 116.75, 122.55,
d
ppm 13.54, 20.31, 20.99, 23.76, 100.38, 110.02, 114.97,
C
6
C
1
1
26.86, 128.79, 129.07, 129.38, 129.98, 137.17, 149.6, 155.03, 151.26, 158.35, 160.08, 161.93, 176.27. The H–H COSY, HSQC
57.20, 159.65, 168.08. Also H–H COSY, HSQC and HMBC and HMBC results are in agreement with the proposed struc-
+
+
+
proved the structure. MS m/z (%): 350 (M , 12.13), 288 (57.85), ture. MS m/z (%): 261 (M + 1, 12.78), 260 (M , 14.02), 205
74 (42.21), 194 (15.78), 182 (51.66), 169 (47.38), 152 (47.8), 120 (80.89), 178 (6.97), 147 (100), 119 (14.53), 104 (6.63), 77 (10), 51
39.18), 97 (57.97), 71, (50.95), 64 (59.97), 51 (100). Anal. for (2.45). Anal. for C12 OS (260.32): calcd: C, 55.37; H, 4.65; N,
C H N O S (350.4): calcd: C, 61.70; H, 4.03; N, 15.99%; found: 21.52%; found: C, 55.25; H, 4.55; N, 21.38%.
2
(
12 4
H N
1
8
14 4 2
C, 61.55; H, 3.96; N, 16.05%.
Synthesis of (E)-5-((amino(1-(5-ethyl-1,3,4-thiadiazol-2-yl)-2-
oxo-5-phenyl-1,2-dihydro-3H-pyrrol-3-ylidene)methyl)amino)-
2-ethyl-7H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-7-one (4)
Synthesis of 1-(5-ethyl-1,3,4-thiadiazol-2-yl)-4,6-dimethyl-2-
oxo-1,2-dihydropyridine-3-carbonitrile (3)
An equimolar mixture of compound 1 (0.4 g, 0.002 mol) and Equimolar amounts of compound 1 (0.4 g, 0.002 mol) and
acetylacetone (0.21 mL, 0.002 mol) in absolute ethanol (15 mL) phenacyl bromide (0.404 g, 0.002 mol) in absolute ethanol (25
containing three drops of piperidine was heated under reux mL) containing three drops of triethylamine was reuxed for
for 3 h. The reaction mixture was allowed to cool and the 3 h. The solid product that formed was ltered off, puried and
precipitate obtained was isolated by ltration and puried recrystallized from dry ethanol to furnish compound 4. Pale
ꢁ
ꢀ1
through recrystallization from ethanol to afford 3. Colorless yellow powder; mp > 300 C; yield 80%; IR (KBr) n/cm : 3408
ꢁ
ꢀ1
1
crystals; mp 175–177 C; yield 89%; IR (KBr) n/cm : 3447 (OH), (NH), 3331, 3142 (NH
2
), 1700, 1666 (2CO). H NMR (400 MHz,
ppm 1.26 (t, 3H, CH ), 1.41 (t, 3H, CH ), 2.95 (q,
1
2221 (CN), 1676 (CO). H NMR (400 MHz, DMSO-d
6
): d
H
ppm DMSO-d
6
): d
H
3
3
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2
1
3
H, CH
2
), 3.19 (q, 2H, CH
2
), 7.02 (s, 1H, pyrimidine H-5), 7.06 (s, precipitate was ltered off, puried by washing with ethanol
+
H, pyrrole H-4), 7.2–7.43 (m, 5H, Ar-H). MS m/z (%): 492 (M , and recrystallized from a mixture of EtOH–DMF (1 : 1) to
1.92), 368 (100), 313 (39.01), 299 (33.81), 262 (46.71), 239 furnish compound 7. Reddish brown powder; mp > 300 C; yield
ꢁ
ꢀ1
1
(
80.47), 186 (30.46), 179 (15.68), 123 (22.79). Anal. for 93%; IR (KBr) n/cm : 3449, 3433, 3406 (3NH), 1646 (CO). H
(492.58): calcd: C, 53.64; H, 4.09; N, 22.75%; NMR (400 MHz, DMSO-d ): d ppm 1.31 (t, 3H, CH ), 2.47 (s,
-pyridine), 2.79 (s, 3H, CH -pyridine), 3.02 (q, 2H, CH ),
.98 (s, 1H, pyridine H-3), 12.33 (s, 1H, NHCO), 12.82 (s, 1H, ]
NH). Anal. for C15 OS (369.41): calcd: C, 48.77; H, 4.09; N,
4.13%; found: C, 48.30; H, 3.98; N, 34.01%.
C
22
H
20
N
8
O
2
S
2
6
H
3
found: C, 53.55; H, 4.01; N, 22.80%.
3H, CH
3
3
2
6
15 9
H N
Synthesis of 4-amino-N-(5-ethyl-1,3,4-thiadiazol-2-yl)-3-
3
phenyl-2-thioxo-2,3-dihydrothiazole-5-carboxamide (5)
To an ethanolic solution (25 mL) of compound 1 (0.4 g, 0.002
mol) containing three drops of triethylamine, elemental sulfur
Synthesis of (E)-2-((5-ethyl-1,3,4-thiadiazol-2-yl)amino)-2-oxo-
N-(1H-1,2,4-triazol-3-yl)acetohydrazonoyl cyanide (8)
(0.064 g, 0.002 mol) and phenyl isothiocyanate (0.23 mL, 0.002
ꢁ
ꢀ1
mol) were added. The reaction mixture was continuously stirred Pale yellow crystals; mp 268–270 C; yield 87%; IR (KBr) n/cm
:
ꢁ
+
at 60 C for 3 h, and then poured into a beaker containing 3440 (NH), 2217 (CN), 1661 (CO). MS m/z (%): 291 (M , 32.62),
a crushed ice/water mixture acidied by a few drops of hydro- 279 (20.83), 258 (19.97), 214 (33.47), 201 (44.55), 185 (38.18), 161
chloric acid. The solid precipitate that formed was isolated by (45), 156 (46.51), 143 (44.53), 129 (57.59), 116 (23.16), 100

ltration, dried, and recrystallized from a mixture of DMF and (17.52), 78 (41.72), 69 (100), 60 (72.81). Anal. for C
9 9 9
H N OS
ethanol (3 : 1) to afford compound 5. Brown powder; mp 248– (291.29): calcd: C, 37.11; H, 3.11; N, 43.28%; found: C, 37.05; H,
ꢁ
ꢀ1
2
1
(
(
(
4
50 C; yield 75%; IR (KBr) n/cm : 3446 (NH), 3373, 3244 (NH
2
), 3.05; N, 43.18%.
