Synthesis, reactions and spectroscopy of 3-benzoyl-6-phenylpyridazines of expected biological activity

Article abstract of DOI:10.1515/znb-1999-0813

Oxidative decyanation of phenyl(6-phenylpyridazin-3-yl)acetonitrile (1) in methanol yielded 3-benzoyl-6-phenylpyridazine (2). Phenyl(6-phenyl-pyridazin-3-yl)methanol (3) has been obtained via NaBH₄ reduction of ketone 2. Reaction of 2 with hydroxylamine or its O-alkyl analogue has been found to yield 3-benzoyloxime-6-phenylpyridazine (4) and alkyloximes (5), respectively. Treatment of 4 with a mixture of acetic acid and sulfuric acid afforded ketone 2 again and not the rearranged products (6 or 7). Beckmann rearrangement has however been achieved for 3-benzoyl(O-ethyloxime)-6-phenylpyyridazine (5a) and oxime 4 giving solely 3-carboxanilide-6-phenylpyridazine (6). 4-Benzoyloxime-3-phenyl-6-chloropyridazine (17) has been synthesized from the corresponding ketone 16.

Full text of DOI:10.1515/znb-1999-0813

Synthesis, Reactions and Spectroscopy of 3-Benzoyl-6-phenylpyridazines
of Expected Biological Activity
Y vette A. Issac
Chemistry Department, Faculty of Science, Benha University, Benha, Egypt
* Reprint requests to Dr. Y. A. Issac. Fax: 00202/4012245
Z. Naturforsch. 54b, 1048-1054 (1999); received December 29, 1998
Pyridazine Derivatives, Biological Activity
Oxidative decyanation of phenyl(6-phenylpyridazin-3-yl)acetonitrile (1) in methanol
yielded 3-benzoyl-6-phenylpyridazine (2). Phenyl(6-phenyl-pyridazin-3-yl)methanol (3) has
been obtained via NaBH4 reduction of ketone 2. Reaction of 2 with hydroxylamine or
its O-alkyl analogue has been found to yield 3-benzoyloxime-6-phenylpyridazine (4) and
alkyloximes (5), respectively. Treatment of 4 with a mixture of acetic acid and sulfuric acid
afforded ketone 2 again and not the rearranged products (6 or 7). Beckmann rearrangement
has however been achieved for 3-benzoyl(0-ethyloxime)-6-phenylpyridazine (5a) and oxime
4 giving solely 3-carboxanilide-6-phenylpyridazine (6), 4-Benzoyloxime-3-phenyl-6-chloro-
pyridazine (17) has been synthesized from the corresponding ketone 16.
Introduction
dazine 2 together with its chem ical reactions o u t-
lined below (Schem e 1) was confirm ed by IR , JH
N M R , m ass spectra and elem ental analysis
(Table I and E xperim ental).
Pyridazine derivatives appear to be of interest
due to their pharm acological activities such as gas-
tric antisecretory, antiulcer [1], hypolipidem ic [2]
and antihistam inic activities [3-5], B ecause of this,
m uch efforts have been devoted to synthesize vari-
ous of pyridazines in order to enhance their p h ar-
m acological activity.
N
NH
C
mi
c
II
c " NH
I
H07H20
I
HO
Ft I Ft
H
I R
H
H ere we wish to report the synthesis of 3-ben-
zoyl-6-phenylpyridazine (2) together with its cor-
responding derivatives. Also, the preparations of
the related chloropyridazinyl derivatives are p re-
sented. Sim ilar pyridazinyl ketones of type 2 have
been reported in a patent [6], and recent literature
reports indicate that they could be obtained via
oxidative decyanation [7-10] of their correspond-
ing acetonitrile derivatives 1 in the presence of tri-
ethylbenzylam m onium chloride (T E B A ) as phase
transfer catalyst. The latter m ethod was adopted in
our study for synthesis of our target com pound 2.
H
<?3
FCT9j VR
-HCHN
Thus, treatm ent of 2 with sodium borohydride in
m ethanol at room tem perature yielded the corre-
sponding alcohol 3 in alm ost quantitative yield. The
’H N M R spectrum of the latter revealed two char-
acteristic doublets with J = 4 Hz at <3 6.05 and 4.96
assignable to the O H and CH protons respectively.
