Novel synthesis of some isatin hydrazones and pyridazinophthalazines

Article abstract of DOI:10.1080/00397911.2010.538484

The acid hydrazides bearing furyl, pyrazolyl, and indolyl rings 2 condense with isatin to give the corresponding hydrazones 3. Ring closure of the latter in an HCl=AcOH mixture led to the construction of a new pyrrolinone ring 4. The hydrazides 2 condensed also with phthalic anhydride to give the corresponding pyridazinophthalazines 5.

Full text of DOI:10.1080/00397911.2010.538484

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Novel Synthesis of Some Isatin
Hydrazones and Pyridazinophthalazines
Wael S. I. Abou-Elmagd a & Ahmed I. Hashem a
a Chemistry Department, Faculty of Science, Ain Shams University,
Cairo, Egypt
Accepted author version posted online: 07 Oct 2011.Version of
record first published: 21 Feb 2013.
To cite this article: Wael S. I. Abou-Elmagd & Ahmed I. Hashem (2013): Novel Synthesis of Some Isatin
Hydrazones and Pyridazinophthalazines, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 43:8, 1083-1091
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Synthetic Communications1, 43: 1083–1091, 2013
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2010.538484
NOVEL SYNTHESIS OF SOME ISATIN HYDRAZONES
AND PYRIDAZINOPHTHALAZINES
Wael S. I. Abou-Elmagd and Ahmed I. Hashem
Chemistry Department, Faculty of Science, Ain Shams University,
Cairo, Egypt
GRAPHICAL ABSTRACT
Abstract The acid hydrazides bearing furyl, pyrazolyl, and indolyl rings 2 condense with
isatin to give the corresponding hydrazones 3. Ring closure of the latter in an HCl=AcOH
mixture led to the construction of a new pyrrolinone ring 4. The hydrazides 2 condensed also
with phthalic anhydride to give the corresponding pyridazinophthalazines 5.
Keywords 2(3H)Furanones; isatinhydrazones; pyridazinophthalazines
INTRODUCTION
Nitrogen-containing heterocyclic compounds are widespread in nature, and
their applications as biologically active pharmaceuticals and agrochemicals are
becoming more important.[1] The development of new efficient methods to synthesize
N-heterocycles with structural diversity is one major interest of modern synthetic
organic chemists.[2] Among a large variety of nitrogen-containing heterocyclic
compounds, heterocycles containing bridgehead azino group have received consi-
derable attention because of their pharmacological properties and clinical
applications.[3]
Received October 4, 2010.
Address correspondence to Wael S. I. Abou-Elmagd, Chemistry Department, Faculty of Science,
Ain Shams University, Abassia 11566, Cairo, Egypt. E-mail: waelmagd97@yahoo.com
1083