+
640 (C]O), 1232 (C]S). MS m/z (%): 364 (M + 1, 3.51), 363
+
M , 17.68), 330 (15.04), 298 (16.81), 266 (16.1), 235 (22.88), 208
51), 136 (53.05), 135 (82.06), 129 (82.36), 93 (31.97), 77 (100), 74
43.85), 60 (26.7). Anal. for C H N OS (363.47): calcd: C,
Synthesis of N-(5-ethyl-1,3,4-thiadiazol-2-yl)-4-imino-4,6-
1,2,4
1,2,4
dihydro-
triazolo[5,1-c]
triazine-3-carboxamide (9)
1
4
13
5
3
A solution of 8 (0.58 g, 0.002 mol) in glacial acetic acid (20 mL)
was reuxed for 3 h, and then le to cool. The formed solid
precipitate was ltered off, puried by washing with ethanol
and recrystallized from a mixture of EtOH–DMF (1 : 1) to
6.26; H, 3.61; N, 19.27%; found: C, 46.22; H, 3.45; N, 19.21%.
General procedure for coupling reaction of 1 with different
primary aromatic amine diazonium salts
ꢁ
furnish compound 9. Orange crystals; mp 290–292 C; yield
ꢁ
ꢀ1
1
To a cold (0–5 C) solution of compound 1 (0.4 g, 0.002 mol) in 90%; IR (KBr) n/cm : 3440, 3331, 3128 (3NH), 1661 (CO). H
pyridine (20 mL) was added the appropriate diazonium chloride NMR (400 MHz, DMSO-d
which was prepared by dissolving sodium nitrite (0.14 g, 0.002 2H, CH ), 8.58 (s, 1H, triazole H-3), 11.84 (s, 1H, NHCO), 14.37
mol) in cold water (3 mL) and adding to a cold solution of the (s, 1H, ]NH). Anal. for C OS (291.29): calcd: C, 37.11; H,
6 H 3
): d ppm 1.30 (t, 3H, CH ), 3.02 (q,
[
2
9
9 9
H N
appropriate aromatic amine (0.002 mol) containing an 3.11; N, 43.28%; found: C, 37.00; H, 3.03; N, 43.12%.
adequate amount of hydrochloric acid (1.5 mL) under contin-
uous stirring conditions] portion-wise over a period of 25 min.
The reaction mixture was kept overnight in the refrigerator, and
then diluted with water. The formed solid that precipitated was
Synthesis of (E)-N-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-
H-pyrazol-4-yl)-2-((5-ethyl-1,3,4-thiadiazol-2-yl)amino)-2-
oxoacetohydrazonoyl cyanide (10a)
Deep yellow crystals; mp 218–220 C; yield 92%; IR (KBr)
1

ltered off, puried by washing in water, then dried and
ꢁ
recrystallized from EtOH and DMF (2 : 1) to afford arylazo
derivatives 6, 8 and 10a–c.
ꢀ
1
1
n/cm : 3420, 3411 (2NH), 2220 (CN), 1736, 1658 (2C]O). H
NMR (400 MHz, DMSO-d ): d ppm 1.31 (t, 3H, CH ), 2.27 (s,
6
H
3
3
H, CH -pyrazole), 3.02 (q, 2H, CH ), 3.18 (s, 3H, NCH ), 7.09
3 2 3
Synthesis of (E)-N-(4,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-3-
yl)-2-((5-ethyl-1,3,4-thiadiazol-2-yl)amino)-2-
oxoacetohydrazonoyl cyanide (6)
(m, 5H, Ar-H), 12.33 (s, 1H, NH), 12.82 (s, 1H, NH). MS m/z (%):
+
+
4
11 (M + 1, 17.75), 410 (M , 2.21), 369 (3.31), 240 (9.15), 229
(
10.51), 156 (7.79), 129 (10.99), 119 (30.09), 91 (32.82), 77 (50.67),
S (410.46): calcd: C,
NH), 2197 (CN), 1646 (CO). MS m/z (%): 371 (M + 2, 5.96), 370 52.67; H, 4.42; N, 27.3%; found: C, 52.59; H, 4.39; N 27.18%.
ꢁ
ꢀ1
18 8 2
Black powder; mp 280–282 C; yield 85%; IR (KBr) n/cm : 3449 56 (100), 54 (27.07). Anal. for C18H N O
+
(
(
2
+
+
M + 1, 21.87), 369 (M , 100), 336 (16.7), 281 (25.17), 271 (16.77),
41 (18.99), 162 (33.41), 146 (36.88), 119 (28.06), 104 (16.43), 78
33.58). Anal. for C H N OS (369.41): calcd: C, 48.77; H, 4.09;
Synthesis of (E)-2-((5-ethyl-1,3,4-thiadiazol-2-yl)amino)-2-oxo-
N-(4-(N-(thiazol-2-yl)sulfamoyl)phenyl)acetohydrazonoyl
cyanide (10b)
(
1
5
15 9
N, 34.13%; found: C, 48.32; H, 4.01; N, 34.03%.
ꢁ
ꢀ1
Orange crystals; mp 265–267 C; yield 95%; IR (KBr) n/cm
3
:
Synthesis of N-(5-ethyl-1,3,4-thiadiazol-2-yl)-4-imino-8,10-
1
469, 3226, 3165 (3NH), 2231 (CN), 1665 (C]O). H NMR (400
0
0
dimethyl-4,6-dihydropyrido[2 ,3 :3,4]pyrazolo[5,1-c][1,2,4]
triazine-3-carboxamide (7)
MHz, DMSO-d ): d ppm 1.30 (t, 3H, CH ), 3.01 (q, 2H, CH ),
6
H
3
2
6.84 (d, 1H, thiazole H-5, J ¼ 4 Hz), 7.26 (d, 1H, thiazole H-4, J ¼
A solution of 6 (0.74 g, 0.002 mol) in glacial acetic acid (25 mL) 4 Hz), 7.81 (d, 2H, Ar-H, J ¼ 8 Hz), 7.97 (d, 2H, Ar-H, J ¼ 8 Hz),
was reuxed for 3 h, and then allowed to cool. The formed 12.37 (s, 1H, ]N–NH), 12.38 (s, 1H, NHSO ), 12.81 (s, 1H,
2
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+
+
13
NHCO). MS m/z (%): 463 (M + 1, 1.02), 462 (M , 4.16), 451 (2.96), 115.16, 128.73, 129.42, 130.51, 136.25, 138.51, 166.51. DEPT
C
3
69 (9.5), 305 (7.88), 250 (10.7), 229 (4.14), 194 (6.01), 156 NMR, H–H COSY, HSQC and HMBC results are in agreement
+
(17.25), 109 (21.87), 97 (49.14), 83 (51.29), 69 (100), 57 (99.58). with the proposed structure. MS m/z (%): 370 (M + 1, 4.67), 369
+
Anal. for C H N O S (462.52): calcd: C, 41.55; H, 3.05; N, (M , 26.96), 351 (6.59), 324 (19), 301 (8.47), 265 (18.23), 243
1
6
14 8 3 3
24.23%; found: C, 41.23; H, 2.95; N, 23.98%.
