Facile and convenient synthesis of pyrazole, pyridine, pyridazine, pyrazolo[3,4-b]pyridine, and pyrazolo[5,1-c][1,2,4]triazine derivatives

Article abstract of DOI:10.1080/00397910802109257

A convenient synthesis of a series of pyrazole, pyridine, pyridinethione, pyridazine, pyrazolo[3,4-b]pyridine, imidazo[1,2-a]pyrimidine, and pyrazolo[5,1-c][1, 2, 4]triazine derivatives incorporating a pyrimidine moiety, via the reactions of the versatile, readily accessible 3-oxo-N-(pyrimid-2-yl) butanamide with the appropriate reagents, is described. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910802109257

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Facile and Convenient
Synthesis of Pyrazole, Pyridine,
Pyridazine, Pyrazolo[3,4-
b]pyridine, and Pyrazolo[5,1-c]
[1,2,4]triazine Derivatives
Nabila A. Kheder a , Yahia N. Mabkhot b & Ahmad M.
Farag a
a Department of Chemistry, Faculty of Science, Cairo
University, Giza, Egypt
b Department of Chemistry, Faculty of Science,
Zamar University, Zamar, Yemen
Version of record first published: 09 Sep 2008.
To cite this article: Nabila A. Kheder, Yahia N. Mabkhot & Ahmad M. Farag (2008):
Facile and Convenient Synthesis of Pyrazole, Pyridine, Pyridazine, Pyrazolo[3,4-
b]pyridine, and Pyrazolo[5,1-c][1,2,4]triazine Derivatives, Synthetic Communications:
An International Journal for Rapid Communication of Synthetic Organic Chemistry,
38:18, 3170-3182
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Synthetic Communications1, 38: 3170–3182, 2008
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910802109257
Facile and Convenient Synthesis of Pyrazole,
Pyridine, Pyridazine, Pyrazolo[3,4-b]pyridine,
and Pyrazolo[5,1-c][1,2,4]triazine Derivatives
Nabila A. Kheder,1 Yahia N. Mabkhot,2 and Ahmad M. Farag1
1Department of Chemistry, Faculty of Science, Cairo University,
Giza, Egypt
2Department of Chemistry, Faculty of Science, Zamar University,
Zamar, Yemen
Abstract: A convenient synthesis of a series of pyrazole, pyridine, pyridi-
nethione, pyridazine, pyrazolo[3,4-b]pyridine, imidazo[1,2-a]pyrimidine, and pyr-
azolo[5,1-c][1,2,4]triazine derivatives incorporating a pyrimidine moiety, via the
reactions of the versatile, readily accessible 3-oxo-N-(pyrimid-2-yl)butanamide
with the appropriate reagents, is described.
Keywords: N-(pyrimid-2-yl)butanamide, imidazo[1,2-a]pyrimidine, pyrazole,
pyrazolo[3,4-b]pyridine, pyrazolo[5,1-c][1,2,4]triazine], pyridazine, pyridinethione
In addition to being essential components of naturally occurring nucleic
acids, pyrimidines are integral parts of biologically important compounds
such as antiviral[1] antiherpes,[2] and cardiovascular agents.[3] On the
other hand, acetamido derivatives, in general, have been found to possess
fungicidal[4] and herbicidal[5] activities. Moreover, amides in which ami-
dic hydrogen has been substituted with a heterocyclic moiety have been
found to possess local anesthetic effects.[6] In view of these reports and
in continuation of our interest in the synthesis of a variety of heterocyclic
systems for biological evaluation,[7–19] we describe here a facile synthe-
sis of pyrazole, pyridinethione, pyrazolo[3,4-b]pyridine, imidazo[1,2-a]
pyrimidine, pyridazine, and pyrazolo[5,1-c][1,2,4]triazine, starting from
the readily accesible 3-oxo-N-(pyrimid-2yl)butanamide.
Received January 18, 2008.
Address correspondence to Ahmad M. Farag, Faculty of Science, Department of
Chemistry, Cairo University, Giza 12613, Egypt. E-mail: afarag49@yahoo.com
3170