Also, treatm ent of 2 with hydroxylam ine hydro-
chloride in the presence of sodium hydroxide af-
forded the oxim e 4 in an excellent yield (95% ).
The isolated oxim e appears to exist as a m ixture
of two tautom eric forms. This conclusion com es
from tic analysis of this product which revealed
the presence of two spots with close /fy values. The
'H N M R spectrum show ed two signals at d = 12.14
and 11.9. The integration of these two signals cor-
Results and Discussion
The required starting diarylacetonitrile 1 was
p repared from 6-phenyl-3-chloropyridazine and
phenylacetonitrile as previously described [1],
T reatm ent of the latter nitrile with T E B A in m eth -
anol and sodium hydroxide under air oxygen af-
forded the ketone 2 in good yield via the following
m echanism . The structure of benzoyl phenylpyri-
0932-0776/99/0800-1048 $06.00 © 1999 Verlag der Zeitschrift für Naturforschung, Tübingen • www.znaturforsch.com
D
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1049
Y. A. Issac • Synthesis, Reactions and Spectroscopoy of 3-Benzoyl-6-phenylpyridazines
Table I. Analytical and spectral data of compounds 2-12.
No.
(method)
Yield
(%)
M.p. ( °C)
(recrystallization
solvent)
Molecular
formula
(MWt)
Elemental analysis
calcd/found
'H NMR (CDC13) d (ppm)
Other
Pvridazine
H-5
(d. 1H) (d, 1H) (Hz)
C
H
N
H-4
'
J4,5
c
17 H 12 N2o
(260.30)
2
96
78.44
78.50
10.76
10.70
8.32
1 0
8.20-8.31 (m, 2H. Ph-2,6 ),
8.08-8.16 (m, 2H. Ph-3,5),
7.66-7.81 (m, 1H, Ph-4),
125-126
(toluene)
4.65
4.59
8.51
7.61-7.65 (m, 5H, Ph-pyridazi-
ne)a
3
4
94
95
157-159
(ethanol)
77.84
77.50
5.38
5.27
1 0 .6 8
8.06
8.35
7.80
8
7.22-8.04 (m, 10H, Ph),
6.05 ( d ,/ = 4Hz, 1H, OH),
4.96 (d. J = 4Hz, 1H, CHOH)
c
c
17 h 14n 2o
(262.31)
10.47
15.26
15.10
8 .0 0
9
8.22-8.30 (m, 2H, Ph-2,6 ),
7.59-7.68 (m, 3H, Ph-3,4,5),
7.42-7.53 (m, 5H, Ph-pyridaz-
ine),
187-188
(toluene)
17 h 13 n 3o
(275.31)
74.17
74.42
4.76
4.75
11.9 (s, 1H, O H)b, 12.14 (s, 1H,
NH)C
5a
(A)
(B)
8.16-8.28 (m, 2H, Ph-2,6 ),
7.22-7.71 (m, 8 H, Ph), 4.12-
4.28 (m, 2H, OCH2),
79
37
150-152
(ethanol)
5.65
5.69
13.85
13.87
8.16
7.96
7.93
7.80
9
C19 H 1 7 N30
(303.37)
75.23
75.58
[1.36, 1.32 (t,
CH3)]ad
J = 7Hz, 3H,
5b
(A)
(B)
9
9
8.10-8.22 (m, 2H, Ph-2,6 ),
7.38-7.62 (m, 8 H, Ph),
[4.09,4.01 (s, 3H, OCH3)]e
74
83
134-136
(cyclohexane)
74.72
74.93
5.23
5.29
14.52
14.26
8 .2 2
7.91
7.76
c
c
18 h 15 n 3o
(289.34)
7.85
8.46
8.76
8.52
(see Fig. 1)
6
6 8
207-208
(acetonitrile)
17 h 13 n 3o
(275.31)
73.56
73.77
4.81
4.78
15.13
14.95f
5.18
5.03
16.00
15.98
8a
8b
8c
9
62
69
89
82
188-189
(methanol)
c
2 3h 18 n 4
78.83
78.72
(350.42)
227-228
(methanol)
C23 H 17N4 C1
71.78
71.62
4.45
4.41
14.56
14.36
8.18
1 0
7.43-7.97 (m, 14H, Ph),
7.95 (s, 1H, NH )8
(384.86)
132-134
(methanol)
C23 H 17N4 C1
71.78
71.57
4.45
4.21
14.56
14.16
(384.86)
4.67
4.58
9.98
9.97
7.91
8.27
7.78
8.03
9
8.06-8.18 (m, 2H. Ph-2,6),
7.29-7.62 (m, 8 H, Ph),
6.59 (s, 1H, CHC1).
