An efficient single step synthesis of pyridazine, pyrazolo[5,1-c]-1,2,4-triazine, 1,2,4-triazolo[5,1-c]-1,2,4-triazine and 1,2,4-triazino[4,3-a]benzimidazole derivatives

Article abstract of DOI:10.3987/COM-08-11559

Coupling of E-1-(l-methylbenzimidazol-2-yl)-3-(N,N, d-dimethylamino)prop-2-enone (1) with the arenediazonium salt gave hydrazonopropanal 5 which underwent cyclocondensation with active methylene compounds to afford substituted pyridazin-6-imine 8 and 11.

Full text of DOI:10.3987/COM-08-11559

HETEROCYCLES, Vol. 78, No. 3, 2009
699
HETEROCYCLES, Vol. 78, No. 3, 2009, pp. 699 - 706. © The Japan Institute of Heterocyclic Chemistry
Received, 26th September, 2008, Accepted, 10th November, 2008, Published online, 12th November, 2008.
DOI: 10.3987/COM-08-11559
AN EFFICIENT SINGLE STEP SYNTHESIS OF PYRIDAZINE,
PYRAZOLO[5,1-c]-1,2,4-TRIAZINE, 1,2,4-TRIAZOLO[5,1-c]-1,2,4-
TRIAZINE AND 1,2,4-TRIAZINO[4,3-a]BENZIMIDAZOLE DERIVATIVES
Mohamed R. Shaaban, Tamer S. Saleh, and Ahmad M. Farag*
Department of Chemistry, Faculty of Science, Cairo University, Giza 12613, Egypt
*Corresponding author: E-mail: afarag49@yahoo.com
Abstract
–
Coupling
of
E-1-(1-methylbenzimidazol-2-yl)-3-(N,N-
dimethylamino)prop-2-enone (1) with the arenediazonium salt gave
hydrazonopropanal 5 which underwent cyclocondensation with active methylene
compounds to afford substituted pyridazin-6-imine 8 and 11. The enaminone 1
coupled also with the diazonium salts prepared from aminopyrazole,
aminotriazole and 2-amino-1H-benzimidazole to afford pyrazolo[5,1-c]-l,2,4-
triazine
15,
1,2,4-triazolo[5,1-c]-1,2,4-triazine
19,
1,2,4-triazino[4,3-
a]benzimidazole 23 derivatives, respectively.
INTRODUCTION
The synthesis of benzimidazole derivatives has attracted a great deal of interest due to their potent
biological and pharmacological activities. For example, many benzimidazole derivatives have
anthelmintic,1,2 antiviral,3 antibacterial,4 antifungal,5 anti-parasitic,6 anticancer,7 and antihistaminic
activities.8 Moreover, benzimidazole derivatives are also well known as anti-HIV,9 anticoagulative10
agents, analgesic,11 anti-inflammatory,11 antihypertensive,12 antineoplastic,13 anxiolytic agents,14,15 and
for treatment of cardiovascular disease.16 In continuation of our studies on the chemistry of E-1-(1-
methylbenzimidazol-2-yl)-3-N,N-dimethylaminoprop-2-enone (1)17,18 and as part of our ongoing program
directed towards developing efficient methods for the synthesis of a variety of heterocyclic systems
incorporating benzimidazole moiety for biological evaluation,19-22 we report here on the utility of the E-1-
(1-methylbenzimidazol-2-yl)-3-(N,N-dimethylamino)prop-2-enone (1) and hydrazonopropanal 5 as
versatile building blocks for the synthesis of the title compounds.
RESULTS AND DISCUSSION
E-1-(1-methylbenzimidazol-2-yl)-3-(N,N-dimethylamino)prop-2-enone (1) coupled with the arene-

