A practical approach for preparation of 2-[(Dialkylamino)-methyl]-4-aryl- 2H-phthalazin-1-ones via mannich reaction of 4-Aryl-2H-phthalazin-1-ones

Article abstract of DOI:10.1081/SCC-200048404

Synthesis of 4-aryl-2H-phthalazin-1-ones 5 and their successive conversion, via the Mannich reaction into 2-[(dialkylamino)-methyl]-4-aryl-2H-phthalazin-1- ones 6, 7, 8, 9 as a way of regiospecific transformation of the 4-methoxybenzanilide 1, is described. In addition, the compounds 5b and 7 appeared to be effective complexing ligands for such metal as Cu(II), Ni(II), Fe(II), and Fe(III).

Full text of DOI:10.1081/SCC-200048404

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A Practical Approach
for Preparation of
2‐[(Dialkylamino)‐methyl]‐4‐aryl‐2H
via Mannich Reaction of
4‐Aryl‐2H‐phthalazin‐1‐ones
Jan Epsztajn a , Zbigniew Malinowski a , Paweł
Urbaniak b & Grzegorz Andrijewski b
a Department of Organic Chemistry , Institute of
Chemistry, University of Łódź , Narutowicza 68,
90‐136, Łódź, Poland
b Department of General and Inorganic Chemistry ,
Institute of Chemistry, University of Łódź , Łódź,
Poland
Published online: 28 Jul 2007.
To cite this article: Jan Epsztajn , Zbigniew Malinowski , Paweł Urbaniak
& Grzegorz Andrijewski (2005) A Practical Approach for Preparation of
2‐[(Dialkylamino)‐methyl]‐4‐aryl‐2H‐phthalazin‐1‐ones via Mannich Reaction of
4‐Aryl‐2H‐phthalazin‐1‐ones, Synthetic Communications: An International Journal for
Rapid Communication of Synthetic Organic Chemistry, 35:2, 179-192, DOI: 10.1081/
SCC-200048404
To link to this article: http://dx.doi.org/10.1081/SCC-200048404
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Synthetic Communicationsw, 35: 179–192, 2005
Copyright # Taylor & Francis, Inc.
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1081/SCC-200048404
A Practical Approach for Preparation of
2-[(Dialkylamino)-methyl]-4-aryl-2H-
phthalazin-1-ones via Mannich Reaction of
4-Aryl-2H-phthalazin-1-ones
Jan Epsztajn and Zbigniew Malinowski
Department of Organic Chemistry, Institute of Chemistry,
´ ´ ´ ´
University of Łodz, Łodz, Poland
Paweł Urbaniak and Grzegorz Andrijewski
Department of General and Inorganic Chemistry, Institute of Chemistry,
´ ´ ´ ´
University of Łodz, Łodz, Poland
Abstract: Synthesis of 4-aryl-2H-phthalazin-1-ones 5 and their successive conversion,
via the Mannich reaction into 2-[(dialkylamino)-methyl]-4-aryl-2H-phthalazin-1-ones
6, 7, 8, 9 as a way of regiospecific transformation of the 4-methoxybenzanilide 1, is
described. In addition, the compounds 5b and 7 appeared to be effective complexing
ligands for such metal as Cu(II), Ni(II), Fe(II), and Fe(III).
Keywords: Metal complexes, heterocycles, organometalic compounds, Mannich
bases, tautomerism
INTRODUCTION
In recent years, a lot of attention has been paid to the synthesis of 2H-
pyridazin-3-ones A and their benzo derivatives, which exhibit biologically
interesting activity.[1] The 2H-pyridazin-3-ones A are central building
Received in Poland October 25, 2004
Address correspondence to Jan Epsztajn, Department of Organic Chemistry,
´ ´ ´ ´
Institute of Chemistry, University of Łodz, Narutowicza 68, 90-136, Łodz, Poland.
Fax: (4842) 6786583; E-mail: epsztajn@uni.lodz.pl

