Utility of hydrazinopiperidinomethanethione in synthesis of thiadiazole, thiadiazine, and pyrazole derivatives

Article abstract of DOI:10.1080/10426500701752960

Hydrazinopiperidinomethanethione 2 was prepared and reacted with active halo compounds, carbon disulfide, phenyliso-thiocyanate, ylidenenitriles, and N,S-acetyls to give thiadiazine 4-7, thiadiazole 8-10, and pyrazole 11,13,14-17 derivatives, respectively

Full text of DOI:10.1080/10426500701752960

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Utility of
Hydrazinopiperidinomethanethione
in Synthesis of Thiadiazole,
Thiadiazine, and Pyrazole
Derivatives
A. A. Amer a , O. A. Omran a & A. Khodairy a
a Chemistry Department, Faculty of Science, Sohag
University, Sohag, Egypt
Version of record first published: 22 Jun 2009.
To cite this article: A. A. Amer , O. A. Omran & A. Khodairy (2009): Utility of
Hydrazinopiperidinomethanethione in Synthesis of Thiadiazole, Thiadiazine, and
Pyrazole Derivatives, Phosphorus, Sulfur, and Silicon and the Related Elements, 184:7,
1653-1664
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Phosphorus, Sulfur, and Silicon, 184:1653–1664, 2009
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500701752960
Utility of Hydrazinopiperidinomethanethione in
Synthesis of Thiadiazole, Thiadiazine, and
Pyrazole Derivatives
A. A. Amer, O. A. Omran, and A. Khodairy
Chemistry Department, Faculty of Science, Sohag University, Sohag,
Egypt
Hydrazinopiperidinomethanethione 2 was prepared and reacted with active halo
compounds, carbon disulfide, phenyliso-thiocyanate, ylidenenitriles, and N,S-
acetyls to give thiadiazine 4–7, thiadiazole 8–10, and pyrazole 11,13,14–17 deriva-
tives, respectively.
Keywords Hydrazinopiperidinomethanethione; thiadiazine; thiadiazole
INTRODUCTION
Thiadiazoles1–3 and pyrazoles4–7 are exhibited a broad spectrum of
pharmacological properties such as anti-inflammatory, antiviral, an-
tipyretic, antitumor, and antibacterial. Thiadiazines are also effi-
cient antibacterial and antifungal compounds,8 and their use in
the treatments of the bacterial Helicobacter pylori and as reverse
transcriptase inhibitors of the human immunodeficiency virus have
been reported.9,10 Recently,11 we have used N,Nꢀ-diphenylpiperidine-1-
carbohydrazonamide in synthesis of pyrazole, triazole, triazine and tri-
azepine derivatives, this prompted us to continue our previous work5,11
to report here synthesis of thiadiazole, thiadiazine, and pyrazole deriva-
tives via the reaction of hydrazinopiperidinomethanethione 2 with the
suitable reagents.
RESULTS AND DISCUSSION
Hydrazinopiperidinomethanethione 2 was prepared by treating 1-
piperidinomethanethione 1 with hydrazine hydrate in 1:1 molar ratio,
Received 20 August 2007; accepted 18 September 2007.
Address correspondence to A. A. Amer, Chemistry Department, Faculty of Science,
Sohag University, Sohag 82524, Egypt. E-mail: Amer1631972@yahoo.com
1653

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A. A. Amer et al.
SCHEME 1
while on using 2 mol of hydrazine hydrate, the hydrazinopiperidino-
formalhydrazone 3 was obtained. IR spectrum of compound 2 showed
absorption peaks at 3463, 3271, and 3194 Cm−1, which corresponded
1
to the presence of NH and NH2 groups, whereas its HNMR showed
singlet signal at δ 10.0 for the NH group, broad signal at 6.0–5.4 for the
NH2 group and multiplet signals at 2.4–1.2 for the aliphatic protons
(c.f. Scheme 1, Table I).
The reaction of compound 2 with active halo compounds namely;
ethyl chloroacetate, chloroacetonitrile, phenacyl bromide, 2,3-dichloro-
naphthoquinone, or ethyl chloroformate in the presence of TEA as a
basic catalyst, gave the corresponding 2-piperidino-5,6-dihydro-4H-1,3,
4-thiadiazin-5-one 4, 5-amino-2-piperidino-6H-1,3,4-thiadiazine 5,
5-phenyl-2-piperidino-6H-1,3,4-thiadiazine
6,
3-piperidino-5,10-
dihydro-1H-naphtho[2,3-e][1,3,4]thiadiazine-5,10-dione 7, and 5-
piperidino-2,3-dihydro-1,3,4-thiadiazol-2-one 8, respectively. The
reaction pathway was assumed to proceed via alkylation on the SH
group followed by nucleophilic attack of the NH2 group at CN, CO with
elimination of EtOH or H2O molecule (c.f. Scheme 2, Table I).
Compound 2 was subjected to react with carbon disulfide or phenyl
isothicyanate to give the corresponding 5-piperidino-2,3-dihydro-1,3,4-
thiadiazole-2-thione 9 and 2(iminophenyl)-5-piperidino-2,3-dihydro-
1,3,4-thiadiazole 10, respectively. IR spectra of compounds 9 and 10
showed the disappearance of the absorption bands corresponding to
NH2 group (c.f. Scheme 3, Table I).
Treatment of compound 2 with ylidenenitriles, namely, p-chloro-,
p-nitro-, or p-hydroxybenzylidenemalononitrile, in the presence of TEA
as a basic catalyst, gave two products—the first was precipitated

