Synthesis of novel Pyridazinonylbenzotriazoles

Article abstract of DOI:10.14233/ajchem.2015.18894

4-Chlorobenzaldehyde (1) was reacted with crotononitrile (2) in the presence of sodium cyanide yielding 4-(4-chlorophenyl)-3-methyl-4-oxobutyronitrile (3) which on refluxing with concentrated HCl gave 4-(4-chlorophenyl)-3-methyl-4-oxobutyric acid (4). The latter, on treatment with fuming nitric acid, yielded 4-(4-chloro-3-nitrophenyl)-3-methyl-4-oxobutyric acid (5), which on treatment with hydrazine hydrate gave 6-(4-chloro-3-nitrophenyl)-5-methyl-4,5-dihydro-2H-pyridazine-3-one (6). Azidation and reduction of 6 with sodium azide gave the amino derivative 7 which on reductive alkylation gave 10(a-i) followed by reduction with commercially available sodium hydrogen sulphide solution gave the substituted diamine derivative 11(a-i). The compound 7 directly undergoes reduction with sodium hydrogen sulphide yielding (8). Finally, 8 and 11(a-i) was converted into the target compounds by diazotized-cyclization with sodium nitrite giving pyridazinonylbenzotriazoles 9 and 12(a-i).

Full text of DOI:10.14233/ajchem.2015.18894

Asian Journal of Chemistry; Vol. 27, No. 10 (2015), 3633-3638
A
SIAN
J
OURNAL OF HEMISTRY
C
http://dx.doi.org/10.14233/ajchem.2015.18894
Synthesis of Novel Pyridazinonylbenzotriazoles
1,*
1
1
2
2
S. SHASHIDHAR REDDY , B. GEORGE VINEEL , S. VENKATAIAH , A. NAIDU and P.K. DUBEY
1CiVenti Chem (India) Private Limited, Plot No-72/A, Part-2, Phase-1, IDA Jeedimetla, Hyderabad-500 055, India
2Department of Chemistry, Jawaharlal Nehru Technological University, Kukatpally, Hyderabad-500 085, India
*Corresponding author: E-mail: shagum09@gmail.com
Received: 2 December 2014;
Accepted: 6 January 2015;
Published online: 22 June 2015;
AJC-17316
4-Chlorobenzaldehyde (1) was reacted with crotononitrile (2) in the presence of sodium cyanide yielding 4-(4-chlorophenyl)-3-methyl-
4-oxobutyronitrile (3) which on refluxing with concentrated HCl gave 4-(4-chlorophenyl)-3-methyl-4-oxobutyric acid (4). The latter, on
treatment with fuming nitric acid, yielded 4-(4-chloro-3-nitrophenyl)-3-methyl-4-oxobutyric acid (5), which on treatment with hydrazine
hydrate gave 6-(4-chloro-3-nitrophenyl)-5-methyl-4,5-dihydro-2H-pyridazine-3-one (6). Azidation and reduction of 6 with sodium azide
gave the amino derivative 7 which on reductive alkylation gave 10(a-i) followed by reduction with commercially available sodium
hydrogen sulphide solution gave the substituted diamine derivative 11(a-i). The compound 7 directly undergoes reduction with sodium
hydrogen sulphide yielding (8). Finally, 8 and 11(a-i) was converted into the target compounds by diazotized-cyclization with sodium
nitrite giving pyridazinonylbenzotriazoles 9 and 12( a-i).
Keywords: Pyridazinone, Benzotriazole, Michael addition, Hydrazinolysis, Diazotized-cyclization, Pyridazinonyl derivatives.
has been shown that the optimum was reached with a methyl
group29.
INTRODUCTION
The syntheses of novel pyridazinonyl derivatives have
gained much importance in recent years. Pyridazinonyl deriva-
tives have been shown to exhibit a variety of pharmacological
activities mostly related to cardiovascular effects1-5. Literature
survey revealed that substituted pyridazinones have been reported
to possess antidepressant6,7, antihypertensive8-10, antithro-
mbotic11, antifungal12,13, antibacterial14,15, antimicrobial16, anti-
inflammatory17-19, anticancer20 activity.
A large number of compounds containing benzotriazole
system have been investigated because of their broad spectrum
of biological activities which include analgesic, antibacterial,
antifungal, antiparasitic, antiviral, anti-inflammatory, anti-
convulsant, DNA cleavage, herbicidal, antitubercular21, anti-
emetic, respiratory syndrome protease inactivation activities
and also as an active ester in the peptide synthesis22 and as
agonists of peroxisome proliferator activated receptors23. In
addition to these considerable biological applications, benzo-
triazoles are important intermediates, protecting groups and
final products in organic chemistry24.
This paper relates to the synthesis of novel 5-methyl-6-
(1-substituted 1H-benzotriazol-5-yl)-4,5-dihydropyridazin-
3(2H)-one derivaties (10a-j). Different strategies for the prepa-
ration of 5-alkylpyridazinones have been reported in the
literature30,31.A modified version of Stetter and Schreckenberg’s
procedure32, in its considerably simplified form, has been
adopted for the current preparation.