180
J. Epsztajn et al.
Figure 1. R1 ¼ H, m, OMe; R2 ¼ aryl, heteroaryl; R3 ¼ 2(CH2)m-amine, –(CH2)m-
aryl.
blocks in a very large number of pharmacological active products, (e.g.,
adenosine A receptor antagonist,[2] antinociceptive agents,[3–5] a-andreno-
ceptor antagonist,[6] and nonprostanoid PGI2 agonist)[7] (Figure 1).
RESULTS AND DISCUSSIONS
In particular, our attention has been focused on obtaining a general synthetic
method for 2-[(dialkylamino)-methyl]-4-aryl-2H-phthalazin-1-ones D. The
reported available methods for the preparation of 4-aryl-2H-phthalazin-1-
ones C core of the desired systems involve in the first step of the Friedel–
Crafts reaction, as a synthetic way for the preparation of the ortho-carbony-
lated aromatic carboxylic acid, which often does not proceed with a desired
positional selectivity,[8–10] and the next step of the reaction, of thus, formed
species with hydrazine.[11–14] The sequence appeared to be unsatisfactory
both in yields and selectivity. The most attractive route so far reported for
the construction of 4-aryl-2H-phthalazin-1-ones is the transformation of
readily available 3-aryl-3-hydroxy-1H-isoindol-1-ones (cyclic tautomers of
ortho-benzoylated aromatic carboxylic acids amides) upon their treatment
with hydrazine monohydrate.[15–17]
The aim of this contribution is to present a general procedure for the
regioselective synthesis of new 2-[(dialkylamino)methyl]-4-pyridyl-2H-
phthalazin-1-ones D. We report herein obtained results based on the
Mannich reaction with the series of corresponding 4-pyridyl-2H-phthalazin-
1-ones C. This method provides access to an efficient synthetic sequence as
a strategy for the transformation of aromatic carboxylic acid B into
desirable phthalazin-1-ones in a three step protocol starting with benzoic
acid anilide (Scheme 1). To this end, anilide 1 was first reacted with butyl-
lithium in THF-hexanes solution[16,18–20] and converted into the bis-(N- and
C-ortho)-lithiated anilide 2. The treatment of the lithiated species with
methyl 4-chlorobenzoeate and methyl pyridinecarboxylates afford the corre-
sponding ortho-benzoylated or ortho-pyridoylated anilides 3 on which a

Synthesis of 4-Aryl-2H-phthalazin-1-ones 5 via Mannich Reaction
181
Scheme 1.
hydrolytic workup was nearly quantitatively converted into cyclic lactol
tautomers: 3-aryl-3-hydroxy-2-phenyl-1H-isoindol-1-ones 4.
Afterward, isoindol-1-ones 4b–d, without isolation (“one-pot”
procedure) reacted with hydrazine monohydrate in boiling propan-1-ol as
solvents furnished the required phthalazin-1-ones 5b–d with good yields.
The pure isoindol-1-one 4a was used for preparation of phthalazin-1-one 5a
(Scheme 2).
For the formed phthalazin-1-ones 5, two keto-enol tautomeric forms could
be assigned. In general, it is known[21] that 1-hydroxyphthalazinones exist pre-
dominantly in the lactam form. In 4-pyridyl-2H-phthalazin-1-ones 5b–d, the
1H NMR spectroscopy indicated that these species exist only in the keto form.
1
The H NMR spectrum of compound 5a showed in DMSO-d6 solution that
this compound exists in both tautomeric forms in the ratio keto-enol
5a : 5a0 ¼ 9 : 1. The indicated relation was not changed after standing.
To provide effective preparation route for the 2-[(dialkylamino)methyl]-
4-aryl-2H-phthalazin-1-ones 6, 7, 8, and 9, the Mannich procedure[22,23] was
applied in the final step. Thus, the treatment of phthalazin-1-ones 5 with
secondary amines and formaldehyde gave the desired Mannich bases with a
good yield. Following that, phthalazin-1-ones 5b, 5c, and 5d were exclusively
converted into N-substituted products; it means compounds 7, 8, and 9
(Scheme 3).
1
The formed compounds were identified by IR, H, and 13C NMR spec-
troscopy. Compounds 7a, 7c, 8c, and 9c appeared to be unstable instead in
these cases; therefore, analytical data FAB: m/z (Mþ) were applied. For all
samples, obtained data were corresponded with calculated molecular masses.

182
J. Epsztajn et al.
Scheme 2. For compounds 3, 4, 5: a: 4-ClC6H4, b: 2-Py, c: 3-Py, d: 4-Py. (i) a)
BuLi/THF-hexanes, 2788C, b) 2788C ! 08C; (ii) a) ArCOOMe/THF, 2788C, b)
.
788C ! rt, MeOH; (iii) NH2NH2 H2O/PrOH, D.
On the other hand, the presence of a large amount of lactim form 5a0 for
phthalazin-1-one 5a rose in the formation both N- and O- substituted Mannich
bases 6a and 6a0 in the ratio 9 : 1 as was indicated in 1H NMR spectroscopy for
1
the just isolated material. The H NMR (CDCl3) of this mixture after 5 days
storage as the solid state showed disappearance of the O-substituted base.
This indicated that the partially formed O-Mannich base 6a0 spontaneously
converts into N-base 6a (Scheme 3). The similarity of 4-(pyridin-2-yl)-2H-
phthalazin-1-one 5b and the corresponding Mannich base 7 in the structure
to 2,20-bipyridines and 2,20 : 60,200-terpyridines,[24–26] which are known to be
excellent chelating ligands for a wide range of metal ions, prompted us to
undertake the study of ligative behavior of the tested species toward a proto-
typed metal centers such as Cu(II), Ni(II), Fe(II), and Fe(III).
Addition of compounds 5b and 7 in methanol-water to the corresponding
salts resulted in the appearance of a charge transfer UV band at ꢀ250 nm
(Table 1).

