New synthetic routes to 1,3,4-thiadiazole derivatives

Article abstract of DOI:10.1080/10426500600614519

Different new 1,3,4-thiadiazolopyridine derivatives (6, 8, 20, 28, and 42) were synthesized from 5-cyanomethyl-1,3-4-thiadiazole (1) and activated nitriles. Also, spiro indolono-thiadiazolopyridine (12) was obtained from the reaction of (1) with 2-(2-oxoi

Full text of DOI:10.1080/10426500600614519

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New Synthetic Routes to 1,3,4-
Thiadiazole Derivatives
A. A. Elagamey a , F. M. A. El-Taweel a & R. A. N.
Abu El-Enein a
a Department of Chemistry, New Damietta, Arab
Republic of Egypt
Published online: 21 Sep 2006.
To cite this article: A. A. Elagamey , F. M. A. El-Taweel & R. A. N. Abu El-Enein
(2006): New Synthetic Routes to 1,3,4-Thiadiazole Derivatives, Phosphorus, Sulfur,
and Silicon and the Related Elements, 181:9, 2155-2176
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Phosphorus, Sulfur, and Silicon, 181:2155–2176, 2006
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500600614519
New Synthetic Routes to 1,3,4-Thiadiazole Derivatives
A. A. Elagamey
F. M. A. El-Taweel
R. A. N. Abu El-Enein
Department of Chemistry, New Damietta,
Arab Republic of Egypt
Different new 1,3,4-thiadiazolopyridine derivatives (6, 8, 20, 28, and 42) were syn-
thesized from 5-cyanomethyl-1,3-4-thiadiazole (1) and activated nitriles. Also, spiro
indolono-thiadiazolopyridine (12) was obtained from the reaction of (1) with 2-(2-
oxoindolin-3-ylidene)malononitrile (10). Other heterocyclic derivatives at position-5
in the thiadiazole ring were obtained for possible use as antimicrobial agents.
Keywords 1,3,4-Thiadiazoles; actived nitriles; thiadiazolopyridine; pyridine; furo[2,3-
b]indole; pyridazine
INTRODUCTION
Alkylazoles are versatile reagents, which have been extensively uti-
lized for the synthesis of polyfunctionally substituted aromatic and het-
eroaromatic systems.1−11 These aromatic and heteroaromatic2 systems
are interesting as potential biodegradable agrochemicals,4,11 pharma-
ceuticals, and intermediates4 in the dye industry.12−14
In general, thiadiazole derivatives have been reported to
be biologically versatile compounds having antimicrobial,15−25
mutagenic,16 anticonvulsant,23,26 cytotoxicity,22,27 antiviral,27,28
antiinflammatory,29−31 antihelicobacterpylori,32 anti-tuberculosis,33
antiimmobility34 and anticancer.35
In continuation of our studies, the utility of N-(5-(cyanomethyl)-
1,3,4-thiadiazol-2-yl)benzamide (1), the arylidenenitriles 2, and active
methylene nitriles 3 as excellent precursors is reported. The present
work has resulted in the formation of novel 1,3,4-thiadiazolopyridine
and 2-substitued 1,3,4-thiadiazole derivatives of expected potential bi-
ological importance.
Received November 20, 2005; accepted December 30, 2005.
Address correspondence to A. A. Elagamey, New Damietta, Department of Chemistry,
Faculty of Science, A. R. Egypt. E-mail: r elagamey@yahoo.com
2155