Convenient Synthesis of Pyridine Derivatives
3171
Scheme 1. Synthetic route of compound 4.
Thus, when 3-oxo-N-(pyrimid-2-yl)butanamide (1) was treated
with dimethylformamide–dimethylacetal (DMF-DMA), it afforded
the corresponding 3-oxo-N-(pyrimid-2-yl)-2-(N,N-dimethylaminomethyl-
ene)butanamide (2) (Scheme 1). The IR spectrum of the latter product
revealed absorption bands at 1650, 1681, and 3365 cmꢀ1 due to two
1
carbonyl and imino functions. Its H NMR revealed signals at d 2.41,
3.21, and 3.26 due to acetyl CH3 protons and N,N-dimethyl protons,
in addition to the D2O-exchangeable signal at d 11.4 due to the NH
proton, and an aromatic multiplet and methine proton in the region
d 8.33–8.80.
Compound 2 was treated with phenylhydrazine, in refluxing ethanol,
to afford the pyrazole derivative 4 (Scheme 1). IR spectrum of compound
4 revealed absorption bands at 1651 and 3150 cmꢀ1 due to carbonyl
1
groups and an imino function. Its H NMR revealed signals at d 2.14
due to CH3 protons, D2O-exchangeable signals at d 8.9 due to a NH
proton, and an aromatic multiplet in the region d 6.67–7.82.
Reaction of equimolar amounts of the butanamide 1 and 2-cyano-2-
(4-chlorophenylmethylene)thioacetamide (5) in the presence of piperdine
afforded 5-acetyl-N-(pyrimid-2-yl)-3-cyano-4-(4-chlorophenyl)-6-oxo-2-
thioxopyridine (6) (Scheme 2). The IR spectrum of compound 6 showed
typical strong absorption bands at 1542, 1674, 1710, and 2222 cmꢀ1 due
to thiocarbonyl, two carbonyls, and a nitrile function, respectively.
Treatment of the pyridinethione 6 with hydrazine hydrate afforded
1H-3-amino-4-(4-chlorophenyl)-5-acetyl-6-oxo-7-(N-pyrimid-2-yl)pyrazolo-
[3,4-b]pyridine (7) (Scheme 2). The IR spectrum of the latter compound
revealed absorption bands at 1674, 1720, 3063, 3132, and 3479 cmꢀ1
due to two carbonyl groups: NH2 and NH functions, respectively. Its
1H NMR spectrum showed signal at d 2.36 due to CH3 protons, two

3172
N. A. Kheder, Y. N. Mabkhot, and A. M. Farag
Scheme 2. Synthetic routes of compounds 6 and 7.
D2O-exchangeable signals at d 7.29 and 10.82 due to NH2 and NH protons,
respectively, and an aromatic multiplet in the region d 7.13–8.56. Also, its
mass spectrum revealed a molecular ion peak at m=z 381.
Treatment of the butanamide 1 with bromine in sodium hydroxide
solution, at room temperature, furnished only one isolable product
(as tested by thin-layer chromatography, TLC) that was identified as
imidazo[1,2-a]pyrimidine 9 (Scheme 3). Compound 9 was thought to
Scheme 3. Synthetic routes of compound 9.

Convenient Synthesis of Pyridine Derivatives
3173
be formed via initial bromination of the methylene group followed by
elimination of hydrogen bromide under the reaction conditions. The IR
spectrum of compound 9 showed absorption bands at 1620 and
1
1674 cmꢀ1 due to two carbonyl groups. Its H NMR revealed signals at
d 2.39 due to CH3 protons, D2O-exchangeable signal at d 12.7 due to
an OH proton, and an aromatic multiplet in the region d 7.33–9.99. Its
mass spectrum showed a molecular ion peak at m=z 177. Compound 9
was alternatively prepared via the reaction of the butanamide 1 with
elemental sulfur in the presence of a catalytic amount of triethylamine
(Scheme 3).
3-Oxo-(N-pyrimid-2-yl)butanamide (1) coupled smoothly with the
diazonium salts of aniline and p-chloroaniline, in ethanol buffered with
sodium acetate, to afford the corresponding hydrazone derivatives
11a, b (Scheme 4). When compound 11b, taken as typical example, was
treated with malononitrile in ethanol, in the presence of a catalytic
amount of piperdine, it afforded 1-(4-chlorophenyl)-3-(pyrimid-2-ylcar-
boxamido)-4-methyl-6-iminopyridazine-5-carbonitrile (12) (Scheme 4).
The IR spectrum of the conjugated carbonyl of amide group should
absorption bands at 2199, 3150, and 3333 cmꢀ1 due to a nitrile function
1
and two NH groups, respectively. Its H NMR spectrum revealed signal
at d 2.49 due to CH3 and two D2O-exchangeable signals at d 10.33 and
Scheme 4. Synthetic routes of compounds 12 and 13.