1084
W. S. I. ABOU-ELMAGD AND A. I. HASHEM
Scheme 1. (i) Ar ¼ C6H5ꢀ; (ii) Ar ¼ C6H4Cl(4-); and (iii) Ar ¼ C6H4OCH3(4-).
2(3H)-Furanones 1 are considered versatile starting materials for the construc-
tion of many heterocyclic systems of synthetic and biological importance.[4] Our
research group was interested in the conversion of these furanones into pyrrolone,[5]
pyrazole,[6] pyridazinone,[7,8] oxadiazole,[9] and triazole[10,11] derivatives. The key
step in these conversions is the formation of the acid hydrazides 2. These hydrazides
are formed by the action of hydrazine hydrate on the furanones 1, a reaction which
occurs smoothly and mostly at room temperature (cf. Scheme 1).
Schiff and Mannich bases of isatin were reported to have a broad spectrum of
biological activities such as antibacterial,[12,13] antifungal,[14,15] anti-HIV,[16] antipro-
tozoal,[17] and antihelminthic[18] activities.
Hydralazine (1-hydrazinophthalazine) was introduced in the early 1950s as an
antihypertensive agent. Recently, several phthalazine derivatives have been reported
to act as modulators of angiogenesis and therefore emerged as powerful clinical tools
in oncology and ophthalmology.[19]
These diverse biological activities sparked our interest in utilizing the
hydrazides 2 for the synthesis of some isatin hydrazone and pyridazinophthalazine
derivatives.
RESULTS AND DISCUSSION
The hydrazides 2a and b were previously prepared by ring opening of the
furanones 1a and b with hydrazine hydrate.[5,8] Using the same procedure, the
hydrazides bearing the indolyl moiety 2c were prepared and characterized.
The infrared (IR) spectra of these products showed the characteristic absorp-
tion bands for the amide nC¼O at 1655 cmꢀ1, normal ketonic nC¼O at 1685 cmꢀ1
,
and nNH at 3340 cmꢀ1. The 1H NMR spectra of these products showed characteristic
signals for the different protons (cf. Experimental). When the hydrazides 2 were
refluxed with isatin in ethanol containing a few drops of acetic acid, the hydrazone
derivatives 3 were obtained as the only isolable products.
Ring closure of the hydrazone derivatives in HCl=AcOH mixture led to
the construction of a new pyrrolinone ring linked to the indolinone nucleus with
the formation of 4 (cf. Scheme 2).

ISATIN HYDRAZONES AND PYRIDAZINOPHTHALAZINES
1085
Scheme 2. (i) Ar ¼ C6H5ꢀ; (ii) Ar ¼ C6H4Cl(4-); and (iii) Ar ¼ C6H4OCH3(4-).
The same products 4 were also obtained by fusion of the hydrazides 2 in neat
with isatin (cf. Experimental). The structures of the products 3 and 4 were confirmed
by their analytical as well as spectral data (cf. Tables 1 and 2).
Condensation of the hydrazides 2 with phthalic anhydride in ethanol
containing a few drops of acetic acid led to the formation of the corresponding
pyridazinophthalazine derivatives, namely 2-heteryl methylene-4-arylpyridazino
[1,2-b]phthalazine-1,6,11(2H)-triones 5 (cf. Scheme 3).
The structures of these derivatives were confirmed by their chemical analyses as
well as their spectral properties (cf. Tables 1 and 2).
EXPERIMENTAL
Melting points were measured on an electrothermal melting-point apparatus.
Elemental analyses were carried out at the Micro-Analytical Unit, Cairo University,
Giza. IR spectra were measured on a Unicam SP-1200 spectrophotometer using the
KBr wafer technique. 1H NMR spectra were measured in dimethylsulfoxide
(DMSO-d6) on a Varian Plus instrument (300 MHz).
5-Aryl-3-heteryl Methylene-2(3H)-furanones (1)
These compounds were prepared according to the procedure described by a
previous investigator.[20]
General Method for the Reaction of the 2(3H)-Furanones with
Hydrazine Hydrates
Hydrazine hydrate (1.1 mmol) was added to a solution of the furanones (1)
(1 mmol) in ethanol (20 ml). The reaction mixture was left at room temperature with
occasional shaking. The product obtained was filtered off, washed with ethanol, and
found to be the acid hydrazide (2).