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HETEROCYCLES, Vol. 78, No. 3, 2009
diazonium salt 2 to afford the corresponding hydrazonopropanal derivative 5 (Scheme 1).
The 1H NMR spectrum of the hydrazonopropanal 5 revealed characteristic signals at δ 9.56 and 12.53 due
to formyl and hydrazone protons, respectively. These chemical shifts indicate that the hydrazone 5
exists in the (E) configuration which is stabilized by intramolecular hydrogen bonding as shown in
Scheme 1.
Me
N
O
N
1
NMe2
Me
N
OH
Me
N
O
H
O
H
Ar N N
OH
Me
N
N
O
N
2
N
N
NMe2
N
N
NMe2
N
Ar
Ar
NMe2
3
4
- NHMe2
Me
N
O
H
C
N
N
O
N H
Ar = p-Me-C6H4
5
Ar
Scheme 1
The formation of compound 5 is assumed to take place via coupling of the diazonium ion 2 at C-2 of the
activated double bond in the enaminone 1, followed by hydrolysis of the dimethylamino moiety at
position 3 into the formyl group by the action of the aqueous base existing in the reaction medium as
shown in Scheme 1.
The obtained hydrazone intermediate 5 has been utilized as a versatile building block for biologically
interesting pyridazinone ring system. Thus, hydrazonopropanal 5 reacted readily and smoothly with
benzoylacetonitrile (6) in the presence of a catalytic amount of piperidine to afford the corresponding 5-
benzoyl-1,6-dihydro-6-imino-3-(1-methylbenzimidazol-2-yl)carbonyl-1-(4-methylphenyl)pyridazine (8)
in a good yield via the non-isolable open structure intermediate 7 (Scheme 2).
The IR spectrum of the reaction product 8 revealed absorption bands at 1649 and 3332 cm-1 due to
1
carbonyl and NH functions, respectively. Its H NMR spectrum revealed the disappearance of the signal
characteristic for the formyl proton.
Similarly, cyclocondensation of the hydrazone 5 with benzthiazol-2-ylacetonitrile (9) afforded the
corresponding 5-(benzthiazol-2-yl)-6-iminopyridazine 11 via the non-isolable intermediate 10 (Scheme
2). The structure of the product 11 was established on the basis of its elemental analysis and spectral data.
1
For example its H NMR spectrum revealed a singlet signal at δ 2.61 due to methyl protons, a singlet

HETEROCYCLES, Vol. 78, No. 3, 2009
701
signal at δ 4.21 due to N-methyl protons, a singlet signal at δ 5.99 due to pyridazine-4-CH proton, a
multiplet in the region of 6.37-8.03 due to aromatic protons, and a broad signal (D2O-exchangable) at δ
11.78 due to NH function. Its IR spectrum revealed absorption bands at 1645 and 3332 cm-1 due to the
carbonyl and NH functions, respectively.
S
O
CN
Me
N
CN
Ph
O
N
9
6
N
CHO
NHAr
- H2O
- H2O
N
5
Me
N
Me
O
N
O
N
S
N
N
N
O
CN
N
NH
CN
NH
Ar
Ar
10
7
Me
Me
N
O
N
O
N
O
N
S
N
N
N
N
N
Ar
NH
Ar
NH
8
Ar = p-MeC6H4
11
Scheme 2
The behavior of the enaminone 1 towards heterocyclic diazonium salts (viz pyrazole, triazole and
benzimidazole-diazonium salts) as potential precursors for a single step synthesis of interesting
biologically active bridgehead heterocyclic ring systems was also investigated. Thus, when the
enaminone 1 was treated with 3-methyl-4-phenyl-1H-pyrazolediazonium chloride (12), it afforded the
corresponding pyrazolo[5,1-c]-[l,2,4]-triazine derivative 15 in single step via the non-isolable
intermediates 13 and 14 which underwent intramolecular cyclization yielding the final bridgehead fused
ring system 15 (Scheme 3). The IR spectrum of the product 15 revealed, no bands corresponding to the
endocyclic NH of the pyrazole derivative 12 and showed a strong carbonyl absorption band at 1648 cm-1.
1
Its mass spectrum showed a peak corresponding to its molecular ion at m/z 368. The H NMR spectrum
of the same product revealed signals at δ 2.73, 4.21 and 10.08 due to CH3, N-CH3 and triazine proton,
respectively, in addition to aromatic protons as a multiplet at δ 7.42-7.94.
A plausible mechanism for the formation of the pyrazolo[5,1-c]-1,2,4-triazine 15 is outlined in Scheme
3. Compound 15 is assumed to be formed via coupling at C-2 of the activated double bond in the