3174
N. A. Kheder, Y. N. Mabkhot, and A. M. Farag
11.76 due to two NH protons, in addition to an aromatic multiplet in the
region d 8.23–8.90.
The hydrazone 11b reacts also with ethyl cyanoacetate to afford the 1-(4-
chlorophenyl)-6-oxo-3-(pyrimid-2-ylcarboxamido)-4-methyl-pyridazin-
5-carbonitrile (13). Heating of the iminopyridazine derivative 12 in acetic
acid=hydrochloric acid mixture afforded a product that was found to be
identical in all respects with compound 13. The IR spectrum of the latter
product showed absorption bands at 1660, 1689, 2120, and 3225 cmꢀ1 due
1
to two carbonyl, nitrile function, and NH groups, respectively. Its H
NMR spectrum revealed signals at d 2.49 due to CH3 and a broad signal
at d 10.90 (D2O-exchangeable) due to NH, in addition to an aromatic mul-
tiplet in the region d 7.24–7.68. Treatment of the butanamide 1 with the
diazonium salt of 3-phenyl-5-aminopyrazole (14) afforded the corres-
ponding 4-methyl-7-phenyl-N-(pyrimidin-2-yl)pyrazolo[5,1-c]-[1,2,4]tria-
zine-3-carboxamide (15) via the none-isolable hydrazone intermediate
11c (Scheme 5). The IR spectrum of the product 15 revealed the presence
of an amide carbonyl absorption band at 1684 cmꢀ1 and one NH band at
1
3360 cmꢀ1. Its H NMR spectrum revealed signals at d 2.49 due to CH3
and a broad signal at d 11.12 (D2O-exchangeable) due to an NH proton,
in addition to an aromatic multiplet in the region d 7.27–8.74.
When the butanamide 1 was trated with benzaldehyde, in the presence
of a catalytic amount of piperdine, it afforded the corresponding 2-phenyl-
methylene-3-oxo-N-(pyrimid-2-ylcarboxamido)butanamide (16) (Scheme 6).
The IR spectrum of compound 16 showed absorption bands at 1655,
1709, and 3234 cmꢀ1 due to two carbonyl groups and the NH function,
Scheme 5. Synthetic route of compound 15.

Convenient Synthesis of Pyridine Derivatives
3175
Scheme 6. Synthetic routes of compound 19.
respectively. Its 1H NMR spectrum revealed a singlet signal at d 2.13 due to
CH3, a broad signal at d 10.03 (D2O-exchangeable) due to the NH proton,
and an aromatic multiplet in the region d 6.55–8.27.
Treatment of compound 16 with malononitrile in the presence of a
catalytic amount of piperidine furnished the corresponding 2-amino-
5-acetyl-4-phenyl-6-oxo-1,4,5,6-tetrahydro-N-(pyrimid-2-yl)pyridine (19)
(Scheme 6). The IR spectrum of compound 19 revealed absorption bands
at 1638, 1651, 2214, 3066, and 3233 cmꢀ1 due to two carbonyl, nitrile, and
1
amino functions, respectively. Its H NMR spectrum exhibited a singlet
signal at d 2.4 due to CH3, two doublets at d 4.82 and 5.48 with
J ¼ 11.22 Hz due to two CH protons, and a broad signal at d 8.17 due
to NH2, in addition to an aromatic multiplet in the region d 7.00–8.37.
Compound 19 was assumed to be formed via an initial Michael-type
adduct 17 followed by an intramolecular cyclization to the final product
19 (Scheme 6). Additionally, the elucidation of structures 19 was
supported chemically through its alternative synthesis from the reaction
of the butanamide 1 with phenylmethylenepropandinitrile 20 under the
same reaction condition.
EXPERIMENTAL
All melting points were measured on a Gallenkamp melting-point
apparatus. The infrared spectra were recorded in potassium bromide