(100), 241 (54.49), 212 (37.02), 186 (35.26), 154 (21.6), 126
(
(
4
39.35), 77 (45.46), 68 (64), 45 (64.59). Anal. for C17
369.46): calcd: C, 55.27; H, 4.09; N, 18.96%; found: C, 55.19; H,
.05; N, 18.91%.
15 5 2
H N OS
Synthesis of (E)-N-(4-(N-(4,6-dimethylpyrimidin-2-yl)
sulfamoyl)phenyl)-2-((5-ethyl-1,3,4-thiadiazol-2-yl)amino)-2-
oxoacetohydrazonoyl cyanide (10c)
Synthesis of (E)-2-cyano-2-(3,4-diphenylthiazol-2(3H)-ylidene)-
N-(5-ethyl-1,3,4-thiadiazol-2-yl)acetamide (13b)
ꢁ
ꢀ1
Orange crystals; mp 208–210 C; yield 90%; IR (KBr) n/cm
:
1
3
588, 3527, 3231 (3NH), 2232 (CN), 1666 (C]O). H NMR (400
ꢁ
ꢀ1
Beige powder; mp 245–247 C; yield 93%; IR (KBr) n/cm : 3446
(
MHz, DMSO-d
pyrimidine), 3.02 (q, 2H, CH
(
6
): d
H
ppm 1.31 (t, 3H, CH
), 6.77 (s, 1H, pyrimidine H-5), 7.98
m, 4H, Ar-H), 12.33 (s, 1H, ]N–NH), 12.79 (s, 1H, NHSO ),
3 3
), 2.27 (s, 6H, 2CH -
1
NH), 2187 (CN), 1626 (CO). H NMR (400 MHz, DMSO-d6):
2
d ppm 1.30 (t, 3H, CH ), 2.96 (q, 2H, CH ), 7.19 (s, 1H, thiazole
H
3
2
2
+
H-5), 7.21–7.61 (m, 10H, Ar-H), 14.49 (s, 1H, NH). MS m/z (%):
12.82 (s, 1H, NHCO). MS m/z (%): 485 (M , 1.79), 451 (1.5), 344
+
+
4
32 (M + 1, 7.15), 431 (M , 8.76), 408 (10.59), 390 (10.12), 373
(
8
5.88), 236 (4.42), 213 (41.28), 200 (6.19), 165 (15.29), 129 (19.51),
(45.29), 69 (46.63), 55 (61.02), 43 (100). Anal. for
(485.54): calcd: C, 47.00; H, 3.94; N, 25.96%;
(
(
(
14.88), 366 (40.31), 316 (22.04), 292 (22.45), 284 (12.94), 250
37.24), 243 (47.44), 241 (27.25), 197 (24.51), 192 (32.43), 152
50.08), 132 (33.16), 102 (40.44), 90 (43.04), 83 (64.41), 53 (64.15),
3
19 19 9 3 2
C H N O S
found: C, 46.92; H, 3.90; N, 25.86%.
17 5 2
51 (100), 43 (57.47). Anal. for C22H N OS (431.53): calcd: C,
61.23; H, 3.97; N, 16.23%; found: C, 61.20; H, 3.93; N, 16.19%.
General procedure for the synthesis of thiazole derivatives 12,
1
3a, b and 14
Synthesis of (E)-2-(4-amino-3-phenylthiazol-2(3H)-ylidene)-2-
cyano-N-(5-ethyl-1,3,4-thiadiazol-2-yl)acetamide (14)
To a stirred solution of KOH (0.11 g, 0.002 mol) in DMF (25 mL),
compound 1 (0.4 g, 0.002 mol) was added. The mixture was
stirred for 30 min, and then phenyl isothiocyanate (0.23 mL,
ꢁ
ꢀ1
Deep green powder; mp 225–227 C; yield 45%; IR (KBr) n/cm
:
3
415 (NH), 3209, 3154 (NH ), 2186 (CN), 1644 (C]O). MS m/z
2
0
6
.002 mol) was added. Stirring the reaction was continued for
+
+
(%): 371 (M + 1, 2.43), 370 (M , 1.52), 359 (5.92), 330 (2.41), 297
9.83), 271 (100), 225 (1.46), 174 (37.98), 129 (79.78), 77 (18.66),
h. Then the appropriate a-halo compound [namely chlor-
(
oacetyl chloride (0.16 mL, 0.002 mol), chloroacetone (0.16 mL,
.002 mol), phenacyl chloride (0.31 g, 0.002 mol) and chlor-
60 (25.27), 51 (42.58). Anal. for C16
14 6 2
H N OS (370.45): calcd: C,
0
51.88; H, 3.81; N, 22.69%; found: C, 51.85; H, 3.79; N, 22.67%.
oacetonitrile (0.13 mL, 0.002 mol)] was added to the resulting
mixture. The reaction mixture was stirred for an additional 3 h.
Then, the reaction mixture was poured into a beaker containing
a crushed ice/water mixture. The formed precipitate was ltered
Synthesis of (E)-2-cyano-N-(5-ethyl-1,3,4-thiadiazol-2-yl)-3-
methylthio)-3-(phenylamino)acrylamide (15)
(
off, dried and puried by recrystallization from EtOH to furnish To a stirred solution of KOH (0.11 g, 0.002 mol) in DMF (25 mL),
compounds 12, 13a, b and 14, respectively.
compound 1 (0.4 g, 0.002 mol) was added. The mixture was
stirred for 30 min, and then phenyl isothiocyanate (0.23 mL,
0.002 mol) was added. The reaction mixture was stirred for 6 h.
Synthesis of (E)-2-cyano-N-(5-ethyl-1,3,4-thiadiazol-2-yl)-2-(5-
Then dimethyl sulfate (0.19 mL, 0.002 mol) was added to the
resulting mixture. Stirring continued for an additional 3 h.
Then, the reaction mixture was poured into a beaker containing
a crushed ice/water mixture. The formed precipitate was ltered
oxo-3-phenylthiazolidin-2-ylidene)acetamide (12)
ꢁ
Reddish brown crystals; mp 240–242 C; yield 92%; IR (KBr)
ꢀ
1
1
n/cm : 3461 (NH), 2211 (CN), 1747, 1656 (2CO). H NMR (400
MHz, DMSO-d ): d ppm 1.27 (t, 3H, CH ), 2.91 (q, 2H, CH ),
6
H
3
2
off, dried and puried by recrystallization from EtOH to afford
4
2
.02 (s, 2H, CH -thiazolidinone), 7.38–7.52 (m, 5H, Ar-H), 14.4
ꢁ
1
5. Colourless crystals; mp 270–272 C; yield 70%; IR (KBr)
+
+
(
(
s, 1H, NH). MS m/z (%): 372 (M + 1, 20.69), 371 (M , 13.43), 329
2.37), 279 (9.19), 243 (76.54), 215 (100), 169 (12.92), 141 (17.58),
ꢀ
1
1
n/cm : 3448, 3313 (2NH), 2227 (CN), 1638 (CO). H NMR (500
MHz, DMSO-d ): d ppm 1.30 (t, 3H, CH ), 2.85 (s, 3H, SCH ),
6
H
3
3
132 (43.76), 124 (26.47), 93 (16.59), 77 (80.99), 73 (12.68), 51
3
.04 (q, 2H, CH ), 7.1–7.49 (m, 5H, Ar-H), 9.8 (s, 1H, NHPh), 9.83
2
(
12.48). Anal. for C16 (371.43): calcd: C, 51.74; H, 3.53;
13 5 2 2
H N O S
1
3
(s, 1H, NHCO). C NMR (125 MHz, DMSO-d
6
C
): d ppm 11.87,
N, 18.86%; found: C, 51.68; H, 3.48; N, 18.82%.
