Novel methods for the synthesis of some pyridazino-, furo-, and polysubstituted pyridazines

Article abstract of DOI:10.1081/SCC-120003146

3,4-Diethoxycarbonyl-5,6-diphenylpyridazine 1 reacted with hydrazine hydrate to form tetrahydropyridazino [4,5-c]pyridazine 2, which reacted with ethyl bromoacetate to give 6,7-diethoxycarbonylmethyl-3,4-diphenyl-5,8-dioxopyridazino [4,5-c]pyridazine 3. However, acetylation of 2 with acetyl chloride gave three different pyridazino[4,5-c]pyridazines 4-6. The reaction of the starting diester 1 with different amounts of phenylmagnesium bromide gave different products 7-10. The structure of product 8 was elucidated by alkaline hydrolysis and hydrazinolysis to afford 11 and 13, respectively. Treatment of 13 with benzaldehyde in piperidine yielded the starting Grignard product 8 and benzalazine 17.

Full text of DOI:10.1081/SCC-120003146

SYNTHETIC COMMUNICATIONS, 32(7), 989–999 (2002)
NOVEL METHODS FOR THE SYNTHESIS
OF SOME PYRIDAZINO-, FURO-, AND
POLYSUBSTITUTED PYRIDAZINES
Alyaa A. Shalaby,1, Manal M. El-Shahawi,1
*
Nabil A. Shams,1 and Suzan Batterjee2
1Chemistry Department, Faculty of Science,
Ain Shams University, Abbassia, Cairo, Egypt
2King Abdulaziz University, Faculty of
Science, Girl Department, Chemistry
Department, Jeddah, Saudi Arabia
ABSTRACT
3,4-Diethoxycarbonyl-5,6-diphenylpyridazine 1 reactedwith
hydrazine hydrate to form tetrahydropyridazino [4,5-c]pyrid-
azine 2, which reactedwith ethyl bromoacetate to give
6,7-diethoxycarbonylmethyl-3,4-diphenyl-5,8-dioxopyridazino
[4,5-c]pyridazine 3. However, acetylation of 2 with acetyl
chloride gave three different pyridazino[4,5-c]pyridazines
4–6. The reaction of the starting diester 1 with different
amounts of phenylmagnesium bromide gave different prod-
ucts 7–10. The structure of product 8 was elucidated by alka-
line hydrolysis and hydrazinolysis to afford 11 and 13,
respectively. Treatment of 13 with benzaldehyde in piperidine
yielded the starting Grignard product 8 andbenzalazine 17.
*Corresponding author.
989
Copyright & 2002 by Marcel Dekker, Inc.
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990
SHALABY ET AL.
In continuation of our previous work on the synthesis of condensed
pyridazine derivatives [1], we reported in this work a new synthesis for pre-
paring 3,4,5,8-dioxo-5,6,7,8-tetrahydropyridazino[4,5-c]pyridazine 2 start-
ing with 3,4-diethoxycarbonyl-5,6-diphenyl-pyridazine 1 [2] andhydrazine
hydrate (Scheme 1). The structure of the product 2 has been verifiedby
analytical data, infrared, mass, and electronic spectra. The electronic spec-
trum of compound 2 carriedout at different pH values (2–11) in a universal
buffer exhibitedthree isosbestic points; indicating that compound 2 must be
present in four tautomeric structures 2a–d. The mass spectrum of compound
2 showedthe molecular ion peak ½Mþ ¼ 316Š is that of the base peak.
ꢀ
The structure 2 was also confirmedby its reaction with ethyl
bromoacetate in the presence of anhydrous potassium carbonate in dry
acetone to give 6,7-diethoxycarbonylmethyl-3,4-diphenyl-5,8-dioxopyrid-
azino[4,5-c]pyridazine 3 (Scheme 1).
The analytical data of 3 indicate that two moles of ethyl bromoacetate
were consumedby each mol of compound 2. Its IR spectrum showed
absorption bands for CO (ester) and CO (cyclic amide) at 1757 and
1684 cmÀ1, respectively, indicating that the reaction has taken place at
-CO-NH- system rather than À C¼NÀ. The mass spectrum of 3 showed
j
ꢀ
OH
the molecular ion peak ½Mþ ¼ 488Š. The principal fragmentation route
involves splitting of ethylene oxide folꢀlowed by ethylene or carbon monox-
ide giving rise to the base peak at ½Mþ ¼ 316Š.
When the pyridazino[4,5-c]pyridazine derivative 2 was allowedto react
with acetyl chloride it gave three products namely; 6,7-diphenyl-3-oxo-
(2H)-pyridazino[4,5-c]pyridazinyl-8-acetate 4, 6,7-diphenyl-8-oxo-(1H)-
pyridazino[4,5-c]pyridazinyl-3-acetate 5 and 1,2-diacetyl-6,7-diphenyl-3,8-
dioxopyridazino[4,5-c]pyridazine 6. The structures of the products 4–6
were verifiedby their IR spectra andtheir mass spectra.
The reaction of 3,4-diethoxy-5,6-diphenylpyridazine 1 with nucleo-
phile derived from Grignard reagent was studied using one to four moles
of phenylmagnesium bromide in diethyl ether and dry benzene (1:1)
mixture as a solvent medium. (Scheme 4).