3176
N. A. Kheder, Y. N. Mabkhot, and A. M. Farag
disks on a pye Unicam SP 3300 and Shimadzu FT IR 8101 PC infrared
spectrophotometers. The NMR spectra were recorded on a Varian
Mercury VX-300 NMR spectrometer. 1H spectra were run at
300 MHz and 13C spectra were run at 75.46 MHz in deuterated chloro-
form (CDCl3) or dimethyl sulphoxide (DMSO-d6). Chemical shifts were
related to that of the solvent. Mass spectra were recorded on a
Shimadzu GCMS-QP 1000 EX mass spectrometer at 70 eV. Elemental
analyses (C, H, N, S) were carried out at the Microanalytical Center
of Cairo University, Giza, Egypt, and the results were in good
agreement ( ꢁ 0.3%) with the calculated values. The starting materials
3-oxo-N-(pyrimid-2-yl)-butanamid(1),[20]
2-cyano-2-(4-chlorophenyl-
methylene)thioacetamide (5),[21] 3-phenyl-(1H)-pyrazole-5-diazonium
chloride (14),[22] and phenylmethylenepropanedinitrile (20)[23] were pre-
pared according to the reported literature.
3-Oxo-2-(N,N-dimethylaminomethylene)-N-(pyrimid-2-yl)butanamide (2)
A mixture of butanamide 1 (3.58 g, 20 mmol) and DMF-DMA (2)
(2.66 cm3, 20 mmol) in 30 cm3 dry xylene was refluxed for 3 h and then
left to cool. The yellow precipitated product was filtered off, washed
with light petroleum, and dried. Recrystallization from EtOH=DMF
afforded yellow crystals. Yield 50%; mp 250–251ꢂC (DMF=EtOH). IR
ꢀ1
(KBr): v 3365 (NH), 1681 (C O), 1650 (C O) cm . 1H NMR
(DMSO-d6) d 2.47 (s, 3H, CH3), 3.21 (s, 3H, CH3), 3.26 (s, 3H, CH3),
8.33–8.80 (m, 4H, ArH’s), 11.4 (s, br, 1H, D2O-exchangeable NH).
Calcd. for C11H14N4O2: C, 56.40; H, 6.02; N, 23.92. Found: C, 56.42;
H, 6.08; N, 23.91.
=
=
Reaction of 3-Oxo-2-(N,N-dimethylaminomethylene)-N-(pyrimid-2-yl)-
butanamide (2) with Phenylhydrazine
Phenyl hydrazine (0.2 cm3, 2 mmol) was added to a solution of 2 (0.468 g,
2 mmol) in 20 cm3 EtOH, and the reaction mixture was refluxed for
4 h, then left to cool. The obtained solid product was filtered off, washed
with EtOH, and dried. Recrystallization from EtOH afforded an
orange product of 1-phenyl-3-methyl-4-(pyrimid-2-ylcarboxamido)-
pyrazole (4). Yield 60%; mp 220–221ꢂC (DMF=EtOH). IR (KBr):
ꢀ1
1
=
n 3150 (NH), 1651 (C O) cm . H NMR (DMSO-d6) d 2.14 (s, 3H,
CH3), 6.67–7.82 (m, 9H, ArH’s), 8.9 (s, br, 1H, D2O-exchangeable
NH). Calcd. for C15H13N5O: C, 64.51; H, 4.69; N, 25.07. Found: C,
64.48; H, 4.66; N, 25.03.