140-142
(cyclohexane)
c
17 h 13 n 2c i
(280.76)
72.73
72.96
Ci9H19 N3
(289.37)
7.72-8.01 (m, 2H, Ph-2,6),
7.41-7.76 (m, 5H, Ph-pyridaz-
ine),
10a
122-124
(cyclohexane)
78.86
78.70
6.62
6.43
14.52
14.51
8
62
7.12-7.34 (m, 3H, Ph-3,4,5),
4.73 (s, 1H. PhCH), 2.24 (s, 6 H,
c h 3).
6.71
6.32
13.32
13.13
67
79
186-187
(cyclohexane)
c
2 1 h 2 1 n 3
79.97
80.31
10b
10c
(315.41)
c
22h 23n 3
80.21
80.65
7.84
6.82
12.75
12.45
8.06
8 .0 2
8
7.71-7.85 (m, 2H, Ph-2,6),
7.46-7.55 (m, 5H, Ph-pyridaz-
ine),
212-213
(ethanol)
(329.44)
7.21-7.34 (m, 3H. Ph-3,4,5),
4.85 (s, 1H, PhCH),
2.21-2.51 (m, 4H, piperidine H-
2 ,6 )
1.41-1.62 (m, 6 H, piperidine H-
3.4,5)
c
2 3h , 9n 3
6 6
144-145
(ethanol)
81.87
81.73
5.68
5.33
12.45
12.15
lOd
11
(337.42)
5.84
5.58
7.82
9
8.14-8.23 (m, 1H. NH),
7.34-7.66 (m, 10H, Ph),
6.71 (d .y = 4Hz, 1H, PhCH),
4.62 (d. J =5, 2H, NH2)
83
138-39
(ethanol)
c
17 h , 6n 4
73.89
73.70
20.27
19.95
8.31
(276.34)
5.42
5.17
8.71-8.22 (4H,m)
8.26-8.31 (m, 2H, NH-NH),
7.45-8.00 (m, 20H. Ph),
6.7 (d, J = 4Hz, 2H, PhCH)la'
12
89
320-322
(DMF:H.O)
(8 :1 )
c 34h 28n 6
(520.63)
78.43
77.99
16.14
15.96
a Recorded from deuteriodimethylsulfoxide; b 4B; c 4A; d (0.5 : 9.5); e (2 : 8); * calculated C17H 13N30 + 1/8 H2;
gexchangeable with D20.
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1050
Y. A. Issac • Synthesis. Reactions and Spectroscopoy of 3-Benzoyl-6-phenylpyridazines
N-NHAr
8 a; Ar = C6H5
b; Ar = C6H4CI-p
c; Ar = C6H4Cl-m
NaBH4
94%
Ac0H /H 2S 0 4
65%
10 a;R = R' = CH3
b; R = R' = -(CH2)4-
C;R = R'=-(CH2)5-
d; R = H, R' = C6H5
SOC1,
5 a; R =
b: R =
11
Scheme 1
responds to one proton and their ratio is 1 : 9
respectively. F urtherm ore, the structure of product
4 is evidenced by its IR spectrum which reveals a
broad absorption band near v - 2840 cm -1, assign-
able to strongly intram olecular hydrogen bonded
O H or H N + group. A ttem pts to separate the two
isom ers w ere m et with failure. Accordingly, the
isolated oxim e 4 was considered to exist as a mix-
ture of the two form s the zw itterionic 4A and the
Z isom er 4B which is predom inant as indicated by
arrangem ent of O -alkyl derivatives obtained.