Synthesis of 4-Aryl-2H-phthalazin-1-ones 5 via Mannich Reaction
183
Scheme 3.
In all investigated metals, absorption at the corresponding wavelength
increased steadily until three equivalents of ligands for compound 5b, and
in the range between two and half and three for Mannich base 7 per one equiv-
alent of metal were added. With a further addition of ligands, the absorption at
the appropriate remained constant. This finding suggests that in 5b with Ni(II)
and Cu(II), octahedral type of complexes are formed. On the other hand, from
Mannich base 7, in the condition used, the mixtures of different species were
arisen. It was observed that for the stability of complexes solutions appeared to
be crucial for the nature of anions present. In the presence of chlorine anions,
the solutions were stable for weeks. If Ni(NO3)2 as the source of Ni2þ was

184
J. Epsztajn et al.
Table 1. The analytical wavelengths of complexes Ni(II),
Cu(II) and Fe(II) with 5b and 7a–c
Cation
Ni(II)
Ligand
Band (nm)
5b
7a
7b
7c
5b
7a
7b
7c
7a
7b
248; 1 ¼ 10.2 ꢁ 103
250; 1 ¼ 9.45 ꢁ 103
250; 1 ¼ 9.8 ꢁ 103
254; 1 ¼ 10.0 ꢁ 103
250; 1 ¼ 9,98 ꢁ 103
248; 1 ¼ 9.65 ꢁ 103
250; 1 ¼ 9.7 ꢁ 103
250; 1 ¼ 9.6 ꢁ 103
248; 1 ¼ 9.95 ꢁ 103
246; 1 ¼ 10.2 ꢁ 103
Cu(II)
Fe(II)
used for formation of complexes with 5b or 7, the obtained solutions
(methanol-water) were stable for 3–5 days, and then the dark yellow
colloid sediments were precipitated and the solutions were decolorized.
The IR spectra of the sediments showed Ni-N(sp2) bands at 450 cm21
,
which confirms the stability of the formed complex compounds. The
formed Fe(II) complexes with studied ligands 5 or 7, if SO242 were applied
as counterions appear to be less stable than corresponding Ni(II) ones.
Specially unstable proved to be Fe(III) complexes. In this case Fe(III) ions
undergo a slow reduction to Fe(II) ions.
In conclusion, we have developed the method for introduction of aroyl
groups at the ortho position of benzanilids, and then the reaction of the
resulting 3-aryl-3-hydroxy-1H-isoindol-1-ones with hydrazine monohydrate
show a considerable versatility for the regiospecific synthesis of 4-aryl-2H-
phthalazin-1-ones. This coupled with an effective aminoalkilation of 4-aryl-
2H-phtalazin-1-ones to the corresponding 2-[(dialkylamino)methyl]-4-aryl-
2H-phthalazin-1-ones. Some of them appeared to be efficient liqands for com-
plexation of such metal centres as Cu(II), Ni(II), Fe(II), and Fe(III).
EXPERIMENTAL
The melting points were determined on a Boetius hot stage apparatus and are
1
uncorrected. H NMR spectra were recorded at 200 MHz and 13C NMR
spectra at 50 MHz on a Varian Gemini 200 BB spectrometer with TMS as
an internal reference. The IR spectra were recorded on a Nexus FT-IR spec-
trometer. A Unicam Helios spectrophotometer was used to obtain electronic
spectra of complex compounds. The UV-VIS spectra were recorded by
means of quartz cuvettes with a path length of 0.1, 0.5, and 1 cm. The data