EXPERIMENTAL
Unless stated otherwise, all reactions were performed
under nitrogen atmosphere. Reactions were monitored by thin
layer chromatography (TLC) on silica gel plates (60 F254),
visualizing with ultraviolet light or iodine spray. Flash chroma-
tography was performed on silica gel 100-200 and 230-400
mesh using hexane, ethyl acetate, dichloro methane. 1H NMR
and 13C NMR spectra were determined in CDCl3, DMSO-d6
and CD3OD solution by using Bruker AC-300 and 400 MHz
spectrometers. Proton chemical shifts (δ) are relative to tetra
methyl silane (TMS, δ = 0.00) as internal standard and expre-
ssed in ppm. Infrared spectra were recorded on a Perkin-
Elmer1720 FT-IR spectrometer (KBr Pellets). Melting points
were determined in a Polmon melting point apparatus and are
uncorrected. Mass spectra were recorded onAgilent 6120 LCMS
instrument giving M+ values either on M+ + 1 or M+ – 1 modes.
In the past, quite a few new drugs belonging to 5-methyl-
6-substituted phenyl pyridazinones were designed25-28. One
prominent fact is the increase in potency exerted by the intro-
duction of a substituent into the pyridazinonyl ring in the 5th
position and thus introducing chirality into the molecule. It

3634 Reddy et al.
Asian J. Chem.
Preparation of 4-(4-chlorophenyl)-3-methyl-4-oxo-
mmol) and cupric sulphate pentahydrate (3.45 g, 18.7 mmol).
The reaction temperature was slowly raised to 70 °Cand main-
tained at this temperature for 24 h. At the end of this period,
the mixture was cooled to room temperature and poured into
water (1 L). The precipitated yellow solid was filtered, washed
with water (300 mL) and dried. The solid was recrystallized
from tetrahydrofuran to get a yellow coloured solidYield: 22 g,
(95 %), m.p.: 244-246 °C, IR (KBr, νmax, cm–1): 3445-3297
(-NH2, str), 3164 (N-H, str), 1632 (NH-C=O, str), 1343 (C-N,
butyronitrile (3): Sodium cyanide (3.5 g, 71.42 mmol) was
added to DMF (350 mL) at 35 °C and stirred for 25 min to get
clear solution. A solution of 4-chlorobenzaldehyde (1) (100 g,
714.2 mmol) in DMF (200 mL) was added to the cyanide
solution over a period of 1.5 h. The mixture was stirred for
0.5 h at 35-38 °C and then crotononitrile (2) (47.8 g, 714.2
mmol) in DMF (200 mL) was added in a drop-wise fashion to
the above reaction mixture in about 45 min. The stirring was
continued for 2-3 h, with the temperature below 40 °C. The
reaction was continuously monitored by TLC. After the comp-
letion of the reaction, the mixture was poured into crushed-
ice (4 L) with stirring. The separated solid was filtered, washed
with water (2 × 1 L) and dried.Yield = 121.3 g, (88 %), m.p.:
49-51 °C. (lit33 m.p.: 52-53 °C).
Preparation of 4-(4-chlorophenyl)-3-methyl-4-oxo-
butyric acid (4):A mixture of 3 (100 g, 518.1 mmol) in conc.
HCl (550 mL) and water (550 mL) was stirred at refluxing
temperature for 5 h, while the reaction was monitored by TLC.
After the completion of reaction, the mixture was cooled to
room temperature and extracted with dichloromethane (300
mL × 3). The total organic layer was washed with water (500
mL) and concentrated under reduced pressure. The resulting
crude residue was dissolved in methyl t-butylether (500 mL)
and then extracted into saturated NaHCO3 solution (200 mL
× 3). The combined aq. layer was cooled to 10 °C, the pH
adjusted to 2-2.5 using conc. HCl and the mixture extracted
with dichloromethane (200 mL × 3). The dichloromethane
layer was dried over anhydrous Na2SO4 and concentrated under
reduced pressure to obtain a residue that was crystallized from
hexane to get an off-white solid. Yield = 79 g, (72 %), m.p.:
78-80 °C. (lit33 m.p. = 80-82 °C).
Preparation of 4-(4-chloro-3-nitrophenyl)-3-methyl-4-
oxobutyric acid (5): Compound 4 (75 g, 353.7 mmol) was
added portion-wise to fuming nitric acid (356.6 g, 5660.9
mmol) at (-) 15 °C, while maintaining the temperature at (-)
10 to (-) 15 °C. Afterwards the mixture was stirred for an
additional 30 min at same temperature, while monitoring the
reaction by TLC. The whole mixture was then poured into
crushed ice (2.5 L) with stirring. The insoluble solid was
filtered off, washed with water (200 mL × 3) and dried.Yield:
82 g, (90 %), m.p.: 110-114 °C. (lit33 m.p.= 114-116 °C).