Convenient Synthesis of Pyridine Derivatives
3177
Reaction of the Butanamide 1 with 2-Cyano-2-(4-chlorophenyl
methylene)thioacetamide (5)
To a mixture of the butanamide 1 (0.358 g, 2 mmol) and 2-cyano-2-(4-
chlorophenyl-methylene)thioacetamide (5) (0.445 g, 2 mmol) in 20 cm3
EtOH, a few drops of piperdine were added. The reaction mixture was
heated under reflux for 2 h. The solid product that precipitated from
the hot solution was filtered off, washed with EtOH, and recrystallized
from DMF to afford yellow crystals of 5-acetyl-N-(pyrimid-2-yl)-3-
cyano-ꢂ4-(4-chlorophenyl)-6-oxo-2-thioxopyridine (6) in 70% yield. Mp
=
=
> 300 C (DMF). IR (KBr): n 2222 (CꢃN), 1710 (C O), 1674 (C O),
ꢀ1
1
=
1574 (C S) cm . H NMR (DMSO-d6) d 2.4 (s, 3H, CH3), 7.15–8.57
(m, 7H, ArH’s), 14.34 (s, 1H, D2O-exchangeable SH). Calcd. for
C18H11N4O2SCl: C, 56.47; H, 2.90; N, 14.64; S, 8.38; Cl, 9.26. Found:
C, 56.49; H, 2.92; N, 14.64; S, 8.39; Cl, 9.25.
3-Amino-5-acetyl-6-oxo-4-(4-chlorophenyl)-1,4,5,6-tetrahydro-7-
(pyrimid-2-yl)pyrazolo[3,4-b]pyridine (7)
Hydrazine hydrate (80%, 0.1 cm3, 1 mmol) was added to a solution of the
pyridinethione 6 (0.384 g, 1 mmol) in 20 cm3 EtOH. The reaction mixture
was heated under reflux for 4 h, then left to cool. The solid product was
filtered off, washed with EtOH, and dried. Recrystallization from DMF
afforded yellow crystals of 7. Yield 70%; mp 285–286ꢂC (DMF). IR
ꢀ1
=
=
(KBr): n 3479 (NH), 3063–3132 (NH2), 1720 (C O), 1674 (C O) cm .
1H NMR (DMSO-d6) d 2.36 (s, 3H, CH3), 7.13–8.56 (m, 7H, ArH’s),
7.29 (s, br, 2H, D2O-exchangeable NH2), 10.82 (s, br, 1H, D2O-exchange-
able NH). MS m=z (%) 383 (16.3), 382 (7.8), 381 (Mþ , 33.6), 366 (100),
340 (6.1), 112 (4.5), 111 (5.5), 78 (2.6), 77 (4.4). Calcd. for C18H13N6O2Cl:
C, 56.78; H, 3.443.44; N, 22.07; Cl, 9.31. Found: C, 56.75; H, 3.48; N,
22.10; Cl, 9.27.
Bromination of 3-Oxo-N-(pyrimid-2-yl)butanamide (1)
To a cold solution of the butanamide 1 (0.358 g, 2 mmol), sodium hydrox-
ide (2 mmol), and 20 cm3 absolute methanol, bromine (0.16 g, 0.05 cm3,
2 mmol) was added portionwise to the resulting solution with continuous
stirring. After complete addition, the reaction was left for 1 h. The solid
product that formed was filtered off, washed with water, and crystallized
from DMF to give white crystals of 3-acetylimidazo[1,2-a]pyrimidin-
2(3H)-one 9, in 80% yꢀie1ld. mp > 300ꢂC (DMF). IR (KBr): n 1674
1
=
=
(C O), 1620 (C O) cm . H NMR (DMSO-d6) d 2.39 (s, 3H, CH3),

