New route for the synthesis of pyrazole, triazole, triazine, and triazepine derivatives

Article abstract of DOI:10.1080/00397910600945894

N,N′-Diphenylpiperidine-1-carbohydrazonamide 1 was prepared and treated with halo compounds, active nitriles, diethylhy malonate, ketones, CS₂, phenylisocyanate, phenylisothiocyanate, LR, ethyl 2-cyano-3,13-dithiomethylacetate, and benzylidenenitriles to give the corresponding triazines 2-4, pyrazoles 5 and 6, triazoles 7, 8, and 10, triazaphosphole 11, and triazepines 12-14, respectively. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910600945894

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New Route for the Synthesis of Pyrazole,
Triazole, Triazine, and Triazepine Derivatives
O. A. Omran a , A. A. Amer a & A. Khodairy a
a Chemistry Department, Faculty of Science , Sohag, Egypt
Published online: 01 Dec 2006.
To cite this article: O. A. Omran , A. A. Amer & A. Khodairy (2006) New Route for the Synthesis of Pyrazole,
Triazole, Triazine, and Triazepine Derivatives, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 36:24, 3647-3653, DOI: 10.1080/00397910600945894
To link to this article: http://dx.doi.org/10.1080/00397910600945894
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Synthetic Communicationsw, 36: 3647–3653, 2006
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910600945894
New Route for the Synthesis of Pyrazole,
Triazole, Triazine, and Triazepine
Derivatives
O. A. Omran, A. A. Amer, and A. Khodairy
Chemistry Department, Faculty of Science, Sohag, Egypt
Abstract: N,N0-Diphenylpiperidine-1-carbohydrazonamide 1 was prepared and treated
with halo compounds, active nitriles, diethylhy malonate, ketones, CS2, phenylisocya-
nate, phenylisothiocyanate, LR, ethyl 2-cyano-3,13-dithiomethylacetate, and benzyli-
denenitriles to give the corresponding triazines 2–4, pyrazoles 5 and 6, triazoles 7,
8, and 10, triazaphosphole 11, and triazepines 12–14, respectively.
Keywords: Pyrazoles, triazepines, triazines, triazoles
Triazole,[1–4] pyrazole,[4,5] triazine,[2,6,7] and triazepine[2,8] derivatives have a
wide range of biological activities including anti-angiogenesis, herbicidal
effects, antimetastatic effects, and antibacterial and fungicidal properties. As
a continuation of our previous work[2–5] on these systems, we report here
the synthesis and reactivity of new pyrazole, triazole, triazine, and triazepine
derivatives via the reaction of compound 1 with some reagents, hoping to
obtain these compounds with enhanced biological activity and medicinal
applications.
RESULTS AND DISCUSSION
N,N0-Diphenylpiperidine-1-carbohydrazonamide 1 was prepared via the
reaction of 1-piperidinethiocarboxanilide[9,10] with phenylhydrazine. Its IR
Received in the U.K. August 16, 2005
Address correspondence to A. Khodairy, Chemistry Department, Faculty of
Science, Sohag 82524, Egypt. E-mail: khodairy@yahoo.com
3647

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O. A. Omran et al.
spectrum showed absorption peaks at 3275 and 3169 cm21 corresponding to
two NH groups.
The reaction of compound 1 with active halo compounds (namely, bromo-
malononitrile, chloroacetonitrile, phenacyl bromide, ethyl chloroacetate, or
chloroacetyl chloride) in the presence of TEA gave the corresponding
5-amino-6-cyano-l,4-diphenyl-3-(piperidin-l-yl)-1,4-dihydro[1,2,4]triazine 2a,
5-amino-1,4-diphenyl-3-(piperidin-1-yl)-1,4-dihydro[1,2,4]triazine 2b 1,4,5-
triphenyl-3-(piperidin-1-yl)-1,4-dihydro[1,2,4]triazin 3, and 1,4-diphenyl-3-
(piperidin-1-yl)-1,4,5,6-tetrahydro[1,2,4]triazin-6-one 4, respectively. The
reaction pathway was assumed to proceed via alkylation of the NH group
followed by nucleophilic attack of the second NH group at the CN or
the C55O groups with elimination of H2O, EtOH, or HCl molecule (c.f.
Scheme 1).
Compound 1 was reacted with malononitrile, cyanoacetamide, or
diethylmalonate in the presence of sodium ethoxide to give 5-amino-3-
anilino-1-phenyl-3-(piperidin-1-yl)-2,3-dihydro-1H-pyrazole-4-carbonitrile 5a,
5-amino-3-anilino-1-phenyl-3-(piperidin-l-yl)-2,3-dihydro-1H-pyrazole-4-
Scheme 1.