Preparation of 6-(4-chloro-3-nitrophenyl)-5-methyl-
4,5-dihydro-2H-pyridazin-3-one (6): To a solution of 5 (80 g,
311.2 mmol) in acetic acid (500 mL), hydrazine hydrate
(16.3 g, 326.7 mmol) was added in a drop-wise manner at
30 °C. Then, the temperature of mixture was slowly raised to
100 °C. The mixture was stirred for 4.5 h at this temperature,
while the reaction was monitored by TLC. At the end of the
reaction, the mixture was cooled to room temperature and
poured into ice-water (3 L) with stirring. The insoluble product
was filtered, washed with water (200 mL × 4) and dried.Yield:
79 g, (95 %), m.p.: 192-195 °C. (lit33 m.p.= 188-190 °C).
Preparation of 6-(4-amino-3-nitrophenyl)-5-methyl-
4,5-dihydro-2H-pyridazin-3-one (7): To a solution of 6 (25 g,
93.6 mmol) in DMSO:H2O (80 mL: 10 mL) were added
L-proline (2.15 g, 18.7 mmol), Na2CO3 (1.98 g, 18.7 mmol),
NaN3 (7.3 g, 112.2 mmol), sodium ascorbate (2.77 g, 14.0
1
str) 2060; H NMR (400 MHz, DMSO-d6) δ: 10.85 (1H, s,
NH), 8.25 (1H, d), 7.85 (1H, dd), 7.75 (2H, bs), 7.1(1H, dd),
3.3 (1H, m), 2.4-2.65 (1H, m) 2.2 (1H, dd), 1.05 (3H, d);
LC-MS: m/z = 249 [M++1].
Preparation of 6-(3,4-diaminophenyl)-5-methyl-4,5-
dihydro-2H-pyridazin-3-one (8): A suspension of 7 (10 g,
40.3 mmol) in methanol (100 mL) was slowly raised to 65 °C,
then the commercially available sodium hydrogen sulphide
(30 % in H2O, w/w) (4.9 g, 40.38.17 mmol) was added drop-
wise to the above reaction mixture at the same temperature.
At this stage, the mixture was stirred for 6 h, while the reaction
was monitored by TLC. At the end of the reaction, methanol
was distilled out under reduced pressure and the residue cooled
to 15 °C. To the latter was added 3N HCl (150 mL) and the
mixture stirred at room temperature for 30 min. The separated
solid was filtered, washed with water (100 mL × 2) and dried
to get brown solid. Yield: 6.3 g, (75 %), m.p.: 178-181 °C.
(lit33 m.p.: 183-185 °C). IR (KBr, νmax, cm–1): 3397-3263 cm–1
(-NH2 broad peak), 1625 cm–1 (amide, C=O); 1H NMR (400
MHz, DMSO-d6) δ: 10.7 (1H, bs), 7.1 (1H, s), 6.9 (1H, d), 6.5
(1H, d), 4.6-4.8 ( 4H, bs, 2NH2) 3.2 (1H, m), 2.6 (1H, dd), 2.1
(1H,d), 1.05 (3H, d). LC-MS: m/z = 218 [M++1].
Preparation of 5-methyl-6-(1H-benzotriazol-5-yl)-4,5-
dihydropyridazin-3(2H)-one (9). To a suspension of 8 (19.23
mmol, 1eq) in acetic acid (50 mL) was added a solution of
NaNO2 (23.07 mmol, 1.2 eq) in 7 mL of water in a drop-wise
fashion at 20-25 °C for 20 min. The mixture was stirred for
4-5 h at 25 °C, while monitoring it by TLC. At the end of this
period, the mixture was poured into ice-water (400 mL) and
stirred for 2 h at room temperature. The separated product
was filtered, washed with water (100 mL × 2) and dried to get
an off-white solid. Pale brown solidYield: 3.2 g, (75 %), m.p.:
1
246-250 °C (dec), H NMR (400 MHz, DMSO-d6) δ: 11.2
(1H, s, NH), 8.3 (1H, s), 7.9 (2H, dd), 3.5 (2H, m), 2.6-2.8
(1H, m) 2.3 (1H, dd), 1.2 (3H, d); LC-MS: m/z = 230 [M++1].
Anal. (%) for C11H11N5O, calc. C, 57.63; H, 4.84; N, 30.55;
Founds: C, 67.51; H, 4.85; N, 30.53.
General preparation method of 6-(4-substituted amino-
3-nitrophenyl)-5-methyl-4,5-dihydro-2H-pyridazin-3-one
(10a-i): To a solution of 7 (40.3 mmol) in acetic acid (150 mL),
was added the corresponding aldehydes or the ketones (formal-
dehyde, acetaldehyde, acetone, isobutyraldehyde, furfural-
dehyde, benzaldehyde, p-chloro benzaldehyde, p-bromo
benzaldehyde, p-flouro benzaldehyde) (44.33 mmol) and the
mixture stirred for 15 min, then cooled to 10 °C and sodium
triacetoxyborohydride (88.66 mmol) was added portion-wise
in about 0.5 h. After the addition, mixture was stirred for 15 h
at room temperature and also monitored the reaction by TLC.
