Synthesis of Some Novel N-Substituted Phthalazinone and Pyridopyridazinone Derivatives

Article abstract of DOI:10.1080/00397911.2015.1025282

Phthalazinone and pyridopyridazinone derivatives 3, 5, and 9 were prepared via reaction ofappropriate lactams 2 and 8 with 2-bromoethylphthalimide, N-tosylaziridine, and N,O-ditosyl derivatives of N-methylethanolamine in a two-step process in the presence

Full text of DOI:10.1080/00397911.2015.1025282

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Synthesis of Some Novel N-Substituted
Phthalazinone and Pyridopyridazinone
Derivatives
Zbigniew Malinowskia, Dariusz Sroczyńskib & Aleksandra K.
Szcześniaka
a Faculty of Chemistry, Department of Organic Chemistry, University
of Łódź, Łódź, Poland
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b Faculty of Chemistry, Department of Inorganic and Analytical
Chemistry, University of Łódź, Łódź, Poland
Accepted author version posted online: 01 Apr 2015.
To cite this article: Zbigniew Malinowski, Dariusz Sroczyński & Aleksandra K. Szcześniak (2015)
Synthesis of Some Novel N-Substituted Phthalazinone and Pyridopyridazinone Derivatives, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,
45:15, 1743-1750, DOI: 10.1080/00397911.2015.1025282
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Synthetic Communications1, 45: 1743–1750, 2015
Copyright © Taylor & Francis Group, LLC
ISSN: 0039-7911 print/1532-2432 online
DOI: 10.1080/00397911.2015.1025282
SYNTHESIS OF SOME NOVEL N-SUBSTITUTED
PHTHALAZINONE AND PYRIDOPYRIDAZINONE
DERIVATIVES
Zbigniew Malinowski,1 Dariusz Sroczyński,2 and
Aleksandra K. Szcześniak1
1Faculty of Chemistry, Department of Organic Chemistry, University of
Łódź, Łódź, Poland
2Faculty of Chemistry, Department of Inorganic and Analytical Chemistry,
University of Łódź, Łódź, Poland
GRAPHICAL ABSTRACT
Abstract Phthalazinone and pyridopyridazinone derivatives 3, 5, and 9 were prepared via
reaction of appropriate lactams 2 and 8 with 2-bromoethylphthalimide, N-tosylaziridine,
and N,O-ditosyl derivatives of N-methylethanolamine in a two-step process in the
presence of MeONa=MeOH or NaH=dimethylformamide (DMF). Starting compounds
2 and 8 were obtained by reaction of hydrazine hydrate with isoindolinones 1 or
azaisoindolinones 6. Selected N-(2-phthalimidoethyl)-phthalazinones were converted into
corresponding 2-[2-(methylamino) ethyl]- derivatives in satisfactory yields by treatment
with hydrazine.
Keywords Alkylation; amines; phthalazinone; pyridopyridazinone
INTRODUCTION
Phthalazinones and azaphthalazinones are an interesting group of organic
compounds containing a 2H-pyridazin-3-one core. Their various derivatives exhibit
Received October 22, 2014.
Address correspondence to Zbigniew Malinowski, University of Łódź, Faculty of Chemistry,
Department of Organic Chemistry, Tamka 12 Street, 91-403, Łódź, Poland. E-mail: zbigmal@uni.lodz.pl
1743