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A. A. Elagamey et al.
RESULTS AND DISCUSSION
It has been found that (1) reacted readily with arylidenemalononitriles
2a,b,d in ethanolic/piperidine to yield thiadiazolo[3,2-a]pyridines (6a–
c) via hydrogen elimination. 1H NMR spectra of the reaction products
revealed no signals at δ ≈ 4.5–5.0 ppm for one proton linked to an sp3
carbon corresponding to pyridine H-4 protons.36 The oxidation of dihy-
droazines by arylidene malononitriles has been observed.37 Thus, struc-
ture 6 was established for the reaction products. The formation of 6 was
assumed to proceed via a Michael type addition of the active methylene
group in 1 to the activated double bonds in the arylidenenitriles 2 to
give Michael adducts 4, which readily cyclized to 5 and dehydrogenated
to afford 6. Compound 6a was also prepared from the reaction of (9) with
malononitrile using the same reaction conditions.
Similarly, compound 1 reacted with 2e in ethanol/piperdine to yield
(8) via ammonia and hydrogen elimination. The same product 8 was
also obtained by reacting (9) with cyanoacetamide (3b). Compound
8 could be directly obtained from boiling 6a in glacial acetic acid
(Scheme 1).
Also, compound 1 reacted with (10) in ethanol catalyzed by piperdine
to afford compound (12). Structure 12 was establised for the reaction
product based on the analytical and spectral data, which is in good
agreement with structure 12 (cf. Experimental section).
Compound 1 condensed with 2,3-indolinedione (13) to yield a product
with the molecular formula C19H11N5SO2 (M+ = 373 m/z). The IR spec-
trum indicated clearly that the reaction product is 15 based on the IR
spectrum, which revealed the absence of signals due to the cyano func-
tion. Thus, was 15 established as a reaction product. Compound 15 was
assumed to be formed via the initial condensation of 2,3-indolinedione
13 with the active methylene group in 1 to give the ylidenic inter-
mediate 14, which readily cyclized to yield the final isolable product
15.
Similarly, compound 1 reacted with 1,2-dihydro-2,3-dimethyl-4-
nitroso-1-phenylpyrazol-5-one (16) to yield a product resulting from the
elimination of water from the reactants. Structure 17 was established
1
for the reaction product on the basis of their IR and H NMR spectra
(cf. Experimental section).
It has been reported that a mixture of aliphatic aldehydes and ac-
tive methylene nitriles can be utilized as a synthetic equivalent of
alkylidenemalononitriles.36,38 By this method, different heterocycles
can be prepared. Thus, the mixture formaldehyde and malononitrile
as a synthetic equivalent of 18 reacted with compound 1 in refluxing
ethanol/piperidene to afford 20. Compound 20 was suggested to be

1,3,4-Thiadiazole Derivatives
2157
SCHEME 1
formed through the first addition of the active methylene in 1 to the
π-deficient center in 18 to give the adducts 19. These were cyclized
to yield 20. The formation of 20 is in accordance with the previously
reported formation of similar systems.8

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A. A. Elagamey et al.
Similarly, compound 1 reacted with a mixture of formaldehyde and 2-
amino-1,1,3-tricyanopropene (22a) or diethyl 2-amino-1-cyanopropene-
1,3-dicarboxylate (22b) in ethanol and in the presence of piperidine as
a catalyst to afford (24a) and (24b), respectively. Structure 24 was es-
tablished from analytical and spectral data (cf. Experimental section).
Compounds 24a,b were proposed to be obtained through first the con-
densation of 1 with formaldehyde to give the intermediate 21, which
added on the active methylene in 22a,b to give the intermediates 23.
The latter cyclized to yield 24a,b (Scheme 3).
The cyclocondensation of compound 1 with ketenedithioacetal 25 re-
sulted in the formation of a product with thiomethanol elimination.
Thiadiadiazol[3,2-a]pyridine 28 was suggested as a reaction product.
Structure 28 was supported from its IR spectrum and elemental anal-
ysis. The formation of 28 was suggested to be found via the addition
of the active methylene group in 1 to give the adduct 26. The latter
eliminated thiomethanol to give the intermediate 27, which cyclized to
28 (Scheme 4).
Also, compound 1 reacted with cyanothioformanilide (29) in ethanol
catalyzed by piperidine to yield 31. The IR spectrum of 31 showed the
presence of an amino group and the absence of cyano functions. Com-
pound 31 was thought to be formed via the sequence demonstrated in
Scheme 4.
N-(5-(cyanomethyl)-1,3,4-thiadiazol-2-yl)benzamide (1) reacted with
mercaptoacetic acid (32) in dry pyridine to give 33. This compound
reacted readily with the arylidenemalononitriles 2a,b in refluxing dry
pyridine to yield (1:1) adducts. Acyclic structures 34 were ruled out by
an 1H NMR spectrum of 35, which revealed in addition to the aromatic
protons, the presence of a signal at δ = 3.96 ppm for the CH2 group and
a signal at δ = 4.64 ppm for pyran H-4. Thus, pyrano[2,3-d]thiazole
structure 35 was established as reaction products. The formation of 35
was proposed to proceed via the Michael type addition of the active
methylene group in the thiazole derivatives 33 to the activated double
bond in 2a,b to give Michael adducts 34, which readily cyclized to yield
35.
Also, compound 33 reacted with ethyl arylidenecyanoacetate (2f) in
refluxing dry pyridine to yield 37 rather 38 as established by the IR
spectrum, which showed an absorption band at υ = 2219 cm−1 corre-
sponding to the cyano group (Scheme 5).
Recently, it has been reported that enaminonitriles were extensively
used as starting material for the synthesis of a variety of heteroaro-
matic systems.36,38−47 In continuation to our studies on the chemistry
of enaminonitriles, the utility of compound 1 as a starting component
for the synthesis of 1,3,4-thiadiazolopyridines is reported. Thus, the