At the end of this period, the mixture was poured into saturated

Vol. 27, No. 10 (2015)
Synthesis of Novel Pyridazinonylbenzotriazoles 3635
NaHCO3 solution (1 L) and then extracted with ethyl acetate
(200 mL × 2). The combined organic layer was washed with
water (200 mL × 2), dried over anh. Na2SO4 and concentrated
under reduced pressure. The crude residue was stirred with
methyl tert-butylether (30 mL) and filtered. The insoluble
product was dried to obtain 10(a-i).
Compound 10a: Orange solid; 6.33 g, (60 %), m.p.: 192-
194 °C, IR (KBr, νmax, cm–1): 3224 (N-H, str), 1627 (NH-C=O,
str), 1346 (C-N, str); 1H NMR (400 MHz, DMSO-d6) δ: 10.95
(1H, S, NH), 8.4 (1H, d), 8.1 (1H, dd), 8 (1H, dd), 7.2(1H,
dd), 4.0 (1H, s), 3.4 (1H, m), 2.6-2.7 (1H, m) 2.25 (1H, dd),
1.1 (3H, d); LC-MS: m/z = 263 [M++1].
Compound 10b: Orange solid; 6.89 g (62 %), m.p.: 185-
188 °C, 1H NMR (400 MHz, DMSO-d6) δ: 10.95 (1H, S, NH),
8.4 (1H, d), 8.1 (1H, dd), 8 (1H, dd), 7.2(1H, dd), 4.0 (1H,
quartet), 3.4 (1H, m), 2.6-2.7 (1H, m) 2.25 (1H, dd), 1.4 (3H,
t), 1.1 (3H, d); LC-MS: m/z = 276 [M++1].
Compound 10c: Orange solid; 8.18 g, (70 %), m.p.: 171-
173 °C, IR (KBr, νmax, cm–1): 3224 (N-H, str), 1627 (NH-C=O,
str), 1346 (C-N, str); 1H NMR (400 MHz, DMSO-d6) δ: 10.95
(1H, S, NH), 8.4 (1H, d), 8.1 (1H, dd), 8 (1H, dd), 7.2(1H,
dd), 4.0 (1H, m), 3.4 (1H, m), 2.6-2.7 (1H, m) 2.25 (1H, dd),
1.3 (6H, d), 1.1 (3H, d); LC-MS: m/z = 291 [M++1].
rature of 65 °C and sodium hydrogen sulphide (commercially
available) (30 % in H2O, w/w) (32.54 mmol, 2.2 eq) was added
drop-wise to the above reaction mixture at the same tempe-
rature. The reaction mixture was then stirred for 6 h at the same
temperature. At the end of this period, methanol was distilled
out under reduced pressure and the residue cooled to 15 °C.
To the mixture, was added 3N HCl (35 mL) and the resulting
mixture was stirred for 30 min. The separated product was
filtered and washed with water (10 mL × 2) and dried.
Compound 11a: Off white solid; 2.87 g, (65 %), m.p.:
171-172 °C, IR (KBr, νmax, cm–1): 3357 (-NH2, str), 3224 (N-
H, str), 1627 (NH-C=O, str), 1346 (C-N, str); 1H NMR (400
MHz, DMSO-d6) δ: 10.75 (1H, S, NH), 8.7 (2H, bs), 7.4 (1H,
d), 7.2 (2H, dd), 6.5 (1H, dd), 3.7 (1H, s), 3.3 (1H, m), 2.6-2.7
(1H, m) 2.25 (1H, dd), 0.9 (3H, d); LC-MS: m/z = 233 [M++1].
Compound 11b: Off white solid; 3.11 g, (70 %), m.p.:
161-163 °C, IR (KBr, νmax, cm–1): 3357 (-NH2, str), 3224 (N-
H, str), 1627 (NH-C=O, str), 1346 (C-N, str); 1H NMR (400
MHz, DMSO-d6) δ: 10.7 (1H, S, NH), 8.8 (2H, bs), 7.5 (1H,
dd), 7.2 (2H, m), 6.6(1H, dd), 3.8 (1H, quartet), 3.2 (1H, m),
2.6-2.7 (1H, m) 2.25 (1H, dd), 1.2 (3H, t), 0.9 (3H, d); LC-MS:
m/z = 247 [M++1].
Compound 11c: Off white solid; 2.6 g, (60 %), m.p.:
153-156 °C, IR (KBr, νmax, cm–1): 3357 (-NH2, str), 3224 (N-
H, str), 1627 (NH-C=O, str), 1346 (C-N, str); 1H NMR (400
MHz, DMSO-d6) δ: 10.7 (1H, S, NH), 8.8 (2H, bs), 7.6 (1H,
dd), 7.3 (2H, m), 6.7 (1H, dd), 3.8 (1H, m), 3.25 (1H, m), 2.6-
2.7 (1H, m) 2.25 (1H, dd), 1.3 (6H, d), 0.9 (3H, d); LC-MS:
m/z = 261 [M++1].
Compound 10d: Orange solid; 9.1 g, (71 %), m.p.: 158-
162 °C, 1H NMR (400 MHz, DMSO-d6) δ: 10.95 (1H, S, NH),
8.4 (1H, d), 8.1 (1H, dd), 8 (1H, dd), 7.2(1H, dd), 3.5 (2H, t),
3.4 (1H, m), 2.6-2.7 (1H, m) 2.25 (1H, dd), 2 ( 1H, m), 0.9
(6H, d), 1.1 (3H, d); LC-MS: m/z = 305 [M++1].