SYNTHESIS OF SOME PYRIDAZINES
991
Scheme 1.
Scheme 2.

992
SHALABY ET AL.
(A) With one mol: When the diester 1 was allowedto react with one
mol of phenylmagnesium bromide, the reaction afforded the diketone 7,
whose structure was deduced from its analytical and spectral data. Its IR
spectrum revealeda sharp bandat 1688 cm À1 characteristic for the carbonyl
stretching frequency of a,b-unsaturatedketone. Its mass spectrum showed
ꢀ
the molecular ion ½Mþ ¼ 440, 0:02Š andthe base peak corresponding to the
ꢀ
fragment dibenzoyl radical ½Mþ ¼ 105Š. The H-NMR spectrum exhibited
1
only a multiplet for 20 protons of the four phenyl groups.
(B) With two moles: The diester reacted with two moles of phenyl-
magnesium bromide to give only one product, which from elemental ana-
lysis, IR andmass spectrum, the structure of the product might be the
lactone structure 8 or 9. Alkaline hydrolysis of the product with 5% etha-
nolic NaOH solution afforded a white crystalline product, and its IR spec-
trum exhibitedthe OH stretching frequency at 3416 cm À1, but lackedany
bandfor carbonyl group. This reaction might proceedvia cleavage of the
proposed lactone ring followed by decarboxylation. The differentiation
between these two possible lactone structures 8 or 9 was only attainedby
comparison of the hydrolysed product 11 or 12 with an authentic sample
Scheme 3.

SYNTHESIS OF SOME PYRIDAZINES
993
preparedby the action of phenylmagnesium bromide on 5-benzoyl-3,4-
diphenylpyridazine 16 [2]. The product carbinol 11 was foundto be identical
(by m.p. andspectral data) with that obtainedby the alkaline hydrolysis of
the initially formedlactone. So, the resulting lactone must be 3,4,5,5-tetra-
phenyl-7- oxofuro[3,4-c]pyridazine 8 not 9.
When the ethanolic solution of the lactone 8 was allowedto react with
hydrazine hydrate on cold, one product could be isolated from the reaction
Scheme 4.