1,3,4-Thiadiazole Derivatives
2159
SCHEME 2

2160
A. A. Elagamey et al.
SCHEME 3

1,3,4-Thiadiazole Derivatives
2161
SCHEME 4

2162
A. A. Elagamey et al.
SCHEME 5

1,3,4-Thiadiazole Derivatives
2163
treatment of 1 with dimethylformamidedimethylacetal (DMFDMA) in
dry xylene at a reflux temperature yielded the propenonitrile 39. Struc-
ture 39 was supported from its 1H-NMR and mass spectra (cf. Experi-
mental section).
The reactivity of 39 toward active hydrogen reagents was investi-
gated. For example, reacting compound 39 with benzoylaminoacetic
acid 40 in dry acetic anhydride at a reflux temperature afforded a prod-
uct via dimethylamine and water elimination and furnished a sole prod-
uct identified as 42. IR, 1H-NMR, and mass spectra are compatible with
structure 42. This compound is suggested to be formed via an initial
addition of the active methylene in benzoylaminoacetic acid 40 to the
activated double bond in 39 to give the intermediate 41, which read-
ily cyclized to yield 42. Compound 42 was also prepared via reacting
1 with methyl 2-benzoylamino-3-(N, N-dimethylamino)propenoate (43)
via dimethylamine and methanol elimination, as shown in Scheme 6.
The reactivity of compound 1 toward 2-arylazopropane dinitriles (45)
and 51 was also studied. Thus, compound 1 was subjected to react with
45 in ethanol containing a few drops of piperidine to give 47. IR and
elemental analysis were compatible with structure 47. Compound 47
was formed through the first addition of the active methylene group in
1 to the cyano group in 45 to give the intermediate 46. The later were
cyclized into 47a,b.
The coupling of 1 with arylidenediazonium chlorides gave the aryl-
hydrazones 48. Trials to prepare 47 by reacting 48 and malononitriles
resulted in the formation of pyridazine 50. Compound 50 was supported
to be formed via the addition of the active methylene group in 3a to give
the intermediates 49. They were cyclized to 50a,b (Scheme 7).
On the other hand, reacting 1 with 3-(3-chloro-4-methylphenyl-
azo)pentan-2,4-dione (51) in ethanol and piperidine as a catalyst to
yield a product for which structure 53 was established as a reaction
product based on IR spectrum, which clearly exihited the presence sig-
nals at 3448 cm−1 for NH, 1672 cm−1 for CO acetyl, and 1654 cm−1
for amidic carbonyl. Compound 53 was proposed to be obtained via the
first condensation of the ketonic carbonyl group in 51 with the active
methylene in 1 to give the intermediate 52, which cyclized to yield 53
(Scheme 7).
BIOLOGICAL ACTIVITIES
Generally, thiadiazole derivatives have been reported to be biologically
versatile compounds as bactericidal, fungicidal, herbicidal, analgesic,
and antifungitoxic activity.48−50

2164
A. A. Elagamey et al.
SCHEME 6

1,3,4-Thiadiazole Derivatives
2165
SCHEME 7

2166
A. A. Elagamey et al.
FIGURE 1
MATERIALS AND METHODS
The antimicrobial activities of the novel 1,3,4-thiadiazole derivatives
compounds were tested against Gram positive bacterium (Bacillus
Cereus), Gram negative bacterium (Escherichia Coli), and two fungi
(Aspergillus Niger and Aspergillus Flavus). 0.2–0.3 mL of about 1,000
µg mL−1 of the different novel 1,3,4-thiadiazole derivatives. Compounds
were taken and transferred to a core (10 mm) made in the plate previ-
ously inoculated by the tested organisms.