1086
W. S. I. ABOU-ELMAGD AND A. I. HASHEM
Table 1. Spectral data of compounds 3–5
IR (nmax) KBr (cmꢀ1
)
Compound
nN-H
nC¼O
1H NMR (DMSO-d6)
3a(i)
3237
1719
1645
d ¼ 3.36 (s, 2H, CH2-CO), 6.63–8.01 (m, 12H, Ar-H), 8.34 (s, 1H,
=
CH), 10.72 (s, 1H, NH-CO, exchangeable), 12.06 (s, 1H,
NH-CO, exchangeable)
3a(ii)
3a(iii)
3b(i)
3335
3141
1722
1660
d ¼ 3.37 (s, 2H, CH2-CO), 6.79–8.11 (m, 11H, Ar-H), 8.32 (s, 1H,
=
CH), 10.90 (s, 1H, NH-CO, exchangeable), 12.01 (s, 1H,
NH-CO, exchangeable)
3222
1715
1663
d ¼ 3.27 (s, 2H, CH2-CO), 3.92 (s, 3H, OCH3), 6.93–7.93 (m, 11H,
=
Ar-H), 8.55 (s, 1H, CH), 10.95 (s, 1H, NH-CO, exchangeable),
12.27 (s, 1H, NH-CO, exchangeable)
d ¼ 3.28 (s, 2H, CH2-CO), 6.58–8.07 (m, 20H, Ar-H), 8.37 (s, 1H,
3318
3132
1728
1673
=
CH), 9.31 (s, 1H, NH-CO, exchangeable), 11.01 (s, 1H,
NH-CO, exchangeable)
3b(ii)
3b(iii)
3c(i)
3206
3250
1729
1717
1673
1712
1667
d ¼ 3.32 (s, 2H, CH2-CO), 6.72–8.13 (m, 19H, Ar-H), 8.29 (s, 1H,
=
CH), 9.85 (s, 1H, NH-CO, exchangeable), 11.69 (s, 1H,
NH-CO, exchangeable)
d ¼ 3.22 (s, 2H, CH2-CO), 3.75 (s, 3H, OCH3), 6.73–8.09 (m, 19H,
=
Ar-H), 8.37 (s, 1H, CH), 9.57 (s, 1H, NH-CO, exchangeable),
12.02 (s, 1H, NH-CO, exchangeable)
d ¼ 3.91 (s, 2H, CH2-CO), 6.23–7.84 (m, 15H, Ar-H þ NH), 8.23 (s,
3356
3254
1710
1685
=
1H, CH), 10.65 (s, 1H, NH-CO, exchangeable), 13.25 (s, 1H,
NH-CO, exchangeable)
d ¼ 3.79 (s, 2H, CH2-CO), 6.51–7.87 (m, 14H, Ar-H þ NH), 8.07 (s,
3c(ii)
3320
3200
1715
1680
=
1H, CH), 10.30 (s, 1H, NH-CO, exchangeable), 12.83 (s, 1H,
NH-CO, exchangeable)
d ¼ 3.72 (s, 2H, CH2-CO), 3.95 (s, 3H, OCH3), 6.90–7.76 (m, 14H,
3c(iii)
3300
3234
1722
1686
=
Ar-H þ NH), 8.03 (s, 1H, CH), 10.97 (s, 1H, NH-CO,
exchangeable), 13.01 (s, 1H, NH-CO, exchangeable)
=
4a(i)
3236
3235
3220
3300
3210
3252
1650
1647
1658
1650
1656
1650
1650
d ¼ 6.83–7.38 (m, 13H, Ar-H), 8.10 (s, 1H, CH), 10.65 (s, 1H,
NH-CO, exchangeable)
=
4a(ii)
4a(iii)
4b(i)
d ¼ 6.71–7.81 (m, 12H, Ar-H), 8.22 (s, 1H, CH), 10.39 (s, 1H,
NH-CO, exchangeable)
d ¼ 3.79 (s, 3H, OCH3), 6.92–8.01 (m, 12H, Ar-H), 8.17 (s, 1H,
=
CH), 10.32 (s, 1H, NH-CO, exchangeable)
=
d ¼ 6.61–7.98 (m, 21H, Ar-H), 8.21 (s, 1H, CH), 10.20 (s, 1H,
NH-CO, exchangeable)
=
4b(ii)
4b(iii)
4c(i)
1658
1662
d ¼ 6.97–7.92 (m, 20H, Ar-H), 8.12 (s, 1H, CH), 11.03 (s, 1H,
NH-CO, exchangeable)
d ¼ 3.91 (s, 3H, ꢀOCH3), 6.93–8.11 (m, 20H, Ar-H), 8.32 (s, 1H,
=
CH), 11.01 (s, 1H, NH-CO, exchangeable)
=
2300
2217
2290
2200
2305
2220
–
1654
1650
1657
2652
1659
1651
1716
1710
1715
1710
1717
1708
d ¼ 6.59–8.03 (m, 16H, Ar-H þ NH), 8.22 (s, 1H, CH), 10.97 (s,
1H, NH-CO, exchangeable)
=
4c(ii)
4c(iii)
5a(i)
d ¼ 6.52–8.09 (m, 15H, Ar-H þ NH), 8.09 (s, 1H, CH), 11.73 (s,
1H, NH-CO, exchangeable)
d ¼ 3.92 (s, 3H, ꢀOCH3), 6.75–8.01 (m, 15H, Ar-H þ NH), 8.30 (s,
=
1H, CH), 12.01 (s, 1H, NH-CO, exchangeable)
=
d ¼ 6.67–8.23 (m, 13H, Ar-H), 8.35 (s, 1H, CH)
=
5a(ii)
5a(iii)
–
–
d ¼ 6.63–8.19 (m, 12H, Ar-H), 8.29 (s, 1H, CH)
d ¼ 3.79 (s, 3H, OCH3), 6.58–8.07 (m, 12H, Ar-H), 8.21 (s, 1H,
=
CH)
(Continued )