994
SHALABY ET AL.
mixture, which might be either hydrazide 13 or pyridazine 14 or 15. The
structure of the product was verified by its IR spectrum and showed a sharp
bandat 1657 cm À1, characteristic for the carbonyl stretching frequency of
amide, and a broad band in the 3170–3506 cmÀ1 region due to NH and OH
stretching frequencies. The presence of such absorption has been considered
compelling evidence for structure 13 or 15 andeliminate N-aminopyrrolo
structure 14. The instability of the product was shown during crystallization,
since it convertedto the original lactone 8 by merely heating in polar sol-
vent. This fact is compatible with structure 13, i.e., open-chain structure.
When compound 13 was allowed to react with ethanolic benzaldehyde solu-
tion in the presence of piperidine, the reaction gave two products. The first
product was found to be identical with the original lactone 8, while the
ꢁ
secondproduct 17 meltedat 91–93 C, andits elemental analysis contained
only C, H, andN. Its IR spectrum lackedany bandcharacteristic for the
NH group, but is retainedC ¼N bandat 1626 cm À1. The mass spectrum of
this product showed the peak of the molecular ion is that of the base peak
ꢀ
½Mþ ¼ 208Š. All these facts indicated that product 17 must be benzalazine
(lit. m.p. 92–93ꢁC); also no m.p. depression was observed when mixed with
an authentic sample prepared by the addition of hydrazine hydrate to ben-
zaldehyde on cold.
(C) With three moles: The reaction of the diester 1 with three moles of
phenylmagnesium bromide afforded two products having exactly the same
elemental analysis but different IR and mass spectral data. One of the two
isolated products was found to be identical (m.m.p and IR) with compound
8. The structure of the secondproduct 9 was deduced from the following
facts: its IR spectrum exhibitedthe absorption bandfor the carbonyl group
of g-lactone at 1788 cmÀ1, i.e., at a slightly longer wavelength than the
carbonyl group of the first product 8. The mass spectrum of compound 8
showing the peak due to the molecular ion is that of the base peak
½Mþ ¼ 440, 100%Š andthe main fragment is formedby the splitting of
ꢀ
CO2 (Scheme 6). However, the mꢀass spectrum of compound 9 showedthe
peak due to the molecular ion ½Mþ ¼ 440, <1%Š. The principal fragmenta-
ꢀ
tion route involvedsplitting the benzyne molecule ½Mþ ¼ 364, 100%Š which
is responsible for the proposedstructure.
(D) With four moles: The reaction of the diester 1 with phenylmagne-
sium bromide (four moles) gave two products. The structure of 10 was
elucidated and established by its elemental analysis, its ÀIR1 spectrum exhib-
itedthe stretching frequency of OH group at 3207 cm
andlack of any
bandcharacteristic for carbonyl group. The mass spectrum of compound 10
showedthe molecular ion peak ½Mþ ¼ 596, 0:19%Š. The principal frag-
ꢀ
mentation route involvedsplitting of phenyl radical andbenzene molecule
giving rise to the base peak ½Mþ ¼ 441, 100%Š. All the aforementionedfacts
ꢀ

SYNTHESIS OF SOME PYRIDAZINES
995
indicate that the product is 3,4-(diphenylhydroxy-methyl)-5,6-diphenylpyr-
idazine 10. The structure of the second product is still under investigation.
EXPERIMENTAL
All melting points taken on the Griffin andGeorg melting point appa-
ratus are uncorrected. IR absorption spectra were taken with a Moltson-
1000 series FTIR spectrometer. 1H-NMR spectra were determined on
Brucker, DRX500, or Brucker, AC-200. The mass spectra were determined
using a AMD 604 spectrophotometer, SHIMADZU single focusing mass
spectrometer at a beam energy 70 ev, or Finnigan SSQ 7000. Elemental
analyses were carriedout at the Microanalytical unit, Faculty of Science,
Ain Shams University by using the Perkin-Elmer 2400CHN Elemental
Analyzer.
Synthesis of 3,4-Diphenyl-5,8-dioxo-5,6,7,8-tetrahydropyridazino-
[4,5-c]pyridazine 2
Reaction of 3,4-diethoxycarbonyl-5,6-diphenylpyridazine 1 with hydra-
zine hydrate: A mixture of compound 1 (4 g) andexcess hydrazine ( ꢂ3 ml)
was refluxedin n-butanol (20 ml) for 2 h. The reaction mixture was left to
cool. The precipitate formedwas separatedby filtration andrecrystallized
from n-butanol to give redcrystals of 2 (89% yield). Compound 2
hadm.p. 315 ꢁC (n-butanol); IR: cmÀ1 3354 (broad, OH), 3285 (broad,
NH), 1689 (CO) and1561 (C ¼N); exact mass measurement: Calcdfor
C18H12N4O2: 316.49. Found: 316 (100%).
Anal. calcdfor C 18H12N4O2; C, 68.36; H, 3.82; N, 17.7%. Found: C,
68.59; H, 4.04; N, 17.43.
Reaction of 3,4-Diphenyl-5,8-dioxo-5,6,7,8-tetrahydropyridazino-
[4,5-c]pyridazine 2 with Ethyl Bromoacetate
Synthesis of 6,7-diethoxycarbonylmethyl-3,4-diphenyl-5,8-dioxo-5,6,7,-
8-tetrahydropyridazino[4,5-c]pyridazine 3: A mixture of compound 2 (0.5 g,
0.0015 mol), ethyl bromoacetate (0.5 ml, 0.003 mol), anhydrous potassium
carbonate (0.34 g) anddry acetone (50 ml) was refluxedfor 27 h. The organic
layer was separatedandevaporatedto give 3 as yellow crystals. Compound 3
ꢁ
hadm.p. 125 C (petroleum–ether 80–100ꢁC) (39% yield); IR: cmÀ1 2991