Synthesis of 4-Aryl-2H-phthalazin-1-ones 5 via Mannich Reaction
185
were recorded over the wavelength range 190–1100 nm. Mass spectra
analyses (FAB) were performed on a Mass Spectrometer MAT95-Finnigan.
The analytical thin-layer chromatography tests (TLC) were carried out on
Merck silica gel plates (Kiselgel 60 F254, layer thickness 0.2 mm), and the
spots were visualized by using UV lamp.
Butyllithium solution in hexanes (Aldrich) was each time titrated be-
fore use. Commercially available hydrazine monohydrate (98%) (Aldrich),
dimethylamine (40%, solution in water) (Loba-Chemie), morfoline
(Reachim), formaldehyde (36%, solution in water) (POCh), 2-(methylami-
no)ethanol (98%) (Aldrich) and N,N,N0,N0-tetramethylethylenediamine
(99.5%) (Aldrich) were used without further purification. Hydrated
nickel(II) chloride, nickel(II) nitrate, copper(II) nitrate, ferrous(III) chloride,
ferrous(II) sulfate, and ferrous(II) chloride (Aldrich and Fluka) were also
used without further purification. Tetrahydrofuran (POCh) was distilled
from sodium benzophenone ketyl immediately before use.
Starting Materials
Anilide 1, methyl esters of 4-chlorobenzoic acid and pyridinecarboxylic acids
were prepared by standard methods from the commercially available corre-
sponding aromatic carboxylic acids.
3-Hydroxy-3-pyridyl-1H-isoindol-1-ones 4b–d were prepared according
to an already reported procedure[16] and were used without isolation and puri-
fication (see “one-pot procedure” of the preparation of 4-pyridyl-2H-phthala-
zin-1-ones). The bis-(N- and C-ortho)-lithiated anilide 2 was generated by a
standard procedure.[16]
Synthesis of 3-(4-chlorophenyl)-3-hydroxy-5-methoxy-2-phenyl-2,3-
dihydro-1H-isoindol-1-one (4a)
A solution of 4-chlorobenzoic acid methyl ester (0.022 mol) in THF (15 cm3)
was added to the solution of the bis-(N- and C-ortho)-lithiated anilide 2 in
THF-hexanes at 2788C under argon. After 0.5 hr at 2788C, the reaction
mixture was warmed to room temperature and stirred for 2 hr. After
quenching, the reaction with methanol (40 cm3) the solution was stirred for
0.5 hr, and then the whole was evaporated to dryness under a reduced
pressure. Water (30 cm3) was added to the obtained residue and the whole
lot was neutralized with the concentrated hydrochloric acid. The resulting
solid was collected by filtration and purified by crystallisation from
methanol-water ¼ 9 : 1 to give the isoindolinon as white crystals (60%).
M.p. 234–2378C; IR (KBr): n ¼ 1684 cm21 (C55O), 3000–3700 cm21 (O-
1
H); H NMR (DMSO-d6): d ¼ 7.77 (d, 2H, J ¼ 8.0 Hz, ArH), 7.48 (d, 2H,
J ¼ 7.7 Hz, ArH), 7.23–7.40 (m, 6H, ArH), 7.09–7.16 (m, 2H, ArH), 6.76

186
J. Epsztajn et al.
(d, 1H, J ¼ 2.2 Hz, 4 ArH,), 3.78 (s, 3H, OMe) ppm; 13C NMR (DMSO-d6):
d ¼ 165.9 (C55O), 163.5, 151.4, 136.1, 136.4, 132.5, 128.3, 128.2, 127.9,
125.5, 125.3, 124.7, 122.0, 116.0, 91.2 (C3), 55.7 (OMe) ppm. Anal. calcd.
for C21H16ClNO3: C 68.95, H 4.41, Cl 9.69, N 3.83. Found: C 68.78, H
4.52, Cl 9.60, N 3.93.
Preparation of 2H-phthalazin-1-ones 5
Synthesis of 4-(4-chlorophenyl)-6-methoxy-2H-phthalazin-1-one (5a)
and 4-(4-chlorophenyl)-6-methoxy-2H-phthalazin-1-ol (5a0)
3-Hydroxyisoindol-1-on 4a (0.0021 mol) and hydrazine monohydrate
(1.6 cm3) were heated to boiling in propan-1-ol (10 cm3) until TLC analysis
(ethyl acetate) indicated the absence of a starting material. After the
reaction was completed, all the volatile materials were removed under
reduced pressure. Water (5 cm3) was added to the residue and the whole
was neutralized with glacial acetic acid. The separated product was
collected by filtration and purified by recrystallization from ethanol-water to
give the white crystals (50%, summary). M.p. 256–2618C; time of reaction:
110 hr; IR (KBr): n ¼ 1676 cm21 (C55O).
1
Lactam form 5a (ꢀ91% in mixture—1H NMR): H NMR (DMSO-d6):
d ¼ 12.79 (s, 1H, NH), 8.27 (d, 1H, J ¼ 8.8 Hz, 8 ArH), 7.53–7.75 (m, 4H,
ArH), 7.48 (dd, 1H, J ¼ 8.9, 2.5 Hz, 7 ArH), 6.99 (d, 1H, J ¼ 2.3 Hz, 5
ArH), 3.84 (s, 3H, OMe) ppm.
1
Lactim form 5a0 (ꢀ9% in mixture—1H NMR): H NMR (DMSO-d6):
d ¼ 12.64 (s, 1H, OH), 8.19 (d, 1H, 8 ArH, J ¼ 8.8 Hz), 7.53–7.75 (m, 4H,
ArH), 7.27 (dd, 1H, 7 ArH, J ¼ 8.7, 2.2 Hz), 6.91 (d, 1H, 5 ArH,
J ¼ 2.3 Hz), 3.84 (s, 3H, OMe) ppm.
13C NMR (DMSO-d6) (for both tautomers forms): d ¼ 162.8 (C55O),
161.9 (C–OH), 159.1, 158.9, 144.7, 134.2, 134.0, 133.8, 133.6, 131.1,
130.7, 128.7, 128.6, 128.5, 121.4, 120.9, 120.0, 109.9, 108.0, 55.6 (OMe)
ppm. Anal. calcd. for C15H11ClN2O2: C 62.84, H 3.87, Cl 12.37, N 9.77.
Found: C 62.79, H 3.85, Cl 12.01, N 9.70.
“One-Pot” Procedure for Preparation of 4-pyridyl-2H-phthalazin-
1-ones 5b–d
The crude material from the reaction of the metalated 4-methoxybenzanilide
with pyridinecarboxylic acids methyl esters and hydrazine monohydrate
(9.5 cm3) in propan-1-ol (47 cm3) were heated under reflux until TLC
analysis (ethyl acetate) of reaction mixture indicated the absence of 1H-
isoindol-1-one. All volatile materials were then removed under reduced