3178
N. A. Kheder, Y. N. Mabkhot, and A. M. Farag
7.33–9.99 (m, 3H, ArH’s), 12.7 (s, 1H, OH). 13C NMR (DMSO-d6) d
27.35, 103.76, 113.51, 135.82, 141.86, 152.50, 159.98, 184.44. MS, m=z
(%) 179 (1.0), 178 (Mþ þ 1, 8.5), 177 (Mþ , 82.9), 176 (1.6), 122 (0.8),
94 (1.6), 79 (26.8), 78 (3.0). Calcd. for C8H7N3O2: C, 54.24; H, 3.98; N,
23.72. Found: C, 54.22; H, 4.00; N, 23.68.
Reaction of 3-Oxo-N-(pyrimid-2-yl)butanamide (1) with
Elemental Sulfur
Ethyl acetoacetate or ethyl cyanoacetate (2 mmol) and a catalytic amount
of triethylamine were added to a solution of the butanamide 1 (0.358,
2 mmol) in 20 cm3 EtOH and elemental sulfur (0.064 g, 2 mmol). The
reaction mixture was heated at 60–65ꢂC for 30 min and then allowed to
cool. The precipitated solid was filtered off, washed with EtOH, and
recrystallized from DMF to afford the same product identical in all
respects (mp, mixed mp, and spectra) with that obtained from the reac-
tion of butanamide 1 with bromine.
General Procedure for the Reaction of 3-oxo-N-(pyrimid-2-yl)-
butanamide (1) with the Diazonium Salts of Aromatic Amines
and 5-Amino-3-Phenylpyrazole
The appropriate diazonium salt of aromatic amines or 5-amino-3-phenyl-
pyrazole (14) (2 mmol) was added to a cold solution of butanamide 1
(0.358 g, 2 mmol) in 50 cm3 EtOH, buffered with sodium acetate
trihydrate (3 g). The addition was carried out portionwise with stirring
at 0–5ꢂC over a period of 30 min. After complete addition, the reaction
mixture was stirred for a further 4 h, then kept in an ice chest for 12 h,
and finally diluted with water. The precipitated solid was collected by
filtration, washed with water, dried, and finally recrystallized from the
proper solvent to afford hydrazones 11a,b and the pyrazolo[5,1-c]-
1,2,4-triazine 15, respectively.
3-Oxo-2-(phenylhydrazono)-N-(pyrimid-2-yl)butanamide (11a)
Yield 92%; mp 174–175ꢂC (EꢀtO1 H). IR (KBr): n 3200 (NH), 3130 (NH),
1
=
=
1670 (C O), 1636 (C O) cm . H NMR (CDCl3) d 2.3 (s, 3H, CH3),
7.24–8.71 (m, 7H, ArH’s), 11.80 (s, br, 1H, D2O-exchangeable, NH),
14.0 (s, br, 1H, D2O-exchangeable, NH). Calcd. for C14H13N5O2: C,
59.36; H, 4.63; N, 24.72. Found: C, 59.39; H, 4.60; N, 24.69.

Convenient Synthesis of Pyridine Derivatives
3179
3-Oxo-2-(4-chlorophenylhydrazono)-N-(pyrimid-2-yl)butanamide (11b)
Yield 80%; mp 180–181ꢂC (EꢀtO1 H). IR (KBr): n 3200 (NH), 3163 (NH),
=
1670 (C O), 1638 (C O) cm . Calcd. for C14H12N5O2Cl: C, 52.92; H,
=
3.81; N, 22.04; Cl, 11.16. Found: C, 52.94; H, 3.85; N, 22.07; Cl, 11.20.
4-Methyl-7-phenyl-N-(pyrimidin-2-yl)pyrazolo[5,1-c][1,2,4]triazine-3-
carboxamide (15)
ꢂ
ꢀ1
=
Yield 85%; mp > 300 C (DMF). IR (KBr): n 3360 (NH), 1684 (C O) cm .
1H NMR (DMSO-d6) d 2.49 (s, 3H, CH3), 7.27–8.74 (m, 9H, ArH’s), 11.12
(s, br, 1H, D2O-exchangeable, NH). MS, m=z (%) 331 (Mþ , 0.6), 209 (1.9),
122 (20.0), 93 (0.4), 79 (14.4). Calcd. for C17H13N7O: C, 61.62; H, 3.96;
N, 29.59. Found: C, 61.68; H, 3.98; N, 29.55.
Reaction of 3-Oxo-2-(4-chlorophenylhydrazono)-N-(pyrimid-2-
yl)butanamide (11b) with Malononitrile and Ethyl Cyanoacetate
A few drops of piperdine were added to an ethanolic solution of the
hydrazone 11b (0.64 g, 2 mmol) and malononitrile (0.165 g, 2.5 mmol)
or ethyl cyanoacetate (0.226 g, 2 mmol), and the reaction mixture was
refluxed for 4 h. The solvent was evaporated under reduced pressure,
and the residue was triturated with EtOH. The solid product was filtered
off, washed with ethanol, and finally purified by recrystallization from
the proper solvent to afford brown crystals of 12 and yellow crystals of
13, respectively.
1-(4-Chlorophenyl)-3-(pyrimid-2-ylcarboxamido)-4-methyl-6-
iminopyridazine-5-carbonitrile (12)
Yield 80%; mp 265–266ꢂC (DMF=EtOH). IR (KBr): n 3333 (NH), 3150
ꢀ1
1
=
(NH), 2199 (CꢃN), 1655 (C O) cm . H NMR (DMSO-d6) d 2.49 (s,
3H, CH3), 8.23–8.90 (m, 7H, ArH’s), 10.33 (s, 1H, D2O-exchangeable,
NH), 11.76 (s, br, 1H, D2O-exchangeable, NH). Calcd. for
C17H12N7OCl: C, 55.82; H, 3.31; N, 26.81; Cl, 9.69. Found: C, 55.79;
H, 3.33; N, 26.78; Cl, 9.72.
1-(4-Chlorophenyl)-6-oxo-3-(pyrimid-2-ylcarboxamido)-4-methyl-
pyridazine-5-carbonitrile (13)
Yield 75%; mp > 300ꢂC (DMF). IR (KBr): n 3225 (NH), 2120 (CꢃN),
ꢀ1
1
=
=
1689 (C O), 1660 (C O) cm . H NMR (DMSO-d6) d 2.49 (s, 3H,