996
SHALABY ET AL.
(C-H aliphatic), 1727 (CO of ester) and1684 (CO amide); exact mass meas-
urement: Calcdfor C 26H24N4O6: 488.220. Found: 489 [M þ 1] (100%).
Anal. calcdfor C 26H24N4O6: C, 63.94; H, 4.95; N, 11.47. Found: C,
64.24; H, 5.03; N, 11.39.
Reaction of 3,4-Diphenyl-5,8-dioxo-5,6,7,8-tetrahydropyridazino-
[4,5-c]pyridazine 2 with Acetyl Chloride
Synthesis of 6,7-diphenyl-3-oxo(2H)pyridazino[4,5-c]pyridazinyl-8-acet-
ate 4; 6,7-diphenyl-8-oxo(1H)pyridazino[4,5-c]pyridazinyl-3-acetate 5 and 1,2-
diacetyle-6,7-diphenyl-3,8-dioxopyridazino[4,5-c]pyridazine 6: Compound 2
(1 g, 0.0032 mol) was refluxedwith excess acetyl chloride (5 ml) for 3 h,
pour into cold water and neutralized with sodium hydroxide solution
(10%), andthe resulting yellow solidwas filteredoff andwashedwith
water. TLC for the crude product showed that there are four products.
Fractional crystallization gave compound 4 m.p. 285ꢁC (benzene) (9%
yield), compound 5, m.p. 308ꢁC (methanol) (13% yield), and compound 6
m.p. 326ꢁC (acetic acid) (23% yield). Compound 4; IR: cmÀ1 3500 (broad,
OH), 3200 (broad, NH), 3061 (CH ar.), 2907 (CH aliphatic), 1777 (CO ester),
1672 (CO amide); exact mass measurement: Calcd for C20H14N4O3: 358.148.
Found: 359 (2.97%) [M þ 1]. Compound 5; IR: cmÀ1 3467 (broad, OH), 3173
(broad, NH), 3084 (CH ar.), 2895 (CH aliphatic), 1777 (CO ester), 1672 (CO
amide); exact mass measurement: Calcd for C20H14N4O3: 358.148. Found:
359 (9.6%) [M þ 1]. Compound 6; IR: 3060 (CH ar.), 2960 (CH aliphatic),
1660 (CO amide).
Anal. calcdfor compound 4; C20H24N4O6: C, 67.02; H, 3.94; N, 15.64.
Found: C, 66.98; H, 3.85; N, 15.56.
Anal. calcdfor compound 5; C20H24N4O6: C, 67.02; H, 3.94; N, 15.64.
Found: C, 67.14; H, 3.81; N, 15.82.
Anal. calcdfor compound 6; C22H16N4O4: C, 65.98; H, 4.03; N, 14.00.
Found: C, 65.75; H, 3.98; N, 13.95.
Action of Grignard Reagents on 3,4-Diethoxycarbonyl-5,6-
diphenylpyridazine 1
A: One Mol of Phenylmagnesium Bromide
Synthesis of 3,4-dibenzoyl-5,6-diphenylpyridazine 7: A solution of
phenylmagnesium bromide [prepared from 0.008 mol bromobenzene and
magnesium (0.008 g-atom)] in dry ether (50 ml) was added to a solution of