Thus, treatm ent of 4 with diethyl or dim ethyl sul-
fates in aqueous sodium hydroxide afforded the
O -alkyloxim es 5a,b respectively. The latter could
be also obtained via an alternative route involving
treatm ent of ketone 2 with the corresponding al-
koxylam ine hydrochloride in ethanol and in the
presence of 10% sodium hydroxide. A s expected,
both com pounds, 5a,b, show ed a m ixture from two
isom ers (Table I). The structure of the latter p ro -
ducts was consistent with their IR, 'H N M R and
the elem ental analysis in addition to the mass
spectrum of 5a which revealed m /z = 303 (84% ),
corresponding to the m olecular ion peak (see E x-
perim ental).
the foregoing
N M R data.
The assignm ent of the Z isom er of the product
4 was further confirm ed by its alkylation and re-
T reatm ent of 5a with polyphosphoric acid af-
forded the dealkylated [11] and the rearranged
product N ,6-diphenylpyridazine-3-carboxyam ide 6
which was identified by com parison with an au-
thentic sam ple of 7 prep ared from benzoyl chlo-
ride and 3-phenyl-6-am inopyridazine, The com-
4A (109b)
4B (90%)
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Y. A. Issac • Synthesis, Reactions and Spectroscopoy of 3-Benzoyl-6-phenylpyridazines
1051
parison included tic, m.p., IR , in addition to the
2D -N M R analysis. The results obtained, clearly
dem onstrate that com pound 6 was the product of
a B eckm ann rearrangem ent of 5a and not com -
pound 7. The structure of 6 was established by the
following facts; a) its m.p. (207-208 °C) was dif-
ferent from that of com pound
7 (m.p. 2 3 1 -
129
129.6
232 °C), b) IR spectra of both com pounds show ed
different N H and C O stretching frequencies, thus,
com pound 6 show ed bands at v = 3343 (N H ) and
135.8
Fig. 2. Proton and carbon assignments of compound 7
based on HMBC experiments.
1682 cm -1 (C O ), while com pound
7 show ed
stretching frequencies at v = 3478 (N H ) cm -1,
1722 (C O ) cm -1, c) both com pounds show ed dif-
ferent signals in 'H N M R and 13C N M R, e.g., com -
pound 6 show ed (C O ) at d = 161.3, while com -
m ent upon treatm ent of 4 w ith polyphosphoric
acid to give 6 (Schem e 1).
A n even m ore convenient access to 3-benzoyl-
pound
7
at <3 166.6 ppm , d) from 2D -H C
Af-arylhydrazone-6-phenylpyridazine
8a-c
was
established by treatm ent of our target ketone 2
with substituted phenylhydrazine hydrochloride in
presence of sodium acetate and m ethanol giving
high yields of hydrazones 8.
correlation, using the H M B C pulse sequence [12].
C om pound 6 show ed a correlation betw een H-4
of pyridazine (d, 8.4) and C O (d = 161.3) while
com pound 7 show ed a correlation betw een CO
(ö = 166.6) and the benzoyl ortho protons at ((3 =
8.14). Total assignm ents of proton and carbon sig-
Transform ation of alcohol
3 into the corre-
sponding chloride 9 was achieved in a satisfactory
nals for both com pounds are illustrated in Fig. 1 yield em ploying thionyl chloride in dry toluene at
and 2. The structure of 6 was also confirm ed by its
mass spectrum which show ed a m olecular ion peak
at m /z = 275 (99% ).
room tem perature.
A ccording to the literature [14], the action of
secondary aliphatic am ines to 4-a-chlorobenzylp-
yridazine was found to result in an attack at the
heteroarom atic system. O n the other hand, attack
of said aliphatic am ines gives 4-a-am inobenzylpyr-
idazine in addition to 20% of isom eric tele-substi-
tution products (4-benzyl-5-am inopyridazines [14].
In contrast, 3-a-chlorobenzylpyridazine derivative
9 has shown to be attacked exclusively at the ben-
zylic carbon atom ('H N M R signals for pyridazinyl
H-4,5 in addition to analysis of the reaction m ix-
ture by tic ), so, treatm ent of the chloro derivative
The foregoing results, w hen taken collectively,
substantiate the Z configuration assigned for, both,
the O -alkyloxim es 5a,b and their precursors 4.