Compound 10e: Orange solid; 7.93 g, (60 %), m.p.:195-
196 °C, 1H NMR (400 MHz, DMSO-d6) δ: 10.95 (1H, S, NH),
9 (1H, t), 8.6 (1H, s), 8 (1H, dd), 7.3 (1H,dd), 7.0, (1H, dd),
6.3 (1H, m), 6.0 (1H, dd), 4.25 (2H, d), 3.4 (1H, m), 2.6-2.7
(1H, m) 2.25 (1H, dd), 1.2 (3H, d); LC-MS: m/z = 329 [M++1].
Compound 10f: Orange solid; 10.22 g, (75 %), m.p.: 202-
204 °C, IR (KBr, νmax, cm–1): 3217 (N-H, str), 1629 (NH-C=O,
str), 1343 (C-N, str); 1H NMR (400 MHz, DMSO-d6) δ: 10.95
(1H, S, NH), 8.9 (1H, t), 8.4 (1H, s), 7.9 (1H, dd), 7.4-7.5(4H,
m), 7.3 (1H, m), 7.0 (1H, dd), 4.7 (2H, d), 3.3 (1H,m), 2.4-2.6
(1H, m) 2.2 (1H, dd), 1.01(3H, d); LC-MS: m/z = 339 [M++1].
Compound 10g: Orange solid; 10.5 g, (70 %), m.p.; 211-
212 °C, 1H NMR (400 MHz, DMSO-d6) δ: 10.95 (1H, S, NH),
8.9 (1H, t), 8.4 (1H, s), 7.9 (1H, dd), 7.5(2H, dd), 7.4 (2H,
dd), 7.2 (1H, dd), 4.85 (2H, d), 3.3 (1H,m), 2.4-2.6 (1H, m)
2.2 (1H, dd), 1.01(3H, d); LC-MS: m/z = 373 [M++1].
Compound 10h: Orange solid; 12.58 g, (75 %), m.p.:
222-224 °C, 1H NMR (400 MHz, DMSO-d6) δ: 10.95 (1H, S,
NH), 8.9 (1H, t), 8.4 (1H, s), 7.9 (1H, dd), 7.65(2H, dd), 7.25
(2H, dd), 7.0 (1H, dd), 4.8 (2H, d), 3.3 (1H,m), 2.4-2.6 (1H,
m) 2.2 (1H, dd), 1.01(3H, d); LC-MS: m/z = 417 [M++1].
Compound 10i: Orange solid; 10.33 g, (72 %), m.p.: 206-
208 °C, 1H NMR (400 MHz, DMSO-d6) δ: 10.95 (1H, S, NH),
8.9 (1H, t), 8.4 (1H, s), 7.9 (1H, dd), 7.2 (2H, dd), 7.0 (1H,
dd), 6.9 (2H, dd), 4.7 (2H, d), 3.3 (1H,m), 2.4-2.6 (1H, m) 2.2
(1H, dd), 1.01(3H, d); LC-MS: m/z = 357 [M++1].
Compound 11d: Pale brown solid; 2.75 g, (62 %), m.p.:
135-137 °C, 1H NMR (400 MHz, DMSO-d6) δ: 10.75 (1H, S,
NH), 8.9 (2H, bs), 7.7 (1H, dd), 7.4 (2H, m), 6.6 (1H, dd), 3.4
(2H, t), 3.2 (1H, m), 2.6-2.7 (1H, m), 2.25 (1H, dd), 1.8 ( 1H,
m), 0.9 (3H, d), 0.75 (6H, d); LC-MS: m/z = 275 [M++1].
Compound 11e: Pale brown solid; 3.2 g, (72 %), m.p.:
1
161-162 °C (dec), H NMR (400 MHz, DMSO-d6) δ: 10.8
(1H, S, NH), 9 (2H, bs), 7.9 (1H, s), 7.7 (2H, m), 7.0 (1H,dd),
6.5, (1H, dd), 6.0 (2H, m), 4.0 (2H, d), 3.3 (1H, m), 2.6-2.7
(1H, m) 2.25 (1H, dd), 1.0 (3H, d); LC-MS: m/z = 299 [M++1].
Compound 11f: Off white solid; 3.46 g, (78 %), m.p.:
170-174 °C (dec), IR (KBr, νmax, cm–1): 3344 (-NH2, str), 3027
(N-H, str), 1630 (NH-C=O, str), 1341 (C-N, str), 1292, 1025;
1H NMR (400 MHz, DMSO-d6) δ: 10.8 (1H, s), 8.5-9 (2H, bs,
NH2), 7.6 (1H, S), 7.2-7.5 (7H, m), 6.6 (1H, d), 4.4 (2H, d),
3.2 (1H, m), 2.6 (1H, m) 2.2 (1H, dd), 1.0 (3H, d); LC-MS:
m/z = 309 [M++1].