1
1
7.45, 24.38, 114.58, 123.6, 124.38, 128.41, 139.45, 157.02,
62.71, 163.68, 164.87, 179.58. DEPT C NMR, H–H COSY,
1
3
Synthesis of (E)-2-cyano-N-(5-ethyl-1,3,4-thiadiazol-2-yl)-2-(4-
methyl-3-phenylthiazol-2(3H)-ylidene)acetamide (13a)
HSQC and HMBC results are in agreement with the proposed
+
+
structure. MS m/z (%): 346 (M + 1, 1.74), 345 (M , 3.78), 344
ꢁ
ꢀ1
Off white crystals; mp 265–267 C; yield 90%; IR (KBr) n/cm
:
(9.39), 331 (9.35), 298 (23.07), 297 (100), 296 (45.5), 252 (93.69),
1
3
486 (NH), 2184 (CN), 1626 (CO). H NMR (500 MHz, DMSO-d ): 237 (9.73), 224 (7.7), 180 (12.87), 156 (12.72), 154 (17.42), 118
6
d ppm 1.28 (t, 3H, CH ), 1.88 (s, 3H, CH -thiazole), 2.91 (q, 2H, (5.91), 85 (16.87), 70 (12.05), 58 (4.37), 44 (10.43). Anal. for
H
3
3
1
3
CH
2
), 7.01 (s, 1H, thiazole H-5), 7.48–7.6 (m, 5H, Ar-H). C NMR
15 15 5 2
C H N OS (345.44): calcd: C, 52.16; H, 4.38; N, 20.27%;
(
125 MHz, DMSO-d
6
): d ppm 13.11, 13.98, 22.71, 106.89, found: C, 52.11; H, 4.32; N, 20.22%.
C
39780 | RSC Adv., 2017, 7, 39773–39785
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RSC Advances
+
General procedure for the synthesis of arylidenes 16a–c
O). MS m/z (%): 357 (M , 6.92), 341 (6.42), 310 (14.8), 309 (37.32),
94 (100), 278 (20.25), 266 (80.14), 251 (11.74), 214 (9.2), 199
(
(
2
An equimolar mixture of cyanoacetamide 1 (0.4 g, 0.002 mol)
and the appropriate aldehyde (namely piperonal, vanilline, and
9.85), 174 (9.81), 159 (18.12), 157 (22.63), 147 (23.35), 130
28.89), 118 (29.54), 104 (29.44), 96 (33.58), 77 (39.75), 70 (42.92),
5 (40.84). Anal. for C16
4-N,N-dimethylbenzaldehyde) (0.002 mol) in ethanol (25 mL)
5
19 7
H N OS (357.44): calcd: C, 53.77; H,
containing piperidine (0.5 mL) was reuxed for 3 h. The ob-
tained product was ltered off and recrystallized from EtOH to
afford compounds 16a–c.
5
.36; N, 27.43%; found: C, 53.72; H, 5.35; N, 27.39%.
General procedure for the synthesis of pyridin-2-ones 18a–d
1
,3
Synthesis of (E)-3-(benzo[d] dioxol-5-yl)-2-cyano-N-(5-ethyl-
1
Method A. Equimolar amounts of 1 (0.4 g, 0.002 mol) and the
appropriate 2-(arylidene)-ethyl cyanoacetate [namely 2-
,3,4-thiadiazol-2-yl)acrylamide (16a)
ꢁ
ꢀ1
Pale yellow crystals; mp 285–287 C; yield 90%; IR (KBr) n/cm
452 (NH), 2221 (CN), 1651 (CO). H NMR (400 MHz, DMSO-d
:
(benzylidene)-ethyl cyanoactate, 2-(4-nitrobenzylidene)-ethyl
1
3
6
):
cyanoactate, 2-(4-chlorobenzylidene)-ethyl cyanoactate, and 2-
(4-N,N-dimethylbenzylidene)-ethyl cyanoactate] (0.002 mol)
were placed in ethanol (25 mL) containing piperidine (0.5 mL),
and the reaction mixture was reuxed for 3 h. The reaction
mixture was allowed to cool. The solid product that was ob-
tained was ltered off and recrystallized from ethanol.
Method B. A mixture of 1 (0.4 g, 0.002 mol), and the appro-
priate aldehyde (namely benzaldehyde, p-nitrobenzaldehyde, p-
chlorobenzaldehyde and 4-N,N-dimethylbenzaldehyde) (0.002
mol), piperidine (0.5 mL), and ethyl cyanoacetate (0.002 mol) in
ethanol (25 mL) was reuxed for 3 h. The reaction mixture was
allowed to cool. The precipitate that formed was isolated by
ltration, dried and puried by recrystallization from EtOH.
Method C. A mixture of 16c (0.33 g, 0.001 mol) and ethyl
cyanoacetate (0.11 mL, 0.001 mol) in ethanol (20 mL) including
piperidine (0.5 mL) was reuxed for 3 h. The obtained product
was isolated by ltration and puried by recrystallization from
ethanol to afford 18d.
d
ppm 1.30 (t, 3H, CH ), 2.98 (q, 2H, CH ), 4.1 (br s, 1H, NH),
H
3
2
6
1
.2 (s, 2H, CH -dioxolane), 7.15 (d, 1H, Ar-H, J ¼ 8 Hz), 7.57 (d,
2
H, Ar-H, J ¼ 8.4 Hz), 7.69 (s, 1H, Ar-H), 8.35 (s, 1H, vinylic-H).
+
+
MS m/z (%): 329 (M + 1, 23.55), 328 (M , 100), 327 (93.83), 299
(
1
14.72), 268 (2.95), 207 (5.52), 200 (57.9), 170 (87.75), 142 (39.55),
14 (70.73), 87 (10.52), 73 (9.88), 63 (7.81). Anal. for
S (328.35): calcd: C, 54.87; H, 3.68; N, 17.06%;
15 12 4 3
C H N O
found: C, 54.85; H, 3.63; N, 16.95%.