Also, oxim e 4 was subjected to a m ixture of ace-
tic and sulfuric acid in order to achieve a B eck-
m ann rearrangem ent. U n d er these very m ild con-
ditions, deoxim ation was achieved, and ketone 2
was obtained instead of any expected rearranged
product 6 or 7. It is w orth to note that deoxim ation
usually takes place under drastic conditions with
very strong reducing, oxidizing or expensive rea-
gents [13]. H ow ever we achieved this rearrange-
9
with secondary aliphatic, arom atic or cyclic
am ines showed a pronounced regioselectivity in
the sm ooth replacem ent of chlorine by A^-nucleo-
philes leading quantitatively to the corresponding
am ino derivatives lOa-d. The structure of the p ro -
ducts is consistent with their IR and !H N M R in
addition to mass spectrum of 10b which revealed
m /z = 315 (0.6% ).
M uch efforts have been devoted to synthesis of
the hydrazine 11. U nfortunately 90% yield of the
disubstituted derivative 12 always was obtained in
addition to a poor yield of com pound 11 despite
of the use of different reaction conditions. Finally,
we have succeeded to obtain com pound 11 in good
Fig. 1. Proton and carbon assignments of compounds 6
based on HM BC experiments.
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1052
Y. A. Issac • Synthesis. Reactions and Spectroscopoy of 3-Benzoyl-6-phenylpyridazines
yield (83% ) by adding a solution of com pound 9 in
m ethanol dropw ise to a stirred hydrazine hydrate
solution at room tem perature. The elem ental
analysis and spectroscopic data of com pounds 11
and 12 are com patible with the assigned struc-
tures (Table I).
Thus, the diarylacetonitrile 15 was conveniently
accessible to synthesize ketone 16. We have so far
failed in the preparation of an analytically pure
sam ple owing to its poor stability, so the crude
chloropyridazinyl ketone 16 was reacted w ith hy-
droxylam ine hydrochloride in the presence of so-
dium hydroxide to afford oxim e 17.
In continuation of our w ork, and due to the
pharm acological potential of pyridazines [15,16],
we extended our efforts tow ards the synthesis of
ketone 16 with a 6-chloro substituent at the pyri-
dazine ring, (Schem e 2). Therefore, we prepared
a-(3-phenyl-6-chloropyridazin-4-yl)phenylaceto-
nitrile (15) in good yield by reaction of 3-phenyl-
4,6-dichloropyridazine (13) via adaption of a pub-
lished procedure [8] to give either com pound 14
or 15. To deduce which com pound had actually
been obtained, the product was subjected to re-
ductive dehalogenation (am m onium form ate/Pd/
C), and the product was com pared with nitrile 1
(Schem e 1). A rem arkable difference betw een the
two nitriles was observed (using tic, m.p., spectro-
scopic analysis) which indicated that our product
is 15 and not 14, so the chlorine at C-4 was re -
placed during the reaction and not at C-6. The IR
spectrum of com pound 15 revealed an absorption
band at v = 2221 (CN) cm -1, while its 'H N M R
show ed a singlet at d = 8.11 (pyridazine H-5), a
m ultiplet at 6.92-7.07 (Ph H-2,6 ), a m ultiplet at
7.21-7.61 (Ph H-3,4,5 and C6H 5 at pyridazine) and
a singlet at 5.93 (benzyl proton) [cf. E xperim en-
tal].
Experim ental
M elting points are uncorrected. E lem ental
analyses w ere perform ed on a C arlo E rb a 1106
analyzer. IR spectra w ere m easured using Perkin
Elm er 298 spectrophotom eter. The *H N M R
spectra were recorded on an V arian G em ini 200
M Hz instrum ent, 13C N M R spectra w ere recorded
at 50 M Hz on X L 200; 2D -H C correlation was ob-
tained on B ruker 360 M H z using a H M B C pulse
sequence, according to [12]. M ass spectra w ere re -
corded on Shim adzu, G C M S-Q P 1000 E X instru-
m ent. All reactions were m onitored by thin layer
chrom atography, carried out on 0.2 m m silica gel
6OF254 (M erck) plates.
The analytical and spectral data of com pounds
2-12 are com piled in Table I and the experim en-
tal, com pounds 15-17 at the experim ental part.