Compound 11g: Off white solid; 3.2 g, (70 %), m.p.;
1
180-182 °C (dec), H NMR (400 MHz, DMSO-d6) δ: 10.85
(1H, S, NH), 8 - 8.5 (2H, bs), 7.4 (1H, s), 7.2 (2H, m), 7.0
(2H, dd), 6.5 (3H, m), 4.3 (2H, d), 3.2 (1H,m), 2.6 (1H, m) 2.2
(1H, dd), 1.0 (3H, d); LC-MS: m/z = 343 [M++1].
Compound 11h: Off white solid; 2.98 g, (65 %), m.p.:
1
193-195 °C (dec), H NMR (400 MHz, DMSO-d6) δ: 10.7
(1H, S, NH), 8 - 8.5 (2H, bs), 7.2 (1H, s), 7.0 (2H, m), 6.7
(2H, dd), 6.3 (3H, m), 4.2 (2H, d), 3.2 (1H,m), 2.5 (1H, m) 2.2
(1H, dd), 1.0 (3H, d); LC-MS: m/z = 387 [M++1].
General procedure for preparation of 6-(3-amino-4-
substituted aminophenyl)-5-methyl-4,5-dihydro-2H-
pyridazin-3-one (11a-i): A suspension of 10 (a-i) (5 g, 14.79
mmol, 1eq) in methanol (75 mL) was slowly raised to a tempe-
Compound 11i: Off white solid; 2.89 g, (63 %), m.p.:
175-177 °C (dec), IR (KBr, νmax, cm–1): 3335 (-NH2, str), 3020

3636 Reddy et al.
Asian J. Chem.
(N-H, str), 1629 (NH-C=O, str), 1335 (C-N, str), 1285, 1025;
1H NMR (400 MHz, DMSO-d6) δ: 10.5 (1H, s, NH), 8.5 (2H,
bs), 7.0 (1H, s), 6.5 (3H, m), 7.0 (1H, dd), 6.1 (3H, m), 4.0
(2H, d), 3.15 (1H,m), 2.4 (1H, m), 2.2 (1H, dd), 1.0 (3H, d);
LC-MS: m/z = 327 [M++1].
General procedure for preparation of 5-methyl-6-(1-
substituted 1H-benzotriazol-5-yl)-4,5-dihydropyridazin-
3(2H)-one derivatives (12a-i): To a suspension of 11a-i (3.88
mmol, 1eq) in acetic acid (100 mL) was added a solution of
NaNO2 (4.66 mmol, 1.2 eq) in 15 mL of water in a drop-wise
fashion at 20-25 °C for 20 min. The mixture was stirred for
4-5 h at 25 °C, while monitoring it by TLC. At the end of this
period, the mixture was poured into ice-water (400 mL) and
stirred for 2 h at room temperature. The separated product
was filtered, washed with water (100 mL × 2) and dried to get
an off-white solid.
Compound 12g: Off-white solid; 1.16 g, (85 %), m.p.;
197-200 °C, 1H NMR (400 MHz, DMSO-d6) δ: 10.95 (1H, S,
NH), 8.9 (1H, t), 8.4 (1H, s), 7.9 (1H, dd), 7.5(2H, dd), 7.4
(2H, dd), 7.2 (1H, dd), 4.85 (2H, d), 3.3 (1H,m), 2.4-2.6 (1H,
m) 2.2 (1H, dd), 1.01(3H, d); LC-MS: m/z = 354 [M++1].Anal.
(%) for C18H16N5OCl calc. C, 61.10; H, 4.56; N, 19.79. Found.
C, 61.07; H, 4.54; N, 19.76.
Compound 12h: Off-white solid; 1.35 g, (88 %), m.p.:
218-220 °C, 1H NMR (400 MHz, DMSO-d6) δ: 10.95 (1H, S,
NH), 8.9 (1H, t), 8.4 (1H, s), 7.9 (1H, dd), 7.65(2H, dd), 7.25
(2H, dd), 7.0 (1H, dd), 4.8 (2H, d), 3.3 (1H,m), 2.4-2.6 (1H,
m) 2.2 (1H, dd), 1.01(3H, d); LC-MS: m/z =398 [M++1].Anal.
(%) for C18H16N5OBr calc. C, 54.28; H, 4.05; N, 17.59; Found.
C, 54.30; H, 4.00; N, 17.57.
Compound 12i: Off-white solid; 1.07 g, (82 %), m.p.:
201-204 °C, 1H NMR (400 MHz, DMSO-d6) δ: 10.95 (1H, S,
NH), 8.9 (1H, t), 8.4 (1H, s), 7.9 (1H, dd), 7.2 (2H, dd), 7.0
(1H, dd), 6.9 (2H, dd), 4.7 (2H, d), 3.3 (1H,m), 2.4-2.6 (1H,
m) 2.2 (1H, dd), 1.01(3H, d); LC-MS: m/z = 338 [M++1].Anal.
(%) for C18H16N5OF calc. C, 64.09; H, 4.78; N, 20.76; Found.
C, 64.12; H, 4.76; N, 20.79.