ISATIN HYDRAZONES AND PYRIDAZINOPHTHALAZINES
1087
Table 1. Continued
IR (nmax) KBr (cmꢀ1
)
Compound
5b(i)
nN-H
–
nC¼O
1H NMR (DMSO-d6)
=
1712
1700
1715
1700
1710
1702
1705
1700
1715
1705
1720
1712
d ¼ 6.13–8.19 (m, 21H, Ar-H), 8.37 (s, 1H, CH)
=
5b(ii)
–
d ¼ 6.27–7.91 (m, 20H, Ar-H), 8.19 (s, 1H, CH)
5b(iii)
5c(i)
–
d ¼ 3.81 (s, 3H, OCH3), 6.15–7.83 (m, 20H, Ar-H), 8.23 (s, 1H,
=
CH)
=
3200
3210
3200
d ¼ 6.19–8.01 (m, 16H, Ar-H þ NH), 8.17 (s, 1H, CH)
=
5c(ii)
d ¼ 6.17–8.07 (m, 15H, Ar-H þ NH), 8.15 (s, 1H, CH)
5c(iii)
d ¼ 3.91 (s, 3H, OCH3), 6.25–7.97 (m, 15H, Ar-H þ NH), 8.13
=
(s, 1H, CH)
Data
2-((1H-Indol-3-yl)methylene)-4-oxo-4-phenylbutanhydrazide (2Ci). Yield
70%, colorless crystals, mp 213–215 ꢁC. IR nmax 3340, 3300, 3210 (NH), 1685, 1655
(C O). 1H NMR (DMSO-d6) d ¼ 3.22 (s, 2H, CH2-CO), 4.31 (s, 2H, NH2,
=
exchangeable), 6.40 (s, 1H, NH-CO, exchangeable), 6.91–8.02 (m, 11H, ArH þ NH),
=
8.31 (s, 1H, CH). Anal.=calcd. for C19H17N3O2 (319): C, 71.46=71.89; H, 5.37=5.16;
N, 13.16=13.30.
2-((1H-Indol-3-yl)methylene)-4-(4-chlorophenyl)-4-oxobutane hydrazide
(2Cii). Yield 55%, colorless crystals, mp 226–227 ꢁC. IR nmax 3320, 3215, 3200
1
=
(NH), 1682, 1660 (C O). H NMR(DMSO-d6) d ¼ 3.30 (s, 2H, CH2-CO), 4.30 (s,
2H, NH2, exchangeable), 6.61 (s, 1H, NH-CO, exchangeable), 7.03–8.09 (m, 10H,
=
ArH þ NH), 8.27 (s, 1H, CH). Anal.=calcd for C19H16ClN3O2 (353.5): C,
64.50=65.02; H, 4.56=4.73; N, 11.88=11.69.
2-((1H-Indol-3-yl)methylene)-4-(4-methoxyphenyl)-4-oxobutan hydrazide
(2Ciii). Yield 60%, colorless crystals, mp 218–219 ꢁC. IR nmax 3290, 3220, 3200 (NH),
1
=
1687, 1650 (C O). H NMR (DMSO-d6) d ¼ 3.37 (s, 2H, CH2-CO), 3.92 (s, 3H,
OCH3), 4.39 (s, 2H, NH2, exchangeable), 6.35 (s, 1H, NH-CO, exchangeable),
=
6.92–7.99 (m, 10H, ArH þ NH), 8.20 (s, 1H, CH). Anal.=calcd. for C20H19N3O3
(349): C, 68.75=68.37; H, 5.48=5.40; N, 12.03=12.35.
General Method for the Reaction of the Acid Hydrazides (2) with Isatin
Isatin (0.01 mol) in ethanol was added to a solution of the hydrazides (2)
(0.01 mol) in ethanol (30 ml) containing a few drops of acetic acid. The reaction mix-
ture was heated under reflux for 6 h. The solvent was distilled off under reduced
pressure, and the solid obtained was washed thoroughly with ethanol, drained
and recrystallized from the suitable solvent (cf. Table 2) to give 2-(furan-
2-ylmethylene)-4-oxo-N-(2-oxoindolin-3-ylidene)-4-aryl butan hydrazide (3a),
2-((1,3-diphenyl-1H-pyrazol-4-yl)methylene)-4-oxo-N-(2-oxoindolin-3-ylidene)-4-aryl