3-Benzoyl-6-phenylpyridazine (2): A solution of
10.84 g (40 m m ol) of 1 [1], 15 ml of 30% N aO H
and 0.80 g (3.5 m m ol) triethylbenzylam m onium
chloride in 200 ml of m ethanol was stirred at 45 °C
for 12 h and air was pum ped through it. Then,
200 ml w ater was added, and the precipitate was
crystallized from toluene. Yield: 10.1 g (96% ); -
IR: v = 1673 (C O ).
16
15
Scheme 2
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Y. A. Issac • Synthesis, Reactions and Spectroscopoy of 3-Benzoyl-6-phenylpyridazines
1053
Phenyl(6-phenylpyridazin-3-yl)m ethanol (3): To
a solution of 2.60 g (10 m m ol) of 2 in 50 ml of
m ethanol 0.10 g (2.5 m m ol) of sodium borohy-
dride was added within 15 m in and the reaction
m ixture was stirred at room tem perature for 2 h.
The m ixture was acidified with 2 N sulfuric acid,
then m ethanol was rem oved in vacuo. The ice-
cooled solution was m ade alkaline with 50% aque-
ous sodium hydroxide. The precipitate was recrys-
tallized from ethanol. Yield: 2.48 g (94% ); - IR:
v = 3159 (O H ).
3-Benzoyloxim e-6-phenylpyridazine (4): A solu-
tion of 2.60 g (10 m m ol) of 2 in 20 ml of m ethanol
was added to a solution of 2.08 g (30 m m ol) of hy-
droxylam ine hydrochloride in 10 ml of w ater, and
10 ml of 10% sodium hydroxide. The m ixture was
refluxed for 45 min. A fter cooling 100 ml w ater
was added and the precipitate was crystallized
from toluene. Yield: 2.61 g (95% ).
N -(6-Phenylpyridazin-3-yl)benzam ide (7): This
com pound was obtained as colourless crystals
from ethanol, m.p. 2 31-232 °C. - 2 -D 'H N M R,
13C N M R (Fig. 2).
C 17H n N ,0 (275.31)
Calcd
C 74.17 H 4.76 N 15.26%,
Found C 73.91 H 4.54 N 15.08%.
3-Benzoyl-N -arylhydrazone-6-phenyl-
pyridazines (8a-c) (G eneral procedure): A solution
of phenylhydrazine hydrochloride or its m -, p-
chloro analogue (10 m m ol) and 2 g of sodium ace-
tate in 10 ml of w ater was added to 2.60 g
(10 m m ol) of 2 in 30 ml of m ethanol, then the m ix-
ture was refluxed for 1 h. The precipitate was crys-
tallized from the appropriate solvent to yield
2.52 g (62% ), 3.11 g (69% ), 3.41 g (89% ) of 8a,8b
or 8c respectively. - IR: v - 3078 (N H ).
R eaction of oxim e 4 with acetic and sulfuric
acids: A m ixture of 1.4 g (5 m m ol) of 4, 100 ml of
acetic acid and 50 ml of sulfuric acid was refluxed
for 4 h, the m ixture was cooled, then 100 g of ice
was aded, then neutralized with am m onium hy-
droxide. The precipitate was crystallized from tol-
uene. Yield: 0.85 g (65% ) of ketone 2.
3-B enzoyl-(0-alkyloxim e)-6-phenylpyridazines
(5a,b) (M ethod A ): A solution of 2.60 g (10 m m ol)
of 2 in 20 ml of ethanol containing 30 m m ol of ap-
propriate alkoxylam ine hydrochloride, 10 ml of
w ater, and 10 ml of 10% sodium hydroxide was
refluxed for 1.5 h, w ork up according to 4. Yield:
2.41 g (79% ) of 5a and 2.13 g (74% ) of 5b, respec-
tively. - MS (70 ev): for 5a, m /z (% ), 303 (84), 302
(100), 274 (65), 258 (31), 244 (94), 104 (381), 77
(98), 51 (67).
M ethod B: The appropriate dialkylsulfate
(30 m ml) was added in portions to a stirred solu-
tion of 2.75 g (10 m m ol) of 4 in 20 ml of ethanol
and 10 ml of 10% sodium hydroxide. Stirring was
continued for 1 h at room tem perature, the excess
dialkylsulfate was evaporated in vacuo, then
100 ml of w ater was added. The separated precipi-
tate was crystallized from the appropriate solvent.