Compound 12a: Off-white solid; 0.75 g, (80 %), m.p.:
1
212-214 °C, H NMR (400 MHz, DMSO-d6) δ: 11.1(1H, s,
NH), 8.4 (1H, s), 8.1 (1H, dd), 7.9 (1H, dd), 5.1 (3H, s), 3.6
(1H, m), 2.8 (1H, m) 2.3 (1H, dd), 1.2 (3H, d); LC-MS: m/z =
244 [M++1]. Anal. (%) for C12H13N5O, calc. C, 59.25; H, 5.39;
N, 28.79; Founds: C, 59.24; H, 5.41; N, 28.77.
RESULTS AND DISCUSSION
Compound 12b: Off-white solid; 0.84 g, (85 %), m.p.: 197-
199 °C, 1H NMR (400 MHz, DMSO-d6) δ: 11.1 (1H, s, NH), 8.5
(1H, s), 8.2 (1H, dd), 7.8 (1H, dd), 5.15 (2H, quartet), 3.5 (1H,
m), 2.6-2.7 (1H, m), 2.25 (1H, dd), 1.7 (3H, t), 1.2 (3H, d); LC-
MS: m/z = 258 [M++1].Anal. (%) for C13H15N5O, calc. C, 60.69;
H, 5.88; N, 27.22; Founds: C, 60.68; H, 5.85; N, 27.24.
Compound 12c: Off-white solid; 0.95 g, (90 %), m.p.:
185-188 °C, IR (KBr, νmax, cm–1) : 3227 (N-H, str), 1676 (NH-
C=O, str), 1342 (C-N, str), 1H NMR (400 MHz, DMSO-d6) δ:
11.1 (1H, s, NH), 8.4 (1H, s), 8.1 (1H, dd), 7.9 (1H, dd), 5.3
(1H, septet), 3.6 (1H, m), 2.8 (1H, m), 2.3 (1H, dd), 1.6 (6H,
d), 1.1 (3H, d); LC-MS: m/z = 272 [M++1]. Anal. (%) for
C14H17N5O calc. C, 61.98; H, 6.32; N, 25.81 Founds: C, 61.95;
H, 6.33; N, 25.78.
Compound 12d: Off-white solid; 0.9 g, (82 %) m.p.: 166-
168 °C, IR (KBr, νmax, cm–1) 1H NMR (400 MHz, DMSO-d6)
δ: 10.95 (1H, S, NH), 8.4 (1H, d), 8.1 (1H, dd), 8 (1H, dd),
7.2(1H, dd), 5.2 (2H, d), 3.5 (1H, m), 2.7 (1H, m), 2.3 (1H,
dd), 2.1 ( 1H, m), 1.3 (6H, d), 1.1 (3H, d); LC-MS: m/z = 286
[M++1]. Anal. (%) for C16H21N5O. calc. C, 64.19; H, 7.07; N,
23.39; Founds: C, 64.21; H, 7.02; N, 23.41.
The reaction sequence leading to the formation of title
compounds is outlined in Scheme-I.
4-Chlorobenzaldehyde underwent Michael addition
with the commercially available crotononirile in the presence
of sodium cyanide in DMF at room temperature giving the
previously reported33 4-(4-chlorophenyl)-3-methyl-4-
oxobutryronitrile (3). The hydrolysis of the Michael adduct 3
with hydrochloric acid at refluxing temperature led to the
formation of β-benzoylpropionic acid derivative i.e. 4-(4-
chlorophenyl)-3-methyl-4-oxobutryric acid (4). The latter, on
nitration, with fuming nitric acid at low temperature, gave
4-chloro-3-nitro acid derivative (5), which on hydrazinolysis
with hydrazine hydrate gave the known33 6-(4-chloro-3-nitro-
phenyl)-5-methyl-2,3,4,5-tetrahydropyridazin-3-one (6).
Compound 6 was converted to 6-(4-amino-3-nitrophenyl)-
5-methyl-2,3,4,5-tetrahydro-pyridazin-3-one (7) by a one pot
azidation-reduction reaction, adopting the reportedprocedure34
using sodium azide, sodium carbonate, sodium ascorbate,
catalytic amount of L-proline and cupper sulphate penthydrate
in acq. DMSO at 70 °C. Compound 7 has been characterized
on the basis of its spectral data. Thus, its IR spectrum (KBr)
showed a characteristic –NH2 group at νmax of 3445-3184 cm-1
(broad peak) and a sharp, strong peak at 1632 cm–1 due to amide
carbonyl group. 1H NMR (DMSO-d6 /TMS) spectrum showed
signals at δ: 10.9 (dihydropyridazinone NH-C=O), 8.35 (d, 1H),
7.85 (dd, 1H), 7.7 (bs, 2H, NH2), 7.1(d, 1H), 3.4 (m, 1H), 2.6
(m, 1H), 2.2 (d, 1H), 1.05 (d, 3H, -CH3). Its LC-MS showed the
molecular ion peak (M++1) at m/z: 249 corres-ponding to a
molecular mass of 248, when recorded in the Q+1 mode.