1744
Z. MALINOWSKI, D. SROCZYŃSKI, AND A. K. SZCZEŚNIAK
diverse biological activities (e.g., antihypertensive,[1] antimicrobial,[2] antiallergic,[3]
and antiplatelet[4]). Moreover, some of these compounds have found use as
pigments[5] and plant growth regulators.[6] In the past few years, 2H-phthalazin-1-
one and its derivatives were also tested as corrosion inhibitors. It has been shown
that in acidic media these type of compounds efficiently inhibit corrosion of alu-
minium, mild steel, and copper.[7]
Continuing our research interest in the synthesis and modification of nitrogen
heterocycles,[8,9] in the present communication, we report results of the preparation
of some phthalazinone and especially pyridopyridazinone derivatives containing
at the lactam nitrogen atom (2-phthalimidoethyl)-, [2-(tosylamino)ethyl]-, and
[2-(methyl(tosyl)amino)ethyl]- substituents, respectively. Furthermore, our interests
involve the possible applications of 2H-pyridazin-3-one derivatives in the different
fields, such as, for example, corrosion protection.
RESULTS AND DISCUSSION
N-(2-Phthalimidoethyl)-, N-(2-aminoethyl)-, and N-[2-(tosylamino)ethyl]-
derivatives of phthalazinones (compounds 3, 4, and 5) and N-[2-(methyl(tosyl)
amino)ethyl]- derivatives of pyridopyridazinones (compounds 9) were synthesized
as shown in Schemes 1 and 2.
The 2H-phthalazin-1-ones 2 (Scheme 1) and pyridopyridazinones 8 (Scheme 2)
were prepared by reaction of appropriate isoindolinones 1, their aza analogs 6, or
keto acids 7 with hydrazine, according to described procedures.[8,9] For our studies,
we chose 2H-phthalazin-1-ones 2 and pyridopyridazinones 8 containing a hydrogen
atom, as well as phenyl, 2-methoxyphenyl, and 2-pyridyl substituents at the pyrida-
zinone ring. Azaphthalazinones 8c and 8d were synthesized from 2- and 4-(2-
methoxybenzoyl) nicotinic acids 7a and b, respectively (Scheme 2) and used without
purification for the alkylation step. ortho-Benzoylated nicotinic acid derivatives 7a
and b were obtained from picolin- and isonicotinanilides.[10]
Scheme 1. Synthesis of compounds 3–5. Reagents and conditions: (i) NH2NH2ꢀH2O, PrOH, 97 °C; (ii)
(a) NaH, DMF, rt; (b) BrCH2CH2NPhth, DMF, rt; (iii) NH2NH2ꢀH2O, EtOH, 78 °C; (iv) (a) MeO-
Na=MeOH, 65 °C; (b) N-tosylaziridine, 65 °C.

SUBSTITUTED PHTHALAZINONES AND PYRIDOPYRIDAZINONES
1745
Scheme 2. Synthesis of compounds 8 and 9. Reagents and conditions: (i) (a) KBH4, MeOH, 20 °C; (b)
HCl; (c) 2-(MeO)C6H4Li, THF; (d) KMnO4, H2O-aceton ¼ 1:1; (ii) NH2NH2ꢀH2O, PrOH, 97 °C; (iii)
(a) MeONa=MeOH, 65 °C; (b) TsOCH2CH2N(Me)Ts, 65 °C.
Afterward, lactams 2 and 8 were converted into derivatives 3, 5, and 9 in a
two-step alkylation process (Schemes 1 and 2) involving in the first stage transform-
ation of compounds 2 or 8 into corresponding sodium salts, and then the final
products were prepared via reactions with the various alkylation agents, shown in
Fig. 1.[11–13] Compounds 3, 5, and 9 could effortlessly be converted into corres-
ponding aminoalkyl derivatives, which are useful intermediates in the synthesis of
a variety of significant compounds.[14]
Phthalimidoethylphthalazinones 3 were prepared by reacting of starting
phthalazinones 2 with 2-(2-bromoethyl)-1H-isoindole-1,3-(2H)-dione, in the pres-
ence of NaH in dry dimethylsulfoxide (DMF) as solvent, at ambient temperature
(Scheme 1). Products 3 were isolated by precipitation with water in moderate yields.
Treatment of derivatives 3 with hydrazine in refluxing EtOH led to the analogs 4
containing free amine group (Scheme 1). 2-Aminoethylphthalazinone 4a was isolated
by column chromatography in 50% yield.[14]
In the case of synthesis of compound 5 (Scheme 1), 2H-phthalazin-1-one was
alkylated with N-tosylaziridine in the presence of MeONa in dry MeOH, giving
N-tosylaminoethyl derivative. The reaction was completed in 10 h and after the
neutralization by solution of HCl (1:1), product was separated in 55% yield.
Benzenesulfonamides 9 (Scheme 2) were obtained under similar conditions.
Treatment of pyridopyridazinones 8 with ditosylated 2-(methylamino)ethanol in
MeOH=MeONa led to the transformation of the starting material and gave N-[(N-
Metyl-N-tosylamino)ethyl]- derivatives 9 in ca. 60% yields.
Figure 1. Alkylation agents.