Yield: 1.14 g (37% ) of 5a and 2.41 g (83% ) of 5b.
3-C arboxanilide-6-phenylpyridazine (6): A mix-
ture of (10 m m ol) of 4 or 5a and 30 g of polyp-
hosphoric acid was kept at 110 °C with stirring for
1 h, the m ixture was cooled, 100 g of ice was added
and the isolated product was crystallized from ace-
tonitrile. Yield: 1.98 g (72% ) and 1.87 g (68% )
respectively. - 2 -D 'H N M R , 13C NM R: (Fig. 1). -
MS (70 ev): m /z (% ), 275 (99), 274 (81), 182 (2),
156 (25), 120 (2), 104 (100), 92 (6), 78 (6), 77 (59),
53 (99).
a-(6-P henylpyridazin-3-yl)benzylchloride
(9):
Thionyl chloride (2 m l) was added to a stirred sus-
pension of 2.62 g (10 m m ol) of 3 in 100 ml of dry
toluene at 0 °C w ithin 15 min. The m ixture was
allowed to warm up to room tem perature and then
stirred for 3 h. A saturated solution of aqueous
sodium hydrogen carbonate was added at 0 °C.
The aqueous layer was extracted with dichloro-
m ethane, the com bined organic extracts w ere
dried over anhydrous sodium sulfate, and then
concentrated in vacuo. The residue was crystal-
lized from cyclohexane to yield 1.72 g (82% ).
a-(6-Phenylpyridazin-3-yl)benzylam ines (lOa-d):
(General procedure): A m ixture of 1.40 g (5 m m ol)
of 9 and 20 mmol of the appropriate am ine in
15 ml of ethanol was refluxed for 5 - 7 h. A fter
cooling, the precipitate was crystallized from ap -
propriate solvent to yield 0.89 g (62% ), 1.52 g
(67% ), 1.29 g (79% ), or 1.19 g (66% ) of 10a, 10b,
10c or lOd respectively. - MS (70 ev): of 10b, m /z
(% ) 315 (0.6), 271 (16), 246 (100), 245 (35), 115
(12), 77(8), 70(2).
a-(6-P henylpyridazin-3-yl)benzylhydrazine (11):
To a stirred sam ple of 30 ml of hydrazine hydrate
a solution of 1.40 g (5 m m ol) of 9 in 10 ml of m eth -
anol was added dropw ise at room tem perature
within 30 min. The stirring was continued for 3 h.
The excess hydrazine and ethanol w ere evapo-
rated in vacuo. The residue was crystallized from
ethanol. Yield: 1.14 g (83% ). - IR: v = 3192 (N H ),
v = 3057 (N H 2). - MS (70 ev): m /z(% ) 276 (20),
275 (2), 199 (12), 121 (100), 119 (10), 77 (35).
N, N '-Bis[a -(6-phenylpyridazin -3-yl) benzyl']-
hydrazine (12): A m ixture of 2.8 g (10 m m ol) of 9
and 10 ml of hydrazine hydrate in 20 ml of ethanol
was refluxed for 2 h. The excess hydrazine hydrate
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1054
Y. A. Issac • Synthesis. Reactions and Spectroscopoy of 3-Benzoyl-6-phenylpyridazines
and solvent w ere rem oved in vacuo. The residue
was crystallized from D M F and w ater (8:1). Yield:
2.31 g (89% ). - IR: v = 3300-3050 (N H -N H ).
a-(3-Phenyl-6-chloropyridazin-4-yl)phenylace-
m ixture was w orked up analogous to the prepara-
tione of 2. Yield: 2.8 g (83% ) m .p 70- 71 °C. - IR:
v = 1669 (C = 0 ).