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1656

1657

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A. A. Amer et al.
SCHEME 2
on hot namely Schiff‘s base 11a−c, and the second 5-amino-4-cyano-3-
(p-chlorophenyl)-1-piperidino-(thioxo)methyl-2,3-dihydro-1H-pyrazole
12a,
5-amino-4-cyano-3-(p-nitrophenyl)-1-piperidino(thioxo)methyl-
2,3-dihydro-1H-pyrazole 12b or amino-4-cyano-3-(p-hydroxyphenyl)-1-
piperidino-(thioxo)methyl-2,3-dihydro-1H-pyrazole 12c was separated
from the filtrate, respectively. Similarly, the reaction of compound 2

Thiadiazole, Thiadiazine, and Pyrazole Derivatives
1659
SCHEME 3
with ethyl p-chloro-, p- nitro – and p- hydroxybenzylidenecyanoacetate
in the presence of TEA gave a mixture of the Schiff‘s base 11a−cand
4-cyano-5-hydroxy-3-(p-chlorophenyl)-1-piperidino(thioxo)methyl-2,3-
dihydro-1H-pyrazole 12d, 4-cyano-5-hydroxy-3-(p-hydroxyphenyl)-
1-piperidino(thioxo)meth-yl-2,3-dihydro-1H-pyrazole 12e, and 4-
cyano-5-hydroxy-3-(p-nitrophenyl)-1-piperidino-(thioxo)methyl-2,3-
dihydro-1H-pyrazole 12f, respectively. Also, on treating compound 2
with p-chlorobenzylidenecyanoacetamide in presence of TEA, gave
a mixture of compounds 11a and 12d, respectively. IR spectra of
compounds 12 showed the presence of absorption bands correspond-
ing to OH,NH2groups in addition to CN group at 3400 cm−1, 3320
cm−1, 3200 cm−1, and 2100 cm−1, respectively. 1H-NMR spectra
showed the disappearance of the peak corresponding to the SH
group and the appearance of the new peak at ∼7.00 ppm corre-
sponding to aromatic protons. In analogy, compound 2 was treated
with cyclohexylidenemalononitrile and TEA to yield a mixture of the
Schiff’s base 13 and 2-amino-3-piperidino(thioxo)methyl-3,4-dihydro-
spiro[4,5]dec-1-en-1-ylcyanide 14. The reaction pathway was assumed
to proceed via the formation of 1:1 adduct A12, which can loss of
active methylene molecule to give Schiff’s bases 11a−c and 13 or
undergo intermolecular cyclization via a nucleophilic attack of the
NH group to the CN or C O group with elimination of ethanol in
case of ethyl arylidenecyanoacetate or ammonia molecule in case of
p-chlorobenzylidenecyanoacetamide to give products 12a−f and 14,

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A. A. Amer et al.
respectively. Another route for the synthesis of compounds 12a−f and
14 was achieved by treating the synthesized Schiff‘s bases 11a−c and
13 with active nitriles in presence of TEA (c.f. Scheme 4, Table I).
It has been reported13,14 that some substituted hydrazines react
with ethoxymethylenemalonmalononitrile or ethyl ethoxymethylene-
cyanoacetate giving the corresponding pyrazoles, which are potential
purine antagonists. In light of these results, it was interest to use
compound 2 for preparation of 5-amino-4-cyano-1-piperidino(thioxo)-
methyl-1H-pyrazole 15 and 5-hydroxy-4-cyano-1-piperidino(thioxo)-
methyl-1H-pyrazole 16 via its reaction with ethoxymethylene-
malononitrile or ethoxymethylenecyanoacetate in presence of TEA,
respectively. The pathway was assumed to proceed via nucleophilic
attack of the NH2 group to the ethylenic bond with elimination of
ethanol molecule, followed by another nucleophilic attack of the NH
group to the CN group (c.f. Scheme 5, Table I).
Treatment of compound 2 with (1-methylthio-1ꢀ-anilinomethyl-
idene)malononitrile or ethyl (1-methylthio-1‘-anilinomethylidene)-
cyanoacetate in presence of TEA, 5-amino-3-anilino-4-cyano-1-
piperidino(thioxo)methyl-1H-pyrazole 17 and 3-anilino-4-cyano-5-
hydroxy-1-piperidino(thioxo)methyl-1H-pyrazole 18, were obtained,
respectively. The IR spectra of compounds 15–18 showed the presence
1
of the CO group in compounds 16 and 18. The H-NMR spectra are
in agreement with the proposed formula. The pathway for the forma-
tion of these products was proceeded through nucleophilic attack of the
NH2 group to the ethylenic bond with elimination of MeSH molecule,
followed by nucleophilic attack of the NH group to the CN group (c.f.
Scheme 5, Table I).
EXPERIMENTAL
All melting points were determined on a Koffler melting points appa-
ratus and are uncorrected. IR spectra were obtained on a Nicolet 710
1
FT-IR Spectrometer. H-NMR spectra were recorded on a Varian EM
360 at 60 MHz using TMS as an internal reference. Elemental analyses
were carried out with an elemental analyzer model 240◦C. Satisfactory
microanalysis (C 0.4, H 0.4, N 0.3%) were obtained for all newly
prepared compounds.
Synthesis of Compound 2
A mixture of 1-piperidinomethanethione 1 (0.01 mol, 1.61 g), hydrazine
hydrate (0.01 mol, 0.50 mL) and ethanol (20 mL) was refluxed for 4 h,
and the mixture was allowed to cool. The separated solid was collected