1,3,4-Thiadiazole Derivatives
2167
TABLE I Antimicrobial Activities of Some
Novel 1,3,4-Thiadiazole Derivatives
Tested Organisms
Compounds
E. Coli
B. Cereus
A. Niger A. Flavues
6c
6d
9
15
17
+
−
−
+
−
−
−
−
−
−
−
−
+
+
−
+
+
−
−
+
+
+
−
−
−
−
+
−
+
+
−
−
−
−
−
−
−
+
−
−
+
−
−
+
20
24b
35a
35b
37
42
−, inactive, +, active.
Bacterial test organisms were grown on nutrient agar while fungi
were grown on Dox agar (pH = 7.2), respectively, and incubated at 28–
30◦C.
Inhibition zones of the test organisms were measured after 24 h for
bacteria and 48 h for fungi.
RESULTS
Eleven compounds (6c, 6d, 9, 15, 17, 20, 24b, 35a, 35b, 37, and 42) were
tested for antimicrobial activity against two bacterial strains of Gram
negative bacterium and Gram-positive bacterium (e.g., Escherichia Coli
and Bacillus Cereus respectively) and two fungal strains of Aspergillus
Niger and Aspergillus Flavus.
All tested products have antimicrobial activities either against the
tested bacteria or the fungi (Table I).
Only two compounds (6c, 15) have antimicrobial activity against Es-
cherichia Coli, while seven compounds (6d, 9, 17, 20, 35b, 37, and 42)
have antimicrobial activity against Bacillus Cereus.
On the other hand, three compounds (17, 35a and 42) showed an-
timicrobial activity against Aspergillus Flavus while three compounds
(17, 24b, and 35a) exhibited antimicrobail activity against Aspergillus
Niger.
CONCLUSION
It has been found that compounds 17, 35a, and 42 are highly ac-
tive against two bacterial strains of Gram negative bacterium and
Gram-positive bacterium (e.g., Escherichia Coli and Bacillus Cereus,

2168

2169

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A. A. Elagamey et al.
respectively) and two fungal strains Aspergillus Niger and Aspergillus
Flavus, in comparison to other synthesized derivatives.
The activity may be attributed to the presence of antipyrinyl, bro-
mide, and bifunctional benzamide groups attached to the thiadiazolyl
rings.
EXPERIMENTAL
All melting points are uncorrected and were measured on Griffin &
George MBF 010T (London) apparatus. Recorded yields correspond to
the pure products. IR (KBr) spectra were recorded on a perkin Elmer
1
SP-880 spectrophotometer, and H-NMR spectra were measured on a
Varian 270 MHz spectrometer in DMSO-d6 as a solvent and TMS as
an internal standard (Chemical shifts are reported in δ units ppm.).
Mass spectra were measured on GS/MS INCOL XL finningan MAT.
Microanalysis was performed on a LECOCHN-932 and carried out in
the Microanalytical Data Units at Cairo and Mansoura Universities.
N-(6,8-Dicyano-7-aryl-5-imino-5H-[1,3,4]thiadiazolo
[3,2-a]pyridin-2-yl)benzamides (6a–c)
Method A
From 1 and cinnamonitriles, preparation of (6a–c). Equimolecular
amounts of 1 (2.44 g, 10 mmoles) and the appropriate cinnamonitriles
2a–c were refluxed in absolute ethanol (50 mL) and in the presence of
piperidine (0.1 mL) for 3 h. The solid products so formed were filtered,
recrystallized, and identified as 6a–c.
Method B
From 2a,b and malononitrile, preparation of (6a,b). To a suspension
of 2a,b (10 mmoles) and malononitrile (0.66 g, 10 mmoles) in ethanol
(50 mL) containing a catalytic amount of piperidine, 0.1 mL was added.
The reaction mixture was refluxed for 5 h. The product so formed was
collected by filtration and recrystallized, and compounds 6a,b formed
by this method were found identical (m.p., mixed m.p., and IR) with
those obtained by Method A.
N-(6,8-Dicyano-7-(4-hydroxyphenyl)-5-oxo-5H-
[1,3,4]thiadiazolo[3,2-a]pyridin-2-yl]benzamide (8)
Method A
From 1 and cinnamonitrile 2, the preparation of (8). Equimolecular
amounts of 1 (2.44 g, 10 mmoles) and the appropriate cinnamonitrile