-
'H N M R (D M SO -d6): d =
8.21(s, 1H, pyridazine H-5), 7.67-7.39 (m , 10H,
Ph).
tonitrile (15): To
a
stirred solution of 2.9 g
(18.33 m m ol) of phenylacetonitrile in 40 ml of dry
toluene 1.9 g ( 47.5 m m ol) of sodium am ide was
added in portions at 0 °C. Then 5.63 g (25 m m ol)
of 3-phenyl-4,6-dichloropyridazine was added. The
m ixture was w orked up according to ref. [8], Yield:
5.6 g (70% ) m.p. 138-139 °C (ethanol), - IR: v =
2221 (CN ). - 'H N M R (D M SO -d6): (3 = 8.11 (s,
1H, pyridazine H -5), 6.92-7.07 (m , 2H, Ph-2,6),
7.21-7.61 (m, 8H, Ph-3,4,5, C6H s-pyridazine), 5.93
(s, 1H, PhC H ).
4-Benzoyloxim e-3-phenyl-6-chloropyridazine
(17): A solution of 1.47 g (5 m m ol) of 16 in 20 ml
of m ethanol was added to a solution of 1.04 g
(15 m m ol) of hydroxylam ine hydrochloride in 5 ml
of w ater and 5 ml of 10% sodium hydroxide then
the m ixture was w orked up analogous to the p rep -
aration of 4. Yield: 1.12 g (72% ) m.p. > 300 °C
(DM F). - IR: v = 3220 (O H ). - ]H N M R (D M SO -
d6): d = 8.33 (s, 1H, pyridazine H -5), 7.79-7.42 (m,
10H, Ph), 12.11 (s, 1H, O H ).
C 18H 12C1N3 (305.77)
C 17H 12C1N30 (309.75)
C alcd
C 70.71 H 3.96 N 13.74%,
Calcd
C 65.91 H 3.90 N 13.57%,
Found C 71.00 H 3.89 N 13.75%.
Found C 65.72 H 3.50 N 13.50%.
A cknow ledgem ent
4-Benzoyl-3-phenyl-6-chloropyridazine (16):
A
solution of 3.06 g (10 m m ol) of 15, 15 ml of 30%
N aO H and 0.23 g (1 m m ol) of triethylbenzylam -
m onium chloride in 50 ml of m ethanol then the
Thanks are due to Institute of O rganic C hem is-
try, Karl Franzens University, G raz-A ustria, for el-
em ental and 2D -N M R analyses.
[9] H. Yamanaka, S. Ohba, Heterocycles 31, 895 (1990).
[10] G. Heinisch, T. Langer, J. Heterocycl. Chem. 30,
1685 (1993).
[11] E. Schmitz, G. Lutze, K. Kirschlce, P. Hubner, Bull.
Soc. Chem. Belg. 101, 6 (1992)
[12] A. Bax, M. F. Summers, J. Am. Chem. Soc. 108,
2093 (1986).
[1] T. Yamada, T. Nobuhara, H. Shimamura, K. Yoshi-
hara, A. Yamaguchi, M. Ohki, Chem. Pharm. Bull.
29, 3433 (1981).
[2] M. J. Ashton, A. Ashford, A. H. Loveless, D. Ridell,
J. Salmon, G. V. W. Stevenson, J. Med. Chem. 27,
1245 (1984) and references cited therin.
[3] A. Kleenmann, J. Engel, „Pharmazeutische Wirks-
toffe“, 2nd Ed., G. Thieme Verlag, Stuttgart (1982).
[4] W. Donald, US Pat. 906, 984, C A . 122, 31542
(1994).
[5] S. Yang, JP 06, 298, 917, C. A. 122. 291815 (1994).
[6] I. Garland, L. Hatton, W. Leeds, E. Parnell, Ger.
Offen 2557956, C. A. 85. 177470 (1976).
[7] C. K. F. Hermann. Y. P. Sachdeva, J. F. Wolfe. Heter-
ocycl. Chem. 24, 1061 (1987).
[13] R. Sanabria, R. Miranda, V. Lara, F. Delgado,
Synth. Commun. 24 (19), 2805 (1994) and refer-
ences cited therein.
[14] G. Heinisch, R. Waglechner. Monatsh. Chem. 115,
1171 (1984).
[15] J. David, R. Thomas, D. Diane, US Pat. 242528,
C. A. 124. 232476 (1995).
[16] M. Guy, C. M. Julian, J. David, US Pat. 261452,
C. A. 124. 290273 (1995).
[8] G. Heinisch, T. Langer, Synth. Commun. 24 (6),
773 (1994).
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