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HETEROCYCLES, Vol. 78, No. 3, 2009
enaminone 1 with the diazonium ion 12 to afford the azo intermediate 13 followed by hydrolysis of
dimethylamino moiety into formyl group (intermediate 14) by action of the aqueous base present in the
reaction medium. The intermediate 14 underwent intramolecular cyclization affording the final product
pyrazolo[5,1-c]-[1,2,4]-triazine 15 (Scheme 3).
Ph
Me
N2 Cl
NH
Me
O
Me
N
O
N
N N
NH
Ph
Me
N
12
N
N
NMe2
N
NMe2
1
13
H2O
-Me2NH
O
H
Me
N
Ph
N
N N
NH
Ph
Me
Me
N
N
N
Me
N
N
N
O
N
O
15
14
Scheme 3
In a similar manner, the enaminone 1 reacted with l,2,4-triazole diazonium nitrate (16) to afford 1,2,4-
triazolo[5,1-c]-[1,2,4]-triazine 19 (Scheme 4). The structure of the product 19 was established on the
basis of its elemental analysis and spectral data (cf. Experimental Part).
The enaminone 1 reacted also with 1H-benzimidazole diazonium sulfate (20) to afford 1,2,4-triazino[4,3-
a]benzimidazole 23 (Scheme 4). The IR spectrum of the latter product revealed a band at 1656 cm1
characteristic for carbonyl absorption. Its mass spectra showed a peak corresponding to its molecular ion
1
at m/z 328. The H NMR spectrum of compound 23 revealed characteristic signals at δ 4.11 and 10.01
due to N-CH3 and triazine protons, respectively in addition a multiplet at δ 7.23-7.73 due to aromatic
protons.
EXPERIMENTAL
All melting points were measured on a Gallenkamp melting point apparatus. The infrared spectra were
recorded in potassium bromide 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 chloroform
(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 e.V. Elemental
analyses (C, H, N, S) were carried out at the Microanalytical Center of Cairo University, Giza, Egypt, the

HETEROCYCLES, Vol. 78, No. 3, 2009
703
results were found to be in good agreement (± 0.3%) with the calculated values.
N2 NO3
NH
H
N
N
N2 HSO4
N
N
16
20
1
O
Me
N
O
Me
N N
N N
NH
N
N
N
NH
N
N
N
NMe2
21
NMe2
17
H2O
-Me2NH
H2O
-Me2NH
O
Me
N
O
Me
N
N N
NH
N N
NH
N
N
N
N
O
H
O
H
N
18
22
-
H2O
-
H2O
Me
N
Me
N
N
N
N
N
N
N
N
N
N
N
N
O
O
19
23
Scheme 4
Benzoylacetonitrile (6),23 benzthiazol-2-ylacetonitrile (9),24 3-methyl-4-phenyl-1H-pyrazole diazonium
chloride (12),25 l,2,4-triazole diazonium nitrate (16),25 and 1H-benzimidazole diazonium sulfate (20)25
were prepared according to the reported literature.
(E)-3-(1-methyl-1H-benzimidazol-2-yl)-3-oxo-2-(2-p-tolylhydrazono)propanal (5).
To a stirred cold solution of the enaminone 1 (0.64 g, 20 mmol) in EtOH (50 mL) was added sodium
acetate trihydrate (8 g). After stirring for 10 min. the mixture was cooled to 0 °C and treated with 4-
methylbenzenediazonium salt solution [prepared by diazotizing p-toluidine (20 mmol) in HCl (6 M, 6
mL) with sodium nitrite solution (1.4 g, 20 mmol) in H2O (15 mL)]. The addition of the diazonium salt
was carried out with rapid stirring over a period of 30 min. The reaction mixture was stirred for further 2