Synthesis of 4-Aryl-2H-phthalazin-1-ones 5 via Mannich Reaction
187
pressure. Water (5 cm3) was added to the obtained residue and the whole was
neutralized with glacial acetic acid. The crude material was washed with the
ethyl acetate (3 ꢁ 15 cm3) to remove some starting anilide 1. The separated
product was purified by recrystallization.
6-Methoxy-4-(pyridin-2-yl)-2H-phthalazin-1-one (5b)
Time of reaction 46 hr; yield: 60% (total form anilide 1); m.p. 221–2258C
(methanol).[16]
6-Methoxy-4-(pyridin-3-yl)-2H-phthalazin-1-one (5c)
Time of reaction 70 hr; yield: 50% (total form anilide 1); m.p. 241–2438C
(acetic acid–water ¼ 1 : 1).[16]
6-Methoxy-4-(pyridin-4-yl)-2H-phthalazin-1-one (5d)
Time of reaction 78 hr; yield: 55% (total form anilide 1); m.p. 244–2498C
(propan-1-ol).[16]
The Mannich Reaction of 2H-phthalazin-1-ones: General
Procedure
For synthesis of 2-aminomethyl-2H-phthalazin-1-ones 6, 7, 8, and 9 in
Mannich reaction conditions dimethylamine (solution in water, 40%),
morfoline or 2-(methylamino)-ethanol were used.
4-Aryl-2H-phthalazin-1-one 5 (0.00197 mol), amine (0.00394 mol) and
formaldehyde (36% solution in water) (0.00488 mol) were heated to boiling
in methanol (40 cm3) for 1.5 hr. Next, the reaction was continued in room
temperature for 12 hr. Afterward, water (50 cm3) was added to the reaction
mixture and whole extracted with chloroform (compounds: 7b,c, 8b,c, 9b,c)
or with benzene (compounds: 6a, 7a, 8a, 9a) (3 ꢁ 40 cm3). The organic
layer was separated and was dried over MgSO4 and then concentrated to
dryness. The Mannich bases were identified without purification.
4-(4-Chlorophenyl)-2-(dimethylaminomethyl)-6-methoxy-2H-
phthalazin-1-one (6a)
1
Yield: 55%; m.p. 136–1408C; IR (KBr): n ¼ 1652 cm21 (C55O); H NMR
(DMSO-d6): d ¼ 8.46 (d, 1H, J ¼ 8.9 Hz, 8 ArH), 7.40–7.64 (m, 4H, ArH),
7.34 (dd, 1H, J ¼ 8.9, 2.5 Hz, 7 ArH), 7.02 (d, 1H, J ¼ 2.5 Hz, 5 ArH),
5.10 (s, 2H, NCH2N), 3.85 (s, 3H, OMe), 2.50 (s, 6H, NMe) ppm; 13C
NMR (DMSO-d6): d ¼ 163.2 (C55O), 159.9, 144.6, 135.3, 133.9, 131.0,