1,3,4-Thiadiazole Derivatives
2171
2e (1.88 g, 10 mmoles) were refluxed in absolute ethanol (50 mL) in the
presence of piperidine (0.1 mL) for 3 h. The solid products so formed
were filtered, recrystallized, and identified as 8.
Method B
From 9a and cyanoacetamide 3b, the preparation of (8). To a sus-
pension of 9 (3.49 g, 10 mmoles) and cyanoacetamide 3b (0.84 g,
10 mmoles) in ethanol (50 mL), a catalytic amount of piperidine (0.1 mL)
was added. The reaction mixture was refluxed for 5 h. The product so
formed was collected by filtration, recrystallized, and identified as 8.
Method C
A suspension of 6a (4.13 g, 10 mmoles) in glacial acetic acid was
refluxed for 2 h. The solvent was removed invacuo, and the remaining
residue was dissolved in hot ethanol. The solid product obtained was
collected by filtration, recryalized, and identified as 8.
N-[5-(1-Cyano-2-(4-hydroxyphenyl)vinyl-1,3,4-thiadiazol-2-
yl]benzamides (9)
Compound 1 (2.44 g, 10 mmoles) in ethanol (50 mL) was treated with ρ-
hydroxybenzaldehyde (1.22 g, 10 mmoles) and a few drops of piperidine.
The mixture was refluxed for 2 h, and then the solvent was concentrated
and allowed to stand at r.t. for ca. 12 h. The product was collected by
filtration and purified by recrystalization from the proper solvents and
identified as (9).
The Preparation of N-[5-Amino-6,8-dicyano-7-((1,3-dihydro-
2H-indol-2-on)spiro)-7H-[1,3,4]thiadiazolo[3,2-a]pyridin-2-
yl]benzamide (12)
To a mixture of 1 (2.44 g, 10 mmoles) and 2-(2-oxoindolin-3-ylidene)
malononitrile (10) (1.95 g, 10 mmoles) in ethanol (50 mL), few drops
of piperidine were added. The reaction mixture was refluxed for 4 h
and cooled, and the formed precipitate was collected by filtration and
recrystallized.
N-(5-(2-Imino-2H-furo[2,3-b]indol-3-yl)-1,3,4-thiadiazol-2-
yl)benz-amide (15)
To a mixture of (2.44 g, 10 mmoles) 1 and (1.47 g, 10 mmoles) of 2,3-
indolinedione (13) in ethanol (50 mL), a catalytic amount of piperidine

2172
A. A. Elagamey et al.
(0.2 mL) was added. The reaction mixture was refluxed for 2 h, and the
solid product deposited was filtered off and recrystallized.
The Preparation ofN-(5-(2,5-Dihydro-2,3-dimethyl-5-oxo-1-
phenyl-1H-pyarazol-4-ylimino)(cyano)methyl)1,3,4-thiadiazol-
2-yl)benzamide (17)
A suspension of 1 (2.44 g, 10 mmoles) and 1,2-dihydro-2,3-dimethyl-4-
nitroso-1-phenylpyrazol-5-one (16) (2.17 g, 10 mmoles) in ethanol (50
mL) containing 2 drops of piperidine was refluxed for 30 min. The pre-
cipitate formed was collected by filtration and recrystallized.
The Preparation ofN-(5-Amino-6,8-dicyano–7H-
[1,3,4]thiadiazolo[3,2-a]pyridin-2-yl)benzamide (20)
To a suspension of 1 (2.44 g, 10 mmoles), malononitrile (0.66 g, 10
mmoles) and formaldehyde 40% (0.9 g, 30 mmoles) in ethanol (50 mL),
a catalytic amount of piperidine (0.1 mL) was added. The reaction mix-
ture was refluxed for 5 h, and the products, so formed, were collected
by filtration, recrystallized, and identified as 20.
The Preparation ofN-(5-(2-Amino-5-cyano-6-
(dicyanomethyl)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)benzamide
(24a) and ethyl 2-(ethoxycarbonyl) (cyano)methyl)-6-amino-5-
(5-(benzamido)-1,3,4-thiadiazol-2-yl) pyridine-3-carboxylate
(24b)
A mixture of 2-amino-1,1,3-tricyanopropene (22a) (1.32 g, 10 mmoles)
or diethyl 2-amino-1-cyanopropene-1,3-dicarboxylate (22b) (2.26 g,
10 mmoles), 1 (2.44 g, 10 mmoles), and formaldehyde 40% (0.9 g,
30 mmoles) in ethanol (30 mL) containing 0.1 mL of piperidine was
heated under refluxed for 5 h. The products, so formed, were collected
by filtration, recrystallized, and identified as 24a,b.
N-(6,8-Dicyano-5-imino-7-(methythio)-5H-
[1,3,4]thiadiazolo[3,2-a] pyridin-2-yl)benzamide (28)
A mixture of [bis(methylsulfonyl)methylene]malononitrile (25) (1.70 g,
10 mmoles) and 1 (2.44 g, 10 mmoles) in ethanol (50 mL) and a catalytic