Synthesis of (E)-2-cyano-N-(5-ethyl-1,3,4-thiadiazol-2-yl)-3-(4-
hydroxy-3-methoxyphenyl)acrylamide (16b)
ꢁ
Deep yellow crystals; mp 140–142 C; yield 92%; IR (KBr)
ꢀ
1
1
n/cm : 3454 (OH), 3350 (NH), 2211 (CN), 1709 (CO). H NMR
400 MHz, DMSO-d ): dH ppm 1.26 (t, 3H, CH ), 2.87 (q, 2H,
(
6
3
CH ), 3.83 (s, 3H, OCH ), 6.89 (d, 1H, Ar-H, J ¼ 8 Hz), 7.43 (d,
2
3
1
8
3
H, Ar-H, J ¼ 8.4 Hz), 7.72 (s, 1H, Ar-H), 8.08 (s, 1H, vinylic-H),
+
.99 (s, 1H, OH), 9.02 (s, 1H, NHCO). MS m/z (%): 331 (M + 1,
+
4.66), 330 (M , 100), 301 (5.1), 299 (2.73), 202 (25.53), 170
(
5
4
36.67), 156 (13.85), 130 (10.67), 114 (11.17), 76 (3.28), 73 (4.35),
Synthesis of 1-(5-ethyl-1,3,4-thiadiazol-2-yl)-6-hydroxy-2-oxo-4-
phenyl-1,2-dihydropyridine-3,5-dicarbonitrile (18a)
6 (1.54). Anal. for C15
14 4 3
H N O S (330.36): calcd: C, 54.54; H,
.27; N, 16.96%; found: C, 54.51; H, 4.23; N, 16.95%.
ꢁ
ꢀ1
Yellow crystals; mp 290–292 C; yield 65%; IR (KBr) n/cm
3
:
1
475 (OH), 2216 (2CN), 1694 (CO). H NMR (400 MHz, DMSO-
Synthesis of (E)-2-cyano-3-(4-(dimethylamino)phenyl)-N-(5-
ethyl-1,3,4-thiadiazol-2-yl)acrylamide (16c)
d6): dH ppm 1.25 (t, 3H, CH ), 2.94 (q, 2H, CH ), 7.21–7.41 (m,
3
2
1
3
5
4
1
2
H, Ar-H). C NMR (125 MHz, DMSO-d ): d ppm 11.96, 24.35,
6 C
ꢁ
ꢀ1
Orange crystals; mp 290–292 C; yield 93%; IR (KBr) n/cm
3
d ppm 1.30 (t, 3H, CH ), 2.98 (q, 2H, CH ), 3.09 (s, 6H, N(CH )
2
8
+
:
4.17, 97.56, 101.15, 114.87, 117.8, 127.36, 127.51, 127.54,
1
455 (NH), 2214 (CN), 1651 (CO). H NMR (400 MHz, DMSO-d
6
):
+
38.21, 153.66, 158.87, 159.87, 160.28. MS m/z (%): 350 (M + 1,
H
3
2
3
+
1.24), 349 (M , 80.58), 348 (100), 332 (8.96), 320 (5.88), 261
), 6.85 (d, 2H, Ar-H, J ¼ 8.8 Hz), 7.93 (d, 2H, Ar-H, J ¼ 8.8 Hz),
(2.92), 165 (5.7), 139 (3.44), 127 (3.16), 85 (3.88), 56 (4.57). Anal.
+
.27 (s, 1H, vinylic-H), 12.85 (s, 1H, NHCO). MS m/z (%): 328 (M
for C17 S (349.37): calcd: C, 58.44; H, 3.17; N, 20.05%;
11 5 2
H N O
+
1, 10.89), 327 (M , 46.31), 298 (1.56), 272 (3.04), 199 (100), 171
found: C, 58.40; H, 3.14; N, 19.99%.
(33.82), 156 (8.7), 128 (2.69), 101 (1.36), 85 (0.94), 73 (2.5). Anal.
for C16 OS (327.40): calcd: C, 58.70; H, 5.23; N, 21.39%;
17 5
H N
found: C, 58.55; H, 5.21; N, 21.33%.
Synthesis of 1-(5-ethyl-1,3,4-thiadiazol-2-yl)-6-hydroxy-4-(4-
nitrophenyl)-2-oxo-1,2-dihydropyridine-3,5-dicarbonitrile
(18b)
Synthesis of 3-amino-5-(4-(dimethylamino)phenyl)-N-(5-ethyl-
1
,3,4-thiadiazol-2-yl)-1H-pyrazole-4-carboxamide (17)
ꢁ
Deep brown powder; mp 250–252 C; yield 85%; IR (KBr)
ꢀ
1
Equimolar amounts of arylidene derivative 16c (0.654 g, n/cm : 3446 (OH), 2199 (2CN), 1670 (CO), 1522 (NO2). MS m/z
0
2
+
.002 mol) and hydrazine hydrate (80%, 0.1 mL, 0.002 mol) in (%): 394 (M , 5.01), 373 (5.45), 336 (5.59), 329 (28.08), 301
0 mL of ethanol were heated under reux for 3 h, then allowed (16.62), 300 (62.34), 292 (1.40), 284 (23.61), 265 (32.96), 257
to cool. The obtained solid precipitate was ltered off, puried (34.87), 256 (100), 255 (25.28), 246 (19.31), 227 (5.23), 192 (4.91),
by washing with ethanol, dried, and recrystallized from EtOH to 137 (6.49), 112 (14.78), 93 (17.79), 80 (23.63), 79 (20.13), 68
ꢁ
furnish compound 17. Yellow powder; mp 295–297 C; yield (12.58), 48 (9.77). Anal. for C17
H
10
N
6
O
4
S (394.37): calcd: C,
ꢀ
1
55%; IR (KBr) n/cm : 3411 (2NH), 3280, 3152 (NH
2
), 1638 (C] 51.78; H, 2.56; N, 21.31%; found: C, 51.74; H, 2.52; N, 21.30%.
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Synthesis of 4-(4-chlorophenyl)-1-(5-ethyl-1,3,4-thiadiazol-2-
yl)-6-hydroxy-2-oxo-1,2-dihydropyridine-3,5-dicarbonitrile
Synthesis of 6-amino-1-(5-ethyl-1,3,4-thiadiazol-2-yl)-4-(4-
nitrophenyl)-2-oxo-1,2-dihydropyridine-3,5-dicarbonitrile
(19b)
(
18c)
ꢁ
ꢀ1
ꢁ
ꢀ1
Yellow powder; mp 265–267 C; yield 82%; IR (KBr) n/cm
:
Brown powder; mp 240–242 C; yield 90%; IR (KBr) n/cm : 3446
), 2210 (2CN), 1636 (CO), 1521 (NO2). MS
+
3
1
2
504 (OH), 2213 (2CN), 1692 (CO). MS m/z (%): 368 (M ꢀ 15, (OH), 3342, 3217 (NH
2
+
+
3.47), 366 (1.08), 353 (11.22), 328 (4.88), 313 (4.31), 297 (6.47), m/z (%): 394 (M + 1, 1.96), 393 (M , 6.7), 363 (2.6), 346 (6.27), 338
65 (9.98), 236 (17.53), 229 (8.88), 159 (11.13), 137 (10.87), 123 (12.77), 311 (6.82), 282 (32.52), 265 (4.76), 236 (3.67), 184 (5.24),
(24.83), 109 (26.98), 97 (50.06), 84 (39.46), 71 (57.77), 69 (100), 57 175 (7.04), 156 (11.69), 136 (33.47), 129 (27.76), 106 (22.56), 90
(
93.35), 43 (91.87). Anal. for C H ClN O S (383.81): calcd: C, (35.21), 89 (65.14), 84 (73.14), 78 (90.14), 69 (75.55), 56 (97.69), 43
1
7
10
5 2
53.2; H, 2.63; N, 18.25%; found: C, 53.15; H, 2.62; N, 18.19%.