188
J. Epsztajn et al.
130.7, 129.8, 128.9, 122.1, 120.0, 107.9, 72.0 (NCH2N), 55.7 (OMe), 42.9
(NMe) ppm. Anal. calcd. for C18H18ClN3O2: C 62.88, H 5.28, Cl 10.31, N
12.22. Found: C 62.68, H 5.35, Cl 10.63, N 12.15.
2-Dimethylaminomethyl-6-methoxy-4-(pyridin-2-yl)-2H-phthalazin-1-
one (7a)
1
Yield: 82% (oil); IR (thin film): n ¼ 1657 cm21 (C55O); H NMR (CDCl3):
d ¼ 8.75 (m, 1H, 6 PyH), 8.44 (d, 1H, J ¼ 8.9 Hz, 8 ArH), 8.01 (d, 1H,
J ¼ 2.6 Hz, 5 ArH), 7.87–7.90 (m, 2H, PyH), 7.36–7.44 (m, 1H, PyH),
7.33 (dd, 1H, J ¼ 8.9, 2.6 Hz, 7 ArH), 5.15 (s, 2H, NCH2N), 3.90
(s, 3H, OMe), 2.52 (s, 6H, NMe) ppm; 13C NMR (CDCl3): d ¼ 163.1
(C55O), 160.2, 155.2, 148.4, 142.6, 137.2, 130.7, 129.2, 124.3, 123.5,
122.2, 120.2, 108.8, 72.0 (NCH2N), 55.6 (OMe), 42.9 (NMe) ppm.
FAB: m/z ¼ 311.4 (M þ ) (100%), 254.2. Molecular mass calcd. for
C17H18N4O2C: 310.36 g/mol.
2-Dimethylaminomethyl-6-methoxy-4-(pyridin-3-yl)-2H-phthalazin-1-
one (8a)
1
Yield: 80%; m.p. 121–1248C; IR (KBr): n ¼ 1648 cm21 (C55O); H NMR
(CDCl3): d ¼ 8.88 (d, 1H, J ¼ 2.1 Hz, 2 PyH), 8.76 (dd, 1H, J ¼ 4.8,
1.4 Hz, 6 PyH), 8.48 (d, 1H, J ¼ 9.0 Hz, 8 ArH), 7.92–7.98 (m, 1H, 4
PyH), 7.49 (dd, 1H, J ¼ 7.9, 5.0 Hz, 5 PyH), 7.36 (dd, 1H, J ¼ 8.8, 2.4 Hz,
7 ArH), 7.01 (d, 1H, J ¼ 2.4 Hz, 5 ArH). 5.12 (s, 2H, NCH2N), 3.86 (s, 3H,
OMe), 2.51 (s, 6H, NMe) ppm; 13C NMR (CDCl3): d ¼ 163.5 (C55O),
159.9, 150.2, 142.8, 136.8, 131.5, 131.0, 130.0, 123.6, 122.2, 120.2, 107.7,
72.1 (NCH2N), 55.8 (OMe), 43.0 (NMe) ppm. Anal. calcd. for
C17H18N4O2: C 65.79, H 5.85, N 18.05. Found: C 65.75, H 5.88, N 17.96.
2-Dimethylaminomethyl-6-methoxy-4-(pyridin-4-yl)-2H-phthalazin-1-
one (9a)
1
Yield: 60%; m.p. 147–1508C; IR (KBr): n ¼ 1647 cm21 (C55O); H NMR
(CDCl3): d ¼ 8.81 (d, 2H, 2, J ¼ 5.8 Hz, 6 PyH,), 8.48 (d, 1H, J ¼ 8.8 Hz,
8 ArH), 7.51 (dd, 2H, J ¼ 4.5, 1.5 Hz, 3 5 PyH,), 7.37 (dd, 1H, J ¼ 8.9,
2.5 Hz, 7 ArH), 7.04 (d, 1H, J ¼ 2.4 Hz, 5 ArH), 5.11 (s, 2H, NCH2N), 3.87
(s, 3H, OMe), 2.51 (s, 6H, NMe) ppm; 13C NMR (CDCl3): d ¼ 163.3
(C55O), 159.8, 150.3, 143.1, 143.0, 130.3, 130.0, 129.4, 123.8, 122.0,
120.1, 108.0, 107.0, 72.0 (NCH2N), 55.7 (OMe), 42.8 (NMe) ppm. Anal.
calcd. for C17H18N4O2: C 65.79, H 5.85, N 18.05. Found: C 65.62, H 5.74,
N 18.01.