Thiadiazole, Thiadiazine, and Pyrazole Derivatives
1661
SCHEME 4

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A. A. Amer et al.
SCHEME 5
by filtration and recrystallized from ethanol to give 2 (cf. Scheme 1,
Table I).
Synthesis of Compound 3
A solution of 1-piperidinomethanethione 1 (0.01 mol, 1.61 g), hydrazine
hydrate (0.02 mol, 1.00 mL) in ethanol (20 mL) was refluxed for 10
h. The reaction mixture was filtered on hot, and the precipitant was
recrystallized from DMF to give compound 3 (cf. Scheme 1, Table I).
Synthesis of Compounds 4–8
An equimolar ratio (0.01 mol) of compound 2 (1.59 g), halo compound
namely; ethyl chloroacetate (1.20 mL), chloroacetonitrile (0.65 mL),
phenacyl bromide (1.99 g), 2,3-dichloronaphthoquinone (2.27 g), or
ethyl chloroformate (1.10 mL), and TEA (1.41 mL) was refluxed in
ethanol (20 mL) for 4 h. The reaction mixture was cooled, and the
separated precipitate was filtered off, washed by water, dried, and re-
crystallized from a suitable solvent to give compounds 4–8, respectively
(cf. Scheme 2, Table I).

Thiadiazole, Thiadiazine, and Pyrazole Derivatives
1663
Synthesis of Compounds 9 and 10
A solution of compound 2 (0.02 mol, 3.23 g), carbon disulfide (0.02 mol,
1.50 mL) or phenyl isothiocyanate (0.02 mol, 2.81 mL) in pyridine (30
mL) was refluxed for 10 h. After cooling, the reaction mixture was
poured into ice-cold water containing drops of HCl. The precipitated
solid was filtered off, dried, and recrystallized from a suitable solvent
(cf. Scheme 3, Table I).
Synthesis of Compounds 11a-c–14 (Method A)
A mixture of 0.01 Mol of compound 2 (1.59 g), arylidinemalononitrile
namely; p-chloro- (1.88 g), p-nitro- (1.99 g), p-hydroxybenzylidene-
malononitrile (1.71 g), ethyl p-chloro- (2.35 g), p-nitro- (2.46 g), p-
hydroxybenzylidenecyanoacetate (2.17 g), p-chlorobenzylidenecyano-
acetamide (2.06 g), or cyclohexylidenemalononitrile (1.46 mL) and TEA
(1.40 mL) in ethanol (30 mL) was refluxed for 3 h. The precipitated solid
so formed on hot was filtered off, washed by ethanol, dried, and recrys-
tallized from a suitable solvent to give compounds 11a−c or 13. The
filtrate was evaporated in vacuo. The solid residue was treated with
pet. ether 40–60◦C and recrystallized to give compounds 12a−f or 14,
respectively (cf. scheme 4, Table I).
Synthesis of Compounds 11a-c–14 (Method B)
A solution of an equimolar amount (0.01 mol) of Schiff’s base 11a–c
or 13 (0.01 mol) and a selective active nitriles namely malononitrile
(0.66 g), ethyl cyanoacetate (1.14 mL) or cyanoacetamide (0.88 g), and
TEA (1.50 mL) in dioxane (40 mL) was refluxed for 3 hrs. On cooling,
the precipitated solid was filtered off, dried, and recrystallized from a
suitable solvent give compounds 12a-f or 14, respectively.
Synthesis of Compounds 15–18
0.01 Mol of compound 1 (1.59 g), ethoxymethylenemalononitrile
(1.36 g), ethyl ethoxymethylenecyanoacetate (1.83 g), (1-methylthio-
1ꢀ-anilinomethylidene)malononitrile (4.30 g) or ethyl (1-methylthio-1ꢀ-
anilinomethyl-idene)cyanoacetate (5.20 g), and triethylamine (1.50 mL)
in ethanol (40 mL) was refluxed for 6 h. The reaction mixture cooled
and the solid formed was filtered, dried, and recrystallized from a
suitable solvent to give compound 15–18, respectively (cf. Scheme 5,
Table I).

1664
A. A. Amer et al.
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