1088

1089

1090
W. S. I. ABOU-ELMAGD AND A. I. HASHEM
Scheme 3. (i) Ar ¼ C6H5ꢀ; (ii) Ar ¼ C6H4Cl(4-); and (iii) Ar ¼ C6H4OCH3(4-).
butanhydrazide (3b), and 2-((1H-indol-3-yl)methylene-4-oxo-N-(2-oxoindolin-3-ylidene)-
4-aryl butanhydrazide (3c).
General Method for the Ring Closure of the Butanhydrazide (3)
Using HCl/AcOH Mixture
A solution of (3) (1 g) in a mixture of HCl (34%)=AcOH(glacial) 1:1 (30 ml) was
heated under reflux for 1 h and then left to cool. The solid obtained was filtered off,
washed with water, and recrystallized from the suitable solvent (cf. Table 2) to give
3-(furan-2-ylmethylene)-2-oxo-5-aryl-2,3-dihydropyrrol-1-ylimino) indolin-2-one (4a),
2-((1,3-diphenyl-1H-pyrazole-4-yl)methylene)-2-oxo-5-aryl-2,3-dihydropyrrol-1-ylimino)
indolin-2-one (4b) and 3-((1H-indol-3-yl)methylene)-2-oxo-5-aryl-2,3-dihydropyrrol-
1-ylimino) indol-2-one (4c).
General Method for the Reaction of the Acid Hydrazides (2) with
Phthalic Anhydride
Phthalic anhydride (0.01 mol) in ethanol was added to a solution of the hydra-
zides (2) (0.01mol) in ethanol (30ml) containing a few drops of acetic acid. The reac-
tion mixture was heated under reflux for 2 h. The solvent was distilled off under
reduced pressure, and the solid obtained was drained and recrystallized from the
suitable solvent (cf. Table 2) to give 2-(furan-2-ylmethylene)-4-arylpyridazino[1,2-
b]phthalazin-1,6,11-(2H)-trione (5a), 2-((1,3-diphenyl-1H-pyrazol-4-yl)methylene)-4-
arylpyridazino[1,2-b] phthalazin-1,6,11-(2H)-trione (5b), and 2-((1H-indol-3-yl)
methylene)-4-arylpyridazino[1,2-b]phthalazine-1,6,11(2H)-trione (5c).
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