Synthesis of 4-Aryl-2H-phthalazin-1-ones 5 via Mannich Reaction
189
6-Methoxy-2-(morpholin-4-ylmethyl)-4-(pyridin-2-yl)-2H-phthalazin-
1-one (7b)
Yield: 60%; m.p. 109–1138C; IR (CDCl3): n ¼ 1653 cm21 (C55O); 1H NMR
(CDCl3): d ¼ 8.74–8.77 (m, 1H, 6 PyH), 8.43 (d, 1H, J ¼ 8.9 Hz, 8 ArH),
7.98 (d, 1H, J ¼ 2.5 Hz, 5 ArH), 7.84–7.94 (m, 2H, PyH), 7.38–7.45
(m, 1H, PyH), 7.34 (dd, 1H, J ¼ 8.9, 2.5 Hz, 7 ArH), 5.21 (s, 2H, NCH2N),
3.91 (s, 3H, OMe), 3.72 (t, 4H, J ¼ 4.6 Hz, OCH2), 2.87 (t, 4H, J ¼ 4.4 Hz,
NCH2) ppm; 13C NMR (CDCl3): d ¼ 163.3 (C55O), 148.6, 137.3, 129.3,
127.7, 124.3, 123.6, 120.3, 109.0, 71.5 (NCH2N), 67.1 (OCH2), 55.6 (OMe),
50.8 (NCH2) ppm. Anal. calcd. for C19H20N4O3: C 64.76, H 5.72, N 15.90.
Found: C 64.92, H 5.70, N 15.98.
6-Methoxy-2-(morpholin-4-ylmethyl)-4-(pyridin-3-yl)-2H-phthalazin-
1-one (8b)
Yield: 72%; m.p. 114–1178C (benzene); IR (KBr): n ¼ 1648 cm21 (C55O);
1H NMR (CDCl3): d ¼ 8.88 (s, 1H, 2 PyH), 8.47 (d, 1H, J ¼ 3.8 Hz, 6
PyH), 8.47 (d, 1H, J ¼ 8.9 Hz, 8 ArH), 7.90–8.00 (m, 1H, 4 PyH), 7.50
(dd, 1H, J ¼ 7.7, 4.9 Hz, 5 PyH,), 7.37 (dd, 1H, J ¼ 8.8, 2.4 Hz, 7 ArH),
7.00 (d, 1H, J ¼ 2.4 Hz, 5 ArH), 5.19 (s, 2H, NCH2H), 3.87 (s, 1H, OMe),
3.72 (t, 4H, J ¼ 4.6 Hz, OCH2), 2.85 (t, 4H, J ¼ 4.5 Hz, NCH2) ppm; 13C
NMR (CDCl3): d ¼ 163.5 (C55O), 160.0, 150.2, 150.1, 142.8, 136.7, 130.9,
129.9, 123.5, 121.9, 120.2, 107.7, 71.5 (NCH2N), 67.1 (OCH2), 55.8
(OMe), 50.9 (NCH2) ppm. Anal. calcd. for C19H20N4O3: C 64.76, H 5.72,
N 15.90. Found: C 64.51, H 5.08, N 15.98.
6-Methoxy-2-(morpholin-4-ylmethyl)-4-(pyridin-4-yl)-2H-phthalazin-
1-one (9b)
Yield: 62%; m.p. 190–1958C (benzene); IR (CDCl3): n ¼ 1655 cm21
1
(C55O); H NMR (CDCl3): d ¼ 8.82 (d, 2H, J ¼ 5.2 Hz, 2, 6 PyH), 8.47
(d, 1H, J ¼ 8.9 Hz, 8 ArH,), 7.54 (d, 2H, J ¼ 6.0 Hz, 3, 5 PyH), 7.34 (dd,
1H, J ¼ 8.9, 2.5 Hz, 7 ArH), 7.03 (d, 1H, J ¼ 2.5 Hz, 5 ArH), 5.19 (s, 2H,
NCH2N), 3.87 (s, 3H, OMe), 3.72 (t, 4H, J ¼ 4.6 Hz, OCH2), 2.84 (t, 4H,
J ¼ 4.7 Hz, NCH2) ppm; 13C NMR (CDCl3): d ¼ 163.4 (C55O), 159.9,
150.4, 143.2, 143.1, 130.3, 130.0, 123.9, 121.9, 120.3, 107.6, 71.6
(NCH2N), 67.1 (OCH2), 55.8 (OMe), 50.8 (NCH2) ppm. Anal. calcd. for
C19H20N4O3: C 64.76, H 5.72, N 15.90. Found: C 64.37, H 5.77, N, 16.01.
2-f[(2-Hydroxyethyl)methylamino]-methylg-6-methoxy-4-(pyridin-2-
yl)-2H-phthalazin-1-one (7c)
Yield: 90% (1H NMR); IR (KBr): n ¼ 1653 cm21 (C55O); 1H NMR (CDCl3):
d ¼ 8.76 (d, 1H, J ¼ 5.0 Hz, 6 PyH), 8.43 (d, 1H, J ¼ 9.0 Hz, 8 ArH), 7.99