Synthesis of Pyrazole, Triazole, Triazine, and Triazepine
3649
Scheme 2.

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O. A. Omran et al.
carboxamide 5b, and ethyl 3-anilino-5-hydroxy-1-phenyl-3-(piperidin-1-yl)-2,3-
dihydro-1H-pyrazole-4-carboxylate 6, respectively (c. f. Scheme 2).
Treatment of compound 1 with p-chlorobenzaldehyde or p-nitroaceto-
phenone in the presence of sodium ethoxide afforded 1-[5-(p-chloro-
phenyl)-1,4-diphenyl-4,5-dihydro-1H-[1,2,4]triazol-3-yl)-piperidine 7a and
1-[5-methyl-5-(p-nitrophenyl)-1,4-diphenyl-4,5-dihydro-1H-[1,2,4]triazol-
3-yl)piperidine 7b, respectively (cf. Scheme 2).
On treatment of compound 1 with carbon disulfide in the presence of
KOH, 1,4-diphenyl-3-(piperidin-l-yl)-4,5-dihydro[l,2,4]triazin-5-thione 8 was
obtained (cf. Scheme 2).
The reaction of compound 1 with phenyl isocyanate or phenyl isothiocya-
nate and TEA gave the corresponding urea and thiourea derivatives 9a,b.
Compound 9a underwent intramolecular cyclization to give triazole derivative
10 on heating in diphenylether (cf. Scheme 2).
The chemistry of Lawesson’s reagent (LR) as thiation reagent has been
studied, and several papers describe its ring-closure reactions with substrates
containing two functional group.[11] Thus, the reaction of compound 1 with
LR in boiling acetonitrile yielded 1-[3-(p-methoxyphenyl)-2,4-diphenyl-3-
sulfido-3,4-dihydro-2H-1,2,4,3-triazaphosphol-5-yl]piperidine 11. Its IR
spectrum showed the following absorption bands at 1610 and 1110 cm21
for the C55N, and P55S groups, respectively (cf. Scheme 2).
Treatment of compound 1 with ethyl 2-cyano-,3,3-dithiomethylacetate in
the presence of TEA gave 7-methylthio-5-oxo-1,4-diphenyll-3-(piperidin-1-
yl)-4,5-dihydro-1H-[1,2,4]triazepin-6-yl carbonitrile 12. Its IR spectrum
revealed that the C55O and CN groups have absorption bands at 1696 and
2196 cm21 respectively. The reaction mechanism was assumed to involve
an addition of the NH group at the ethylenic bond with elimination of
MeSH molecule, followed by a nucleophilic attack of the second NH group
at C55O group with elimination of EtOH molecule (cf. Scheme 3).
Finally, the reaction of compound 1 with benzylidene-malononitrile or
ethyl benzylidenecyanoacetate in the presence of TEA afforded 6-cyano-5-
imino-l,4-diphenyl-3-(piperidin-l-yl)-4,5-dihydro-lH-[l,2,4] triazepine 13 or
6-cyano-5-oxo-1,4-diphenyl-3-(piperidin-1-yl)-4,5-dihydro-1H-[1,2,4]triaze-
pine 14, respectively. The reaction pathway proceeded via a nucleophilic
attack of the NH group to the ethylenic bond followed by a nucleophilic
addition of the second NH group to the CN group or the C55O group with
elimination of EtOH molecule (cf. Scheme 3).
EXPERIMENTAL
Synthesis of Compounds 1
A mixture of 1-piperidinethiocarboxanilide[9,10] (0.01mol, 2.2 g) and phenyl-
hydrazine (0.01 mol, 1.08 mL) in ethanol (20 mL) was refluxed for 15 h. The