SYNTHESIS OF SOME PYRIDAZINES
997
diester 1 (3 g; 0.008 mol) in dry benzene (50 ml). The mixture was refluxed
for 5 h on water-bath, left overnight at room temperature, then decomposed
with a saturatedsolution of ammonium chloride. The ethereal layer was
separated, dried over anhydrous sodium sulphate and concentrated under
reduced pressure to give coꢁmpound 7. Compound 7 was obtainedas yellow
crystals, hadm.p. 196–197 C (pet. ether 80–100ꢁC) (15% yield); IR: cmÀ1
1688 (CO of a,b-unsaturatedketone); exact mass measurement: Calcdfor
C30H20N2O2: 440.496. Found: 440 (0.02%), 311 (4.37%), 230 (0.02%), 178
(2.00%), 105 (100%) and77 (44.43%). 1H-NMR (CDCl3): 7.98–7.22 (m,
20H, 4 ꢃ C6H5).
Anal. calcdfor C 30H20N2O2: C, 81.79; H, 4.58; N, 6.37%. Found: C,
81.52; H, 4.54; N, 6.24.
B: Two Moles of Phenylmagnesium Bromide
Synthesis of 3,4,5,5-tetraphenyl-7-oxofuro[3,4-]pyridazine 8: A solution
of the phenylmagnesium bromide [prepared from 0.016 mol bromobenzene
and magnesium (0.016 g.-atom)] in dry ether (50 ml) was added to a solution
of diester 1 (3 g, 0.008 mol) in dry benzene (50 ml). The mixture was refluxed
for 5 h on a boiling water-bath, left overnight at room temperature, then
decomposed with a saturated solution of ammonium chloride. The ethereal
layer was separated, filtered, dried, and concentrated under reduced pressure
to give furo[3,4-c] pyridazine 8. Compound 8 was obtainedas yellow crys-
ꢁ
tals, hadm.p. 190 C (ethanol) (46% yield); IR: cmÀ1 1792 (CO of cyclic
lactone); exact mass measurement: Calcdfor C 30H20N2O2: 440.496. Found:
440.
Anal. calcdfor C 30H20N2O2: C, 81.79; H, 4.58; N, 6.37%. Found: C,
81.64; H, 4.68; N, 6.08.
C: Three Moles of Phenylmagnesium Bromide
Synthesis of 3,4,5,5-tetraphenyl-7-oxofuro[3,4-c]pyridazine
8
and
3,4,7,7-tetraphenyl-5-oxofuro[3,4-c]pyridazine 9: A solution of phenyl-
magnesium bromide [0.024 mol of bromobenzene and magnesium (0.024 g-
atom)] in dry ether (75 ml) was added to a solution of diester 1 (3 g,
0.008 mol) in dry benzene (50 ml). The reaction mixture was refluxed for
5 h on a boiling water bath, left overnight at room temperature, then decom-
posedwith a saturatedsolution of ammonium chloried. The ethereal
layer was separated, dried over anhydrous sodium sulphate, filtered and
concentrated under reduced pressure. Fractional crystallization of the