1746
Z. MALINOWSKI, D. SROCZYŃSKI, AND A. K. SZCZEŚNIAK
The identity of isolated phthalazinone and pyridopyridazinone derivatives 3, 4,
5, and 9 (Schemes 1 and 2) was confirmed by microanalysis and NMR, infrared (IR),
and mass (MS) spectroscopy. In all experiments, we only observed the formation of
N-alkylated products 3, 5, and 9. Melting points, yields, and spectral data are shown
in the experimental section and presented in the supporting information. Addition-
ally, we have performed the preliminary studies of inhibitory properties of selected
synthetized compounds on the corrosion of bearing steel 100Cr6 in acidic media
using the potentiodynamic polarization method. The initial results suggest that
compounds 3d and 9b can act as corrosion inhibitors.
CONCLUSIONS
In summary, we described an efficient route to synthesize of N-substituted
derivatives of phthalazinones and pyridopyridazinones via an alkylation reaction
with 2-bromoethylphthalimide, N-tosylaziridine, and N,O-ditosyl-N-methylethano-
lamine. Because of the ease of future transformation of the obtained derivatives, they
could be valuable materials in organic synthesis.
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 tetramethylsilane (TMS) as
an internal reference. IR spectra were recorded on a Nexus FT-IR spectrometer.
Mass spectra analyses were performed on 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 using an ultraviolet lamp.
3-Hydroxy-1H-isoindolin-1-ones 1, pyrrolopyridinones 7, 2H-phthalazin-1-
ones 2, pyridopyridazinones 8, N-(2-bromoethyl)phthalimide, N-tosylaziridine, and
toluene-4-sulfonic acid 2-[methyl-(toluene-4-sulfonyl)-amino]-ethyl ester were
prepared according to an already reported procedure.[8–13] Reagents were purchased
from Sigma-Aldrich=Fluka and used without further purification. Solvents were
purified by conventional methods.
1
The H NMR spectra of compounds 3, 4, 5, and 9 showed two characteristic
signals attributable to two groups of methylene protons and additionally, for
derivatives 5 and 9, the presence of singlets at 2.30–2.36 ppm and 2.90–2.92 ppm
corresponding to a methyl group of 4-toluenesulfonyl moiety and N-Me protons,
respectively. The 1H NMR spectra of 4 displayed the presence of the primary amine
protons as characteristic broad singlets at 1.40–1.75 ppm.
General Procedure for Preparation of 2-[2-(1-Oxo-1H-phthalazin-2-
yl)-ethyl]-isoindole-1,3-diones 3
The reaction was carried out under argon. A solution of 2H-phthalazin-1-one 2
(3.95 × 10ꢁ3 mol) in dry DMF (50 cm3) was added slowly to a stirred suspension of
sodium hydride (4.25 mol) in dry DMF (10 cm3). The reaction mixture was stirred

SUBSTITUTED PHTHALAZINONES AND PYRIDOPYRIDAZINONES
1747
at room temperature for 45 min. Next, the whole lot was cooled to 0 °C and the
solution of N-(2-bromoethyl)phthalimide (5.92 × 10ꢁ3 mol) in dry DMF (10 cm3)
was added in portions. At first the mixture was kept for 5 h at 0 °C and later for
16 h at ambient temperature. After this time the reaction mixture was poured
into an ice-water mixture (100 cm3) and next extracted with CHCl3 (3 × 50 cm3).
The combined extracts were dried over MgSO4 and concentrated under
vacuum. The isoindole-1,3-dione 3 