Synthesis of Pyrazole, Triazole, Triazine, and Triazepine
3651
Scheme 3.
precipitated product formed on hot was filtered off and crystallized
(cf. Scheme 1).
Synthesis of Compounds 2–4
Compound 1 (0.01 mol, 2.93 g) [halo compound, namely bromomalononitrile
(1.44 g), chloroacetonitrile (0.65 mL), phenacyl bromide (1.99 g), ethyl chlor-
oacetate (1.22 mL), or chloroacetyl chloride (1.1 mL) and TEA (1.4 mL)] was
refluxed in ethanol (20 mL) for 4 h. On cooling, the formed precipitate was
filtered off and crystallized (cf. Scheme 1).
Synthesis of Compounds 5a,b and 6
Compound 1 (0.02 mol, 0.58 g), malononitrile (0.13 g), cyanoacetamide
(0.17 g), diethyl malonate (0.32 mL), and sodium ethoxide (0.06 g of Na in

3652
O. A. Omran et al.
30 mL ethanol) were refluxed for 3 h. On cooling, the reaction mixture was
poured into ice-cold water (50 mL) containing HCl (5 mL). The precipitated
solid was filtered, dried, and crystallized (cf. Scheme 2).
Synthesis of Compounds 7a,b
A mixture of compound 1 (0.003 mol, 0.87 g) and p-chloro-benzaldehyde
(0.003 mol, 0.42 g) or p-nitroacetophenone (0.003 mol, 0.49 g) in sodium
ethoxide solution (0.003 mol, 0.05 g of Na in 25 mL of ethanol) was
refluxed for 4 h. On cooling, the reaction mixture was poured into ice-cold
water (40 mL) containing HCl (5 mL). The precipitated solid was filtered
off, dried, and crystallized (cf. Scheme 2).
Synthesis of Compound 8
A mixture of compound 1 (0.02 mol, 0.58 g), carbon disulphide (0.02 mol,
0.15 mL), potassium hydroxide (0.02 mol, 0.11 g in 2 mL of water), and
ethanol (30 mL) was refluxed for 4 h. On cooling, the reaction mixture was
poured into ice-cold water (50 mL) containing HCl (5 mL). The precipitated
solid was filtered off, dried, and crystallized (cf. Scheme 2).
Synthesis of Compounds 9a,b
Compound 1 (0.02 mol, 0.58 g), phenylisocyanate (0.23 mL) or phenylisothio-
cyanate (0.27 mL), and triethylamine (0.28 mL) were dissolved in dry benzene
(20 mL) and refluxed for 10 h. The reaction mixture was left to cool; the formed
precipitate was filtered off and crystallized (cf. Scheme 2).
Synthesis of Compound 10
Compound 9a (0.01 mol, 0.41 g) was suspended in diphenylether (10 mL) and
refluxed for 1 h. On cooling, the formed precipitate was filtered off and crys-
tallized (cf. Scheme 2).
Synthesis of Compound 11
A mixture of compound 1 (0.01 mol, 2.94 g), LR (0.01 mol, 2.02 g), and
acetonitrile (40 mL) was refluxed for 12 h until no more of the reactants
could be detected by thin-layer chromatography (TLC). The solvent was evap-
orated to dryness under reduced pressure. The residue was triturated with
ethanol. The separated solid was filtered off and crystallized (cf. Scheme 2).

Synthesis of Pyrazole, Triazole, Triazine, and Triazepine
Synthesis of Compound 12
3653
Compound 1 (0.02 mol, 5.8 g), ethyl 2-cyano-3,3-dithio-methylacetate
(5.2 g), and triethylamine (2.8 mL) were refluxed in ethanol (20 mL) for
3 h. The reaction mixture was left to cool; the formed precipitate was
filtered off, dried, and crystallized (cf. Scheme 3).
Synthesis of Compounds 13 and 14
Compound 1 (0.02 mol, 0.58 g), benzylidenemalononitrile (0.31 g) or ethyl
benzylidenecyanoacetate (0.4 g), and triethylamine (0.3 mL) were refluxed
in DMF (40 mL) for 3 h. The reaction mixture was left to cool and poured
into ice-cold water (50 mL) containing HCl (5 mL). The formed precipitate
was filtered off and crystallized (cf. Scheme 3).
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