998
SHALABY ET AL.
solidobtainedfrom ethanol gave two products
8 and 9. Compound 8
(34% yield) hadthe same m.p., elemental analysis andspectral data as
the product already separated from two moles of Grignard regent with
ꢁ
diester 1. Compound 9 was obtainedas yellow crystals, m.p. 230 C (etha-
nol) 13% yield); IR: cmÀ1 1788 (CO for cylic lactone); ms: 440(<1%).
Anal. calcdfor C 30H20N2O2: C, 81.79; H, 4.58; N, 6.37%. Found: C,
82.10; H, 4.74; N, 6.12.
D: Four Moles of Phenylmagnesium Bromide
Synthesis of 3,4-(diphenylhydroxymethyl)-5,6-diphenylpyridazine 10:
A solution of phenylmagnesium bromide [0.032 mol of bromobenzene and
magnesium (0.032 g-atom)] in dry ether (75 ml) was added to a solution of
diester 1 (3 g, 0.008 mol) in dry benzene (50 ml). The reaction mixture was
refluxedfor 5 h on a boiling water-bath, left overnight at room temperature,
then decomposed with a saturated solution of ammonium chloride. The
ethereal layer was separated, dried, and evaporated under reduced pressure.
Fractional crystallization 10 was obtainedas white crystals, had
m.p. 136–138ꢁC (methanol) (18% yield); IR: cmÀ1 3204 (broad, OH),
3061 (–CH ar.); exact mass measurement: Calcdfor C 42H22N2O2: 596.7.
Found596 (0.19%), 519 (24.47%), 518 (67.68%), 517 (29.29%), 442
(6.85%), 441 (100%).
Anal. calcdfor C 42H22N2O2: C, 84.53; H, 5.41; N, 4.70. Found: C,
84.32; H, 5.48; N, 4.93.
Alkaline Hydrolysis of 3,4,5,5-Tetraphenyl-7-oxofuro-
[3,4-c]pyridazine 8
Synthesis of 5(3,4-diphenylpyridazinyl)diphenylcarbinol 11: Compound
8 (0.5 g) was refluxed for 2 h with 10 ml. (5%) alcoholic sodium hydroxide
solution. On cooling, colourless crystals of 11 were formed(60% yield).
ꢁ
Compound 11 hadm.p. 230 C; IR: cmÀ1 3416 (OH), 3060 (CH ar.).
Anal. Calcdfor C 29H22N2O: C, 84.02; H, 5.31; N, 6,76. Found: C,
84.30; H, 5.22; N, 6.95.
The Action of Phenylmagnesium Bromide on
5-Benzoyl-3,4-diphenylpyridazine 16
Synthesis of 5(3,4-diphenylpyridazinyl)diphenycarbinol 11: A solution of
phenylmagnesium bromide (0.012 mol bromobenzene and magnesium

SYNTHESIS OF SOME PYRIDAZINES
999
(0.012 g,-atom)) in dry ether (50 ml) was added to a solution of compound
16 (2 g, 0.006 mol) in dry benzene (50 ml). The mixture was heated under
reflux for 5 h, left overnight at room temperature, then decomposed with a
saturated solution of ammonium chloride. The ethereal layer was separated,
dried over anhydrous sodium sulphate, filtered, and concentrated under
reduced pressure. The resulting solid product was collected by filtration
andthe recrystallizedfrom ethanol. The product obtainedwas foundto
be identical with compound 11 which was obtainedfrom alkaline hydrolysis
of compound 8 (m.m.p. andspectral data).
Hydrazinolysis of 3,4,5,5-Tetraphenyl-7-oxofuro[3,4-c]pyridazine 8
Synthesis of 3,4-diphenyl-5-(diphenylhydroxymethyl)pyridazine-6-acid
hydrazide 13: Compound 8 (0.2 g) was allowedto react with excess hydra-
zine hydrate in ethanol (15 ml) at room temperature for 2 h. A white product
13 was precipitated and separated by filtration and dried under vacuum;
IR: cmÀ1 1675 (CO amide).
Reaction of 3,4-diphenyl-5-(diphenylhydroxymethyl)pyridazine-6-acid
hydrazide 13 with benzaldehyde: Compound 13 (0.16 g) in 15 ml ethanol
was allowed to react with benzaldehyde (0.5 ml) in the presence of piperi-
dine, for 24 h on cold. The yellow precipitate was collected by filtration and
recrystallizedfrom ethanol to give the original lactone 8 (m.mp. andsuper-
impossable of spectral data). The slow evaporation of the filtrate gave
yellow crystals, which upon crystallization from petroleum–ether 60/80ꢁC,
yields benzalazine 17, m.p. 90–91ꢁC; IR: cmÀ1 1626 (C¼N); exact mass
measurement: Calcdfor C 14H12N2: 208.24. Found: 208.
REFERENCES
1. Shams, N.A.; Enayat, E.I.; Shalaby, A.A.; El-Abbady, S.A. J. Parkt.
Chem. 1987, B 329, 271–276.
2. Shalaby, A.A.; El-Shahawi, M.M.; Shams, N.A.; Batterjee, S. Synthetic
Communication 1999, 29(23), 4141–4152.
Receivedin the USA April 5, 2001