The amino nitro compound 7 on condensation with
various aldehydes and ketones gave the corresponding Schiff’s
bases which on reduction with sodium triacetoxyborohydride
(STAB) in acetic acid at room temperature afforded reductively
alkylated derivatives 10(a-i), which have been characterized
on the basis of their spectral and analytical data.
Compound 12e: Off-white solid; 0.95 g, (80 %), m.p.:
1
193-195 °C, H NMR (400 MHz, DMSO-d6) δ: 11 (1H, s,
NH), 8.45 (1H, s), 81 (1H, dd), 7.9 (1H,dd), 7.2 (1H, dd), 6.7
(1H, m), 6.4 (1H, dd), 6.2 (2H, s), 3.65 (1H, m), 2.6-2.8 (1H,
m) 2.3 (1H, dd), 1.2 (3H, d); LC-MS: m/z = 310 [M++1].Anal.
(%) for C16H15N5O2. calc. C, 62.13; H, 4.89; N, 22.64; Found.
C, 62.11; H, 4.86; N, 22.67;
Compound 12f: Off-white solid; 1.07 g, (87 %), m.p.:
186-189 °C, IR (KBr, νmax, cm–1): 3215 (N-H, str), 1675 (NH-
C=O, str), 1347 (C-N, str); 1H NMR (400 MHz, DMSO-d6) δ:
11 (1H, s, NH), 8.35 (1H, s), 8.15 (1H, dd), 7.8 (1H, dd), 7.3-
7.45 (5H, m), 7.3 (1H, m), 6.0 (2H, s), 3.6 (1H,m), 2.7-2.8
(1H, m) 2.3 (1H, dd), 1.1 (3H, d); LC-MS: m/z = 320 [M++1].
Anal. (%) for C18H17N5O calc. C, 67.72; H, 5.35; N, 21.92;
Found. C, 67.70; H, 5.37; N, 21.93;

Vol. 27, No. 10 (2015)
Synthesis of Novel Pyridazinonylbenzotriazoles 3637
COOH
COOH
CN
CHO
O
O
O
HCl
NaCN
AcOH/N2H4
HNO3
CN
- 15 °C
DMF/ RT
1 0 °C
NO2
100°C
Cl
Cl
Cl
Cl
(1)
O
(2)
(3)
(5)
(4)
O
O
O
NH
N
O
NH
N
NH
N
NH
N
NH
N
NaN3/DMSO/70°C
STAB
AcOH/NaNO2
NaSH/MeOH
then sodium
ascorbate
NO2
AcOH/10°C
NO2
25°C
NH2
N
70°C
NO2
N
N
R
NH
NH
Cl
R
NH2
(7)
R
(12a-i)
(6)
(11a-i)
(10a-i)
NaSH MeOH
70 °C
O
O
NH
N
NH
N
AcOH/ NaNO2
25 °C
N
NH2
HN
NH2
(8)
N
(9)
R
= a) Methyl, b) Ethyl, c) Isopropyl, d) Isobutyl, e) f urf uryl, f) Ph-CH2-, g) p-Cl-Ph-CH2-
h) p-Br-Ph-CH2-, i) p-F-Ph-CH2- .
Scheme-I
Compound 10(a-i) on reduction with 30 % aq. sodium
hydrogen sulphide (NaSH) in methanol at refluxing tempe-
rature for 6 h gave the corresponding diamine derivatives i.e.,
6-(3-amino-4-(substituted amino)phenyl)-5-methyl-2,3,4,5-
tetrahydro-pyridazin-3-one 11(a-i) which have been charac-
terized on the basis of their spectral and analytical data.
Direct reduction of compound 7 with NaSH gave the 6-
(3,4-diaminophenyl)-5-methyl-2,3,4,5-tetrahydropyridazin-3-
one (8), which has been characterized on the basis of its spectral
data. Thus, its IR spectrum (KBr) showed a characteristic peaks
at νmax of 3397-3263 cm–1 (-NH2 broad peak) and a sharp,
strong peak at 1625 cm–1 due to amide carbonyl group1H NMR
(DMSO-d6/TMS) spectrum showed signals at δ: 10.7 (dihydro-
pyridazinone NH-C=O), 7.1 (s, 1H), 6.9 (d, 1H), 6.5 (d, 1H),
4.6-4.8 (bs, 4H, 2NH2) 3.2 (m, 1H,CH), 2.6 (dd,1H), 2.1
(d,1H), 1.05 (d, 3H, CH3).
In another sequence of reaction, 8 and 11(a-i) were treated
with aq. NaNO2 in acetic acid at room temperature giving 5-
methyl-6-(1-substituted 1H-benzotriazol-5-yl)-4,5-dihydro-
pyridazin-3(2H)-one derivatives 9 and 12(a-i) respectively. The

3638 Reddy et al.
Asian J. Chem.
latter have been characterized on the basis of their IR, 1H NMR
spectra and LC-MS data.
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ACKNOWLEDGEMENTS
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The authors are thankful to the authorities of Civenti Chem
(India) Pvt. Ltd., IDA, Jeedimetla, Hyderabad, India, for
providing laboratory facilities. The authors are also grateful
to the authorities of J.N.T. University, Hyderabad, India for
encouragement.
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