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h at 0 °C, and then left for 6 h at 4 °C in a refrigerator. The resulting solid was collected by filtration,
washed thoroughly with water, then dried. The crude product was recrystallized from EtOH to give the
hydrazone 5 in 85% yield. mp 197-199 ˚C. IR (KBr) ν max /cm-1: 3343 (NH), 2758 (CH formyl), 1675
(CO), 1648 (CO), 1611 (C=N); 1H NMR (DMSO-d6): δ 2.88 (s, 3H, CH3), 4.02 (s, 3H, N-CH3), 7.01-8.03
13
(m, 8H, Ar-H’s), 9.56, (s, 1H, CHO), 12.53, (s, 1H, D2O-exchangeable, NH); C NMR (DMSO-d6): δ
21.99, 32.09, 110.92, 114.98, 124.65, 128.8, 129.68, 129.79, 137.58, 139.26, 140.56, 141.25, 142.50,
149.08, 189.89, 191.96; MS (m/z) 320 (M+, 48%). Anal. Calcd for C18H16N4O2: C, 67.49; H, 5.03; N,
17.49. Found: C, 67.57; H, 5.01; N, 17.43.
Reaction of (E)-3-(1-methyl-1H-benzimidazol-2-yl)-3-oxo-2-(2-p-tolylhydrazono)propanal (5) with
benzoylacetonitrile (6) and benzthiazol-2-ylacetonitrile (9).
General Procedure
To a solution of 5 (3.2 g, 10 mmol) was added benzoylacetonitrile (6) or benzthiazol-2-ylacetonitrile (9)
(10 mmol), in EtOH (50 mL) and 3 drops of piperdine. The reaction mixture was refluxed for 3-4 h, then
poured into ice cold H2O, and neutralized with dil. HCl. The resulting solid product was collected by
filtration, washed with EtOH and finally recrystalized from DMF, to afford the pyridazine derivative 8
and 11, respectively.
(5-Benzoyl-6-imino-1-p-tolyl-1,6-dihydropyridazin-3-yl)(1-methyl-1H-benzoimidazol-2-yl)methanone
(8).
Yield 69%. mp 250-252 ˚C. IR (KBr) υmax /cm-1: 3332 (NH), 1649 (CO), 1598 (C=N); 1H NMR (DMSO-
d6): δ 2.69 (s, 3H, CH3), 4.18 (s, 3H, NCH3), 6.01 (s, 1H, pyridazine-4-CH), 6.56-8.28 (m, 13H, Ar-H’s),
13
11.19 (s, 1H, NH, D2O-exchangeable). C NMR (DMSO-d6): δ 22.38, 30.06, 110.92, 111.23, 114.24,
115.23, 123.86, 128.8, 129.68, 129.79, 133.65, 136.66, 138.25, 139.87, 140.56, 140.20, 142.26, 147.0,
152.98, 160.20, 185.29, 189.52; MS (m/z) 447 (M+, 52%). Anal. Calcd for C27H21N5O2: C, 72.47; H,
4.73; N, 15.65. Found: C, 72.40; H, 4.86; N, 15.59.
(5-(Benzothiazol-2-yl)-6-imino-1-p-tolyl-1,6-dihydropyridazin-3-yl)(1-methyl-1H-benzoimidazol-2-
yl)methanone (11).
Yield 75%. mp 278-280 ˚C. IR (KBr) υmax /cm-1: 3332 (NH), 1645 (CO); 1614 (C=N); 1H NMR (DMSO-
d6): δ 2.61 (s, 3H, CH3), 4.21 (s, 3H, NCH3), 5.99 (s, 1H, pyridazine-4-CH), 6.37-8.03 (m, 12H, Ar-H’s),
11.78 (s, 1H, NH, D2O-exchangeable); MS (m/z) 476 (M+, 42%). Anal. Calcd for C27H20N6OS: C, 68.05;
H, 4.23; N, 17.64; S, 6.73 . Found: C, 68.21; H, 4.12; N, 17.61; S, 6.71.
Reaction of (E)-1-(1-methylbenzimidazol-2-yl)-3-(N,N-dimethylamino)prop-2-enone (2) with
diazonium salt of heterocyclic amines 12, 16 and 19.
General Procedure