(98.7), 41 (100). Anal. for C H N O S (393.38): calcd: C, 51.91;
17 11 7 3
H, 2.82; N, 24.92%; found: C, 51.88; H, 2.8; N, 24.89%.
Synthesis of 4-(4-(dimethylamino)phenyl)-1-(5-ethyl-1,3,4-
thiadiazol-2-yl)-6-hydroxy-2-oxo-1,2-dihydropyridine-3,5-
dicarbonitrile (18d)
Synthesis of 6-amino-4-(4-chlorophenyl)-1-(5-ethyl-1,3,4-
thiadiazol-2-yl)-2-oxo-1,2-dihydropyridine-3,5-dicarbonitrile
ꢁ
ꢀ1
(19c)
Orange powder; mp 285–287 C; yield 82%; IR (KBr) n/cm
3
3
(
(
(
:
+
ꢁ
ꢀ1
445 (OH), 2209 (2CN), 1705 (CO). MS m/z (%): 392 (M , 3.00), Pale yellow crystals; mp 245–247 C; yield 84%; IR (KBr) n/cm
70 (3.08), 369 (5.40), 351 (4.94), 330 (3.73), 328 (5.18), 304 3445 (OH), 3338, 3197 (NH ), 2211 (2CN), 1639 (CO). MS m/z
20.99), 287 (8.14), 271 (31.05), 248 (16.77), 240 (100), 207 (%): 383 (M + 1, 98.26), 382 (M , 100), 381 (10.98), 366 (15.4),
45.35), 185 (23.2), 181 (48.16), 176 (11.13), 156 (62.39), 153 356 (18.74), 337 (34.57), 320 (4.39), 295 (9.77), 294 (2.52), 270
31.52), 138 (20.18), 121 (18.63), 86 (82.77), 84 (51.31), 60 (45.65), (2.54), 255 (1.86), 199 (3.23), 190 (1.10), 161 (2.38), 138 (3.31),
:
2
+
+
5
5
2 (49.38), 44 (98.88). Anal. for C19
8.15; H, 4.11; N, 21.42%; found: C, 58.12; H, 4.08; N, 21.38%. Anal. for C17
1.95%; found: C, 53.32; H, 2.8; N, 21.89%.
H
16
N
6
O
2
S (392.44): calcd: C, 125 (7.84), 113 (1.87), 86 (1.97), 84 (2.96), 73 (3.12), 56 (1.99).
H
11ClN OS (382.83): calcd: C, 53.34; H, 2.90; N,
6
2
General procedure for the synthesis of pyridin-2-ones 19a–d
Synthesis of 6-amino-4-(4-(dimethylamino)phenyl)-1-(5-ethyl-
,3,4-thiadiazol-2-yl)-2-oxo-1,2-dihydropyridine-3,5-
dicarbonitrile (19d)
malononitrile, 2-(4-chlorobenzylidene)-malononitrile, and 2-(4- Orange crystals; mp 275–277 C; yield 90%; IR (KBr) n/cm
Method A. Equimolar amounts of 1 (0.4 g, 0.002 mol) and the
1
appropriate
2-(arylidene)-malononitrile
[namely
2-
(
benzylidene)-malononitrile,
2-(4-nitrobenzylidene)-
ꢁ
ꢀ1
:
1
N,N-dimethylbenzylidene)-malononitrile] (0.002 mol) were 3446 (OH), 3430, 3202 (NH
placed in ethanol (25 mL) containing piperidine (0.5 mL), and (400 MHz, DMSO-d ): d ppm 1.29 (t, 3H, CH
the reaction mixture was reuxed for 3 h. The reaction mixture N(CH )2), 4.27 (q, 2H, CH
), 6.84 (d, 2H, Ar-H, J ¼ 9.2 Hz), 7.96
was allowed to cool. The solid product that was obtained was (d, 2H, Ar-H, J ¼ 8.8 Hz), 8.12 (s, 1H, NH). MS m/z (%): 392 (M +
2
), 2209 (2CN), 1705 (CO). H NMR
6
H
3
), 3.1 (s, 6H,
3
2
+
+

ltered off and recrystallized from ethanol.
1, 5.29), 391 (M , 49.7), 387 (9.7), 368 (22.58), 326 (43.61), 288
Method B. A mixture of 1 (0.4 g, 0.002 mol), and the appro- (11.82), 272 (34.44), 247 (23.23), 246 (19.36), 228 (58.36), 211
priate aldehyde (namely benzaldehyde, p-nitrobenzaldehyde, p- (18.54), 206 (48.02), 198 (100), 196 (44.36), 169 (59.65), 155
chlorobenzaldehyde and 4-N,N-dimethylbenzaldehyde) (0.002 (48.75), 140 (39.06), 131 (24.87), 113 (16.55), 105 (49.41), 99
mol), piperidine (0.5 mL), and malononitrile (0.002 mol) in (77.15), 94 (22.16), 77 (34.14), 52 (37.48), 50 (46.43). Anal. for
ethanol (25 mL) was reuxed for 3 h. The reaction mixture was
19 17 7
C H N OS (391.45): calcd: C, 58.30; H, 4.38; N, 25.05%; found:
allowed to cool. The precipitate that formed was isolated by C, 58.10; H, 4.35; N, 25.02%.

ltration, dried and puried by recrystallization from EtOH.
Method C. A mixture of 16c (0.33 g, 0.001 mol) and malo-
Synthesis of (Z)-2-cyano-N-(5-ethyl-1,3,4-thiadiazol-2-yl)-2-(4-
phenyl-1,3-dithiol-2-ylidene)acetamide (21)
nonitrile (0.07 g, 0.001 mol) in ethanol (25 mL) containing
piperidine (0.5 mL) was heated under reux for 3 h. The ob-
tained product was isolated by ltration and puried by
recrystallization from ethanol to afford 19d.
To a stirred solution of KOH (0.11 g, 0.002 mol) in DMF (25 mL),
compound 1 (0.4 g, 0.002 mol) was added. Aer stirring for
30 min, carbon disulde (0.12 mL, 0.002 mol) was added. The
reaction mixture was stirred for 12 h, and then phenacyl
bromide (0.41 g, 0.002 mol) was added to the resulting mixture.