3180
N. A. Kheder, Y. N. Mabkhot, and A. M. Farag
CH3), 7.24–7.68(m, 7H, ArH’s), 10.9 (s, D2O-exchangeable, NH). Calcd.
for C17H11N6O2Cl: C, 55.67; H, 3.02; N, 22.91; Cl, 9.67. Found: C, 55.62;
H, 3.06; N, 22.88; Cl, 9.62.
2-Phenylmethylene-3-oxo-N-(pyrimid-2-ylcarboxamido)butanamide (16)
A few drops of piperdine were added to an ethanolic solution of the buta-
namide 1 (0.358 g, 2 mmol) and benzaldehyde (0.212 g, 2 mmol), and the
reaction mixture was refluxed for 4 h. The solvent was evaporated under
reduced pressure, and the residue was triturated with EtOH. The solid
product was filtered off, washed with ethanol, and purified by recrystal-
lization from EtOH to afford pale yellow crystals of 16 in 70% yield. Mp
ꢂ
=
219–220 Cꢀ1(DMF=EtOH). IR (KBr): n 3234 (NH), 1709 (C O), 1655
1
=
(C O) cm . H NMR (CDCl3) d 2.13 (s, 3H, CH3), 6.55–8.27 (m, 9H,
ArH’s), 10.03 (s, 1H, D2O-exchangeable, NH). Calcd. for C15H13N3O2:
C, 67.40; H, 4.90; N, 15.72. Found: C, 67.46; H, 4.88; N, 15.77.
Synthesis of 5-Acetyl-2-amino-6-oxo-4-phenyl-1,4,5,6-tetrahydro-1-
(pyrimid-2-yl)pyridine-3-carbonitrile (19)
Method A
An equimolar amount of the malononitrile (0.132 g, 2 mmol), and a few
drops of pipredine were added a solution of 2-phenylmethylene-3-oxo-N-
(pyrimid-2-ylcarboxamido)butanamide (16) (0.267 g, 2 mmol) in 20 cm3
EtOH. The reaction mixture was heated under reflux for 2 h, then
allowed to cool to room temperature. The solid product was collected
by filtration, washed with EtOH, and then recrystallized from the
DMF=EtOH to give yellow crystals of 19. Yield 80%; mp 265–266ꢂC
(DMF=EtOH). IR (KBr): n 3233–3066 (NH2), 2214 (CꢃN), 1651
ꢀ1
1
=
=
(C O), 1638 (C O) cm . H NMR (DMSO-d6) d 2.40 (s, 3H, CH3),
4.82 (d, 1H, J ¼ 11.22 Hz), 5.48 (d, 1H, CH, J ¼ 11.22 Hz), 7.00–8.37
(m, 8H, ArH’s), 8.17 (s, br, 2H, D2O-exchangeable, NH2). Calcd.
for C18H15N5O2: C, 64.86; H, 4.54; N, 21.01. Found: C, 64.83; H, 4.49;
N, 21.03.
Method B
An equimolar amount of the butanamide 1 (0.358 g, 2 mmol) and a few
drops of piperdine were added to a solution of phenylmethylenepropan-
dinitrile (20) (0.308 g, 2 mmol) in 20 cm3 EtOH, and the reaction mixture

Convenient Synthesis of Pyridine Derivatives
3181
was heated under reflux for 2 h. The solid product that formed was
collected by filtration, washed with EtOH, and then recrystallized from
DMF=EtOH to give a product identical in all respects (mp, mixed mp,
and spectra) with 19 obtained from method A above.
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