1,3,4-Thiadiazole Derivatives
2173
amount (0.1 mL) of piperidine was refluxed for 3 h. The formed solid
was collected by filtration and recrystallized.
N-(5-(4-Amino-2,5-dihydro-2-imino-1-phenyl-5-thioxo-1H-
pyrrol-3-yl)-1,3,4-thiadiazol-2-yl)benzamide (31)
To a suspension of 1 (2.44 g, 10 mmoles) in ethanol (50 mL) were added
(1.62 g, 10 mmoles) 1-cyanothioformanilide (29) and (0.1 mL) triethy-
lamine. The reaction mixture was heated at a reflux temperature for
2 h, and the product obtained was filtered and recrystallized.
The General procedure for the preparation of
N-(5-((5-Amino-6-cyano-7-(aryl)-7H-pyrano[2,3-
d]thiazol-2-yl)methyl-1,3,4-thiadiazol-2-yl)benz-amide (35a,b)
and N-(5-(6-cyano-7-(4-hydroxyphenyl)5-oxo-5H-pyrano
[2,3-d]thiazol-2-yl)methyl-1,3,4-thiadiazol-2-yl)benzamide
(37)
Equimolecular amounts (3.0 g, 10 mmoles) of 33 with the appropriate
cinnamonitrile 2a,b (10 mmoles) were refluxed in dry pyridine (30 mL)
for 3 h. The solvent was removed in vacuo, and the product was tritu-
rated with ethanol. The solid products so formed were washed several
times with ethanol and then recrystallized and identified as 35a,b and
37, respectively.
The Preparation of 2-(5-Benzoylamino-1,3,4-thiadiazol-2-yl)-
1-(N,N-diamino)propenonitrile (39)
Dimethylformamide dimethylacetal (1.19 g, 10 mmoles) was added to
1 (2.44 g, 10 mmoles) in dry xylene (50 mL), and the reaction mixture
was refluxed for 6 h. The removal of solvent under reduced pressure
yielded the crude product, which was recrystallized.
The Preparation of N-(8-Cyano-6-benzoylamino-5-oxo-5H-
[1,3,4]thiadia-zolo[3,2-a]pyridin-2-yl)benzamide (42)
A mixture of 1 (2.44 g, 10 mmoles) and methyl β-(N, N-dimethylamino)-
α-benzoylaminopropenoate (43) (2.48 g, 10 mmoles) in glacial acetic
acid were refluxed for 6 h, then the solvent was concentrated to its
half volume and then left to cool to r.t. The precipitate was collected by
filtration and recrystallized.

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A. A. Elagamey et al.
The General procedure for the preparation of
N-(5-(5-Amino-2-(aryl)-6-cyano-2,3-dihydro-3-imino-pyridazin-
4-yl)-1,3,4-thiadiazol-2-yl)benzamide (47a,b) and N-(5-(2-(3-
chloro-4-methylphenyl)-6-acetyl-2,3-dihydro-3-imino-5-
methylpyridazin-4-yl)-1,3,4-thiadia-zol-2-yl)benzamide (53)
A solution of 1 (2.44 g, 10 mmoles) in ethanol (50 mL) was treated
with 45 or 51 (0.01 mol) and a few drops of piperidine. The reaction
mixture was reflux for 3 h and then left to cool to r. t. The solids formed
were collected by filtration, recrystallized, and identified 47a,b and 53,
respectively.
The Preparation of N-5-[(Arylhydrazano)cyanomethyl]-2-
ylbenzamide (48a,b)
To a well-stirred and cold solution of 1 (2.44 g, 10 mmoles) in ethanol
(50 mL) containing sodium acetate trihydrate (2.5 g) was added diazo-
nium salt soltution prepared from 10 mmoles of the hydrochloride salt
of the amine used and sodium nitrite solution (0.7 g, in 20 H2O) at such
a rate that the temperature was kept below 5˚ C. After the complete
addition, the mixture was stirred for 15 min and left overnight in a
refrigerator. The crude product was filtered, washed with dilute cold
ethanol, dried, and recrystallized as 48a,b.
N-(5-(4-Amino-1-(aryl)-5-cyano-1,6-dihydro-6-imino-pyridazin-
3-yl)-1, 3,4-thiadiazol-2-yl)benzamide (50a,b)
A solution of 48 (10 mmoles) in ethanol (50 mL) was treated with 3a
(0.66 g, 10 mmoles) and few drops of piperidine. The reaction mixture
was reflux for 3 h and then left to cool to r.t. The solid formed was
collected by filtration, recrystallized, and identified as (50a,b).
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