Stirring was continued in the presence of ethanol for an addi-
tional 6 h. Then, the reaction mixture was poured into a beaker
Synthesis of 6-amino-1-(5-ethyl-1,3,4-thiadiazol-2-yl)-2-oxo-4-
phenyl-1,2-dihydropyridine-3,5-dicarbonitrile (19a)
ꢁ
ꢀ1
Yellow powder; mp 240–242 C; yield 75%; IR (KBr) n/cm
:
3
444 (OH), 3343, 3208 (NH ), 2212, 2163 (2CN), 1638 (CO). MS containing a crushed ice/water mixture. The formed precipitate
2
+
m/z (%): 348 (M , 1.38), 330 (7.03), 329 (11.78), 298 (2.47), 201 was ltered off, dried and puried by recrystallization from
ꢁ
(2.9), 156 (13.48), 135 (26.66), 129 (33.61), 119 (16.51), 100 (8.53), EtOH to yield 21. Pale yellow powder; mp 275–277 C; yield 85%;
ꢀ1
9
3 (23.43), 77 (100), 74 (75.38), 73 (43.98), 60 (82.11), 45 (72.42). IR (KBr) n/cm : 3421 (NH), 2204 (CN), 1647 (CO). MS m/z (%):
+
+
12 6
Anal for C17H N OS (348.38): calcd: C, 58.61; H, 3.47; N, 373 (M + 1, 4.07), 372 (M , 8.73), 357 (14.78), 355 (44.95), 333
24.12%; found: C, 58.57; H, 3.42; N, 24.05%.
(21.48), 313 (16.82), 285 (11.9), 270 (88.53), 264 (14.2), 251 (9.09),
39782 | RSC Adv., 2017, 7, 39773–39785
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199 (7.67), 178 (13.55), 156 (15.94), 126 (11.2), 113 (32.26), 105 30 min, carbon disulde (0.12 mL, 0.002 mol) was added. Stir-
(
(
89.81), 96 (57.73), 83 (62.68), 77 (100), 73 (78.59), 69 (40.34), 58 ring was continued for 12 h, and then dimethyl sulfate (0.38 mL,
61.95), 45 (69.49). Anal. for C H N O S (372.48): calcd: C, 0.004 mol) was added dropwise to the resulting mixture. Stirring
1
6
14 4 2 3
51.59; H, 3.25; N, 15.04%; found: C, 51.57; H, 3.21; N, 15.00%. was continued for an additional 6 h. Then, the reaction mixture
was poured into a beaker containing a crushed ice/water
Synthesis of 4-amino-5-benzoyl-N-(5-ethyl-1,3,4-thiadiazol-2-
yl)-2-mercaptothiophene-3-carboxamide (22)
mixture. The formed precipitate was ltered off, dried and
puried by recrystallization from EtOH to furnish 24. Pale
ꢁ
ꢀ1
yellow powder; mp 210–212 C; yield 90%; IR (KBr) n/cm : 3445
To a stirred solution of KOH (0.11 g, 0.002 mol) in DMF (25 mL),
compound 1 (0.4 g, 0.002 mol) was added. Aer stirring for
1
(
6
NH), 2188 (CN), 1642 (C]O). H NMR (500 MHz, DMSO-d ):
d ppm 1.39 (t, 3H, CH ), 2.53 (s, 6H, 2SCH ), 3.27 (q, 2H, CH ).
H
3
3
2
3
0 min, carbon disulde (0.12 mL, 0.002 mol) was added. Stir-
ring was continued for 12 h, and then phenacyl bromide (0.41 g,
.002 mol) was added to the resulting mixture. The reaction
1
3
C NMR (125 MHz, DMSO-d ): d ppm 11.94, 12.23, 16.71,
6
C
1
3
21.49, 90.76, 117.89, 157.24, 163.65, 165.91, 171.62. DEPT
C
0
NMR, H–H COSY, HSQC and HMBC results are in agreement
mixture was reuxed in the presence of triethylamine (0.5 mL)
for an additional 3 h. Then, the reaction mixture was poured into
a beaker containing a crushed ice/water mixture. The formed
precipitate was ltered off, dried and puried by recrystallization
+
with the proposed structure. MS m/z (%): 300 (M , 1.67), 253
(
1
3.91), 217 (0.80), 186 (5.96), 170 (39.01), 161 (5.11), 142 (6.59),
10 (23), 91 (34.23), 84 (22.77), 83 (100), 73 (28.82), 56 (21.85), 45
(33.82). Anal. for C10 OS (300.42): calcd: C, 39.98; H, 4.03;
ꢁ
H
12
N
4
3
from EtOH to afford 22. Green powder; mp 285–287 C; yield
ꢀ
1
N, 18.65%; found: C, 39.95; H, 4.00; N, 18.55%.
9
1
CH
0%; IR (KBr) n/cm : 3413 (NH), 3296 (NH
2
), 2622 (SH), 1718,
): d ppm 1.31 (t, 3H,
), 7.43–7.6 (m, 5H, Ar-H), 8.35 (br s, 2H,
NH2). C NMR (125 MHz, DMSO-d ): d ppm 12.37, 23.29,
1
645 (2C]O). H NMR (500 MHz, DMSO-d
), 2.95 (q, 2H, CH
6
H
3
2
Synthesis of N-(5-ethyl-1,3,4-thiadiazol-2-yl)-7-imino-5-
1
3
6
C
1,2,4
(methylthio)-1,7-dihydro-
triazolo[1,5-a]pyrimidine-6-
1
1
06.41, 122.18, 126.83, 128.29, 130.71, 140.48, 156.65, 159.56,
62.33, 167.14, 168.66, 185.86. DEPT C NMR, H–H COSY,
carboxamide (25)
1
3
To a solution of compound 24 (0.4 g, 0.0013 mol) in pyridine (25
mL), 3-amino-1H-1,2,4-triazole (0.112 g, 0.0013 mol) was added.
The reaction mixture was reuxed for 3 h, and then le to cool.
The formed precipitate was isolated by ltration, then puried
by recrystallization from EtOH to afford 25. Deep yellow powder;
HSQC and HMBC results are in agreement with the proposed
structure. MS m/z (%): 390 (M , 0.53), 357 (15.3), 356 (45.6), 355
+
(51.44), 339 (5.42), 300 (3.63), 292 (6.64), 286 (6.85), 249 (9.58),
234 (12.13), 201 (5.62), 172 (3.72), 158 (6.35), 146 (10.13), 129
(
(
25.42), 105 (100), 93 (4.04), 86 (10.04), 77 (93.59), 74 (29.31), 70
12.4), 51 (16.5). Anal. for C H N O S (390.49): calcd: C, 49.21;
ꢁ
ꢀ1
mp 190–192 C; yield 52%; IR (KBr) n/cm : 3464, 3433, 3409
1
6
14 4 2 3
+
(
(
(
(
(
(
3NH), 1642 (CO). MS m/z (%): 336 (M , 11.45), 332 (24.08), 325
32.54), 306 (14.82), 302 (64.48), 300 (37.42), 291 (29.25), 289
8.13), 257 (12.77), 251 (22.55), 228 (43.51), 225 (21.62), 199
23.43), 183 (24.76), 175 (54.19), 153 (30.74), 119 (54.27), 95
H, 3.61; N, 14.35%; found: C, 49.16; H, 3.55; N, 14.22%.
Synthesis of (E)-2-cyano-N-(5-ethyl-1,3,4-thiadiazol-2-yl)-2-(4-
oxo-1,3-dithiolan-2-ylidene)acetamide (23)
49.89), 79 (32.62), 64 (100), 57 (27.07). Anal. for C11
336.4): calcd: C, 39.28; H, 3.6; N, 33.31%; found: C, 39.22; H,
.45; N, 33.28%.
12 8 2
H N OS
To a stirred solution of KOH (0.11 g, 0.002 mol) in DMF (25 mL),
compound 1 (0.4 g, 0.002 mol) was added. Aer stirring for
3
30 min, carbon disulde (0.12 mL, 0.002 mol) was added. The
reaction mixture was stirred for 12 h, and then chloroacetyl
chloride (0.16 mL, 0.002 mol) was added dropwise to the Synthesis of 2-cyano-2-(1,3-dihydro-2H-benzo[d]imidazol-2-
resulting mixture. Stirring was continued for an additional 6 h. ylidene)-N-(5-ethyl-1,3,4-thiadiazol-2-yl)acetamide (26)
Then, the reaction mixture was poured into a beaker containing
a crushed ice/water mixture. The formed precipitate was ltered
To a solution of compound 24 (0.4 g, 0.0013 mol) in pyridine (20
mL), o-phenylenediamine (0.15 g, 0.0013 mol) was added. The
off, dried and puried by recrystallization from EtOH to give 23.
reaction mixture was reuxed for 3 h, and then le to cool. The
ꢁ
Reddish brown powder; mp 190–192 C; yield 45%; IR (KBr)
formed solid product was isolated by ltration, then puried by
ꢀ
1
1
n/cm : 3456 (NH), 2209 (CN), 1684, 1630 (2CO). H NMR (400
recrystallization from EtOH to afford 26. Beige powder; mp 265–
MHz, DMSO-d
s, 2H, CH -dithiolane). MS m/z (%): 312 (M , 9.15), 289 (6.36),
88 (25.24), 270 (42.28), 270 (42.28), 238 (25.78), 217 (5.68), 207
6.58), 191 (1.58), 180 (15.27), 160 (25.57), 146 (21.17), 129 (40.19),
): d
6 H
ppm 1.29 (t, 3H, CH
3
), 3.01 (q, 2H, CH
2
), 4.07
ꢁ
ꢀ1
2
(
67 C; yield 65%; IR (KBr) n/cm : 3451, 3303, 3130 (3NH), 2219
+
(
2
1
CN), 1679 (C]O). H NMR (500 MHz, DMSO-d ): d ppm 1.35
6 H
2
(
(
2
t, 3H, CH
3 2
), 3.07 (q, 2H, CH ), 7.47–7.64 (m, 4H, Ar-H), 7.93 (s,
13
H, 2NH), 8.35 (s, 1H, NH). C NMR (125 MHz, DMSO-d ):
6
1
5
3
10 (22.33), 86 (36.67), 76 (39.55), 64 (100), 60 (76.21), 59 (45.6),
4 (29.34), 45 (54.26). Anal. for C H N O S (312.38): calcd: C,
8.45; H, 2.58; N, 17.94%; found: C, 38.41; H, 2.55; N, 17.90%.
d
C
ppm 13.85, 22.76, 97.26, 116.89, 123.87, 127.70, 132.21,
57.04, 162.61, 165.99, 175.77. DEPT C NMR, H–H COSY,
13
1
0
8 4 2 3
1
HSQC and HMBC results are in agreement with the proposed
+
structure. MS m/z (%): 312 (M , 9.15), 294 (7.74), 272 (3.49), 257
Synthesis of 2-cyano-N-(5-ethyl-1,3,4-thiadiazol-2-yl)-3,3-
bis(methylthio)acrylamide (24)
(
(
6.15), 251 (39.84), 232 (7.57), 205 (29.08), 135 (30.82), 112
63.99), 107 (100), 93 (36.94), 87 (54.24), 68 (72.37), 44 (88.96).
To a stirred solution of KOH (0.11 g, 0.002 mol) in DMF (25 mL), Anal. for C14
12 6
H N OS (312.35): calcd: C, 53.83; H, 3.87; N,
compound 1 (0.4 g, 0.002 mol) was added. Aer stirring for 26.91%; found: C, 53.81; H, 3.85; N, 26.88%.
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Laboratory bioassay
4 I. Khan, S. Ali, S. Hameed, N. H. Rama, M. T. Hussain,
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Laboratory experiments were conducted to study the insecti-
cidal activity of the newly synthesized tested compounds
nd
against the 2 instar larvae of S. littoralis. The experiments
34
were carried out using the leaf dip technique. Six concentra-
tions of each compound were formulated as emulsions in
solvent, and 0.1% Triton X-100 was used as a surfactant. The
emulsions were used immediately aer preparation. For larvi-
cidal action, fresh castor bean leaves were dipped in the tested
concentrations for 10 seconds. The treated leaves were le in
the shade to dry before being offered to the larvae. The larvae
were allowed to feed on the treated leaves for 48 hours and then
changed to untreated leaves. Three replicates of 10 larvae each
were used for each concentration in addition to the control.
Control (check) tests were carried out using the same technique.
Castor bean leaves were dipped in a solution of 0.1% Triton X-
6
M. Yusuf, R. A. Khan and B. Ahmed, Bioorg. Med. Chem. Lett.,
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7
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1
00 and solvent at the same ratio used in the synthesized
compound tests. Larval mortality counts were calculated at 1, 2,
, 4, 5, 6 and 7 days aer exposure period. Mortality was cor-
21, 6527.
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3
35
rected according to Abbott's formula, and then subjected to
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36
13 K. A. M. El-Bayouki, M. M. Aly, Y. A. Mohamed,
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different tested compounds in order to determine the most
effective one. Slope values of the tested compounds were also
estimated. In addition, the efficacy of the different compounds
was measured by comparing the tested compounds with the
most effective compound using the following equation: toxicity
index ¼ LC50 of the most effective compound/LC50 of the tested
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In the present work, a novel series of different heterocyclic
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successfully synthesized and characterized. These compounds
were evaluated for their insecticidal activities against the cotton
leafworm, S. littoralis. Compounds 10b, 10c and 7 proved to be
promising insecticidal agents since they clearly showed higher
activities than the other tested compounds.
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Financial support from Chemistry Department, Faculty of
Science, Mansoura University and Plant Protection Research
Institute, Agricultural Research Centre, Egypt is gratefully
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