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To a stirred cold solution of the enaminone 1 (2 mmol) in pyridine (30 mL) was added the
appropriate diazonium salt prepared from 5-amino-3-methyl-4-phenylpyrazole 12, 3-amino-l,2,4-triazole
16 or 2-aminobenzimidazole (20) (2 mmol) portionwise over a period of 30 min at 0-5 ºC. After
complete addition, the reaction mixture was stirred for further 3 h at 0-5 ºC then left in a
refrigerator for 6 h. The precipitated solid was collected by filtration, washed with water and dried.
Recrystallization from DMF/H2O afforded the corresponding fused ring systems 15, 19 and 23,
respectively.
(1-Methyl-1H-benzoimidazol-2-yl)(7-methyl-8-phenylpyrazolo[5,1-c]-1,2,4-triazin-3-yl)methanon (15).
1
Yield 80%. mp > 300 ˚C. IR (KBr) υmax /cm-1: 1648 (CO), 1597 (C=N); H NMR (DMSO-d6): δ 2.73 (s,
3H, CH3), 4.21 (s, 3H, N-CH3), 7.42-7.94 (m, 9H, Ar-H’s), 10.08 (s, 1H, triazine-4-CH); 13C NMR
(DMSO-d6): δ 20.10, 31.66, 110.97, 111.22, 114.24, 115.23, 123.86, 124.89, 127.85, 128.28, 129.68,
133.65, 136.66, 138.25, 140.25, 145.60, 150.23, 183.22; MS (m/z) 368 (M+, 42%). Anal. Calcd for
C21H16N6O: C, 68.47; H, 4.38; N, 22.81. Found: C, 68.59; H, 4.36; N, 22.71.
[1,2,4]Triazolo[5,1-c][1,2,4]triazin-3-yl(1-methyl-1H-benzoimidazol-2-yl)methanone (19).
Yield 72%. mp > 300 ˚C. IR (KBr) υmax /cm-1: 1656 (CO), 1607 (C=N); 1H NMR (DMSO-d6): δ 4.11 (s,
3H, NCH3), 7.08-7.18 (m, 4H, Ar-H’s), 7.27 (s, 1H, triazole-7-CH), 9.77 (s, 1H, triazine-4-CH); 13C
NMR (DMSO-d6): δ 31.46, 111.22, 120.68, 123.15, 124.89, 128.42, 135.76, 138.32, 140.56, 146.23,
147.16, 150.23, 182.93 (CO); MS (m/z) 279 (M+, 38%). Anal. Calcd for C13H9N7O: C, 55.91; H, 3.25; N,
35.11. Found: C, 55.99; H, 3.21; N, 35.07.
3-(1-Methylbenzimidazol-2-oyl)-1,2,4-triazino[4,3-a]benzimidazole (23).
Yield 70%. mp > 300 ˚C. IR (KBr) υmax /cm-1: 1652 (CO), 1607 (C=N); 1H NMR (DMSO-d6): δ 4.11 (s,
3H, N-CH3), 7.23-7.73 (m, 8H, ArH’s), 10.01 (s, 1H, triazine-4-CH); 13C NMR (DMSO-d6): δ 31.84,
111.98, 121.69, 123.33 124.99, 128.55, 126.97, 128.45, 136.87, 138.32, 124.27, 141.61, 144.10, 156.33,
184.88; MS (m/z) 328 (M+, 45%). Anal. Calcd for C18H12N6O: C, 65.85; H, 3.68; N, 25.60. Found: C,
65.72; H, 3.79; N, 25.62.
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