190
J. Epsztajn et al.
(d, 1H, J ¼ 2.4 Hz, 5 ArH), 7.80–7.96 (m, 2H, PyH), 7.38–7.45 (m, 1H,
PyH), 7.33 (dd, 1H, J ¼ 8.9, 2.5 Hz, 7 ArH), 5.21 (s, 2H, NCH2N), 3.90
(s, 3H, OMe), 3.73 (t, 2H, J ¼ 5.0 Hz, OCH2), 3.20 (br s, 1H, OH), 2.92
(t, 2H, J ¼ 4.9 Hz, NCH2), 2.54 (s, 3H, NMe) ppm; 13C NMR (CDCl3):
d ¼ 163.3 (C55O), 160.3, 155.1, 148.6, 143.1, 137.3, 130.8, 129.3, 124.3,
123.6, 122.2, 120.4, 109.0, 71.2 (NCH2N), 59.1 (OCH2), 56.5 (NCH2),
55.7, (OMe), 40.4 (NMe). FAB: m/z ¼ 341.3 (M þ ), 254.3 (100%).
Molecular mass calcd. for C18H20N4O3: 340.39 g/mol.
2-f[(2-Hydroxyethyl)methylamino]-methylg-6-methoxy-4-(pyridin-3-
yl)-2H-phthalazin-1-one (8c)
Yield: 96% (1H NMR); IR (KBr): n ¼ 1652 cm21 (C55O); 1H NMR (CDCl3):
d ¼ 8.88 (d, 1H, J ¼ 1.4 Hz, 2 PyH), 8.77 (dd, 1H, J ¼ 4.8, 1.6 Hz, 6 PyH),
8.48 (d, 1H, J ¼ 8.8 Hz, 8 ArH), 7.91–7.97 (m, 1H, 4 PyH), 7.50 (ddd, 1H,
J ¼ 7.8, 4.8, 0.7 Hz, 5 PyH), 7.37 (dd, 1H, J ¼ 6.7, 2.5 Hz, 7 ArH), 7.01
(d, 1H, J ¼ 2.4 Hz, 5 ArH), 5.19 (s, 2H, NCH2N), 3.86 (s, 3H, OMe),
3.71–3.76 (m, 2H, OCH2), 3.22 (br s, 1H, OH, (D2O)), 2.91 (t, 2H,
J ¼ 5.2 Hz, NCH2), 2.54 (s, 3H, NMe) ppm; 13C NMR (CDCl3): d ¼ 163.5
(C55O), 159.9, 150.3, 150.1, 143.1, 136.7, 130.9, 130.0, 123.6, 122.1,
120.3, 107.7, 71.3 (NCH2N), 59.1 (OCH2), 56.5 (NCH2), 55.8 (OMe), 40.8
(NMe) ppm. FAB: m/z ¼ 341.4 (M þ ), 254.3 (100%). Molecular mass
calcd. for C18H20N4O3: 340.39 g/mol.
2-f[(2-Hydroxyethyl)methylamino]-methylg-6-methoxy-4-(pyridin-4-
yl)-2H-phthalazin-1-one (9c)
Yield: 80% (1H NMR); IR (KBr): n ¼ 1645 cm21 (C55O); 1H NMR (CDCl3):
d ¼ 8.81 (dd, 2H, J ¼ 4.5, 1.5 Hz, 2, 6 PyH), 8.48 (d, 1H, J ¼ 9.0 Hz, 8 ArH),
7.54 (dd, 2H, J ¼ 4.4, 1.6 Hz, 3, 5 PyH), 7.37 (dd, 1H, J ¼ 8.9, 2.5 Hz, 7 ArH),
7.03 (d, 1H, J ¼ 2.4 Hz, 5 ArH), 5.18 (s, 2H, NCH2N), 3.87 (s, 3H, OMe), 3.73
(t, 2H, J ¼ 5.2 Hz, OCH2), 3.0–3.5 (br s, 1H, OH), 2.90 (t, 2H, J ¼ 5.2 Hz,
NCH2), 2.54 (s, 3H, NMe) ppm. FAB: m/z ¼ 341.3 (M þ ), 254.3 (100%).
Molecular mass calcd. for C18H20N4O3: 340.39 g/mol.
General Procedure for the Preparation of Complexes
All experiments were carried out at 298.2 + 0.2 K in methanol-water mixtures
containing 84.2% methanol by weight. The ionic strength was maintained at
0.1 mol/dm3 with the NaClO4 stock solution. The UV-VIS spectra of Fe2þ
,
Fe3þ, Ni2þ, and Cu2þ complexes were recorded for individual ions and for
mixtures covering the metal-ligand ratio range between 1 : 0.5 and 1 : 5. The
solid ligand was added to solution of the metal salts. The final concentrations

Synthesis of 4-Aryl-2H-phthalazin-1-ones 5 via Mannich Reaction
191
for metal ions were from 1022 mol/dm3 to 5 ꢁ 1024 mol/dm3. The spectra
were recorded within the 5 min following the preparation of the solutions
and then after 6, 24, 48, 72, and 120 hr. Addition of ligands to the solutions
of metal ions resulted in the appearance of a charge transfer band at
ꢀ250 nm. The absorption in all cases increased steadily until exactly three
equivalents of ligands were added. With further addition of ligands the absor-
bance of CT bands remained constant (Table 1).
ACKNOWLEDGMENT
´ ´
We are grateful to the University of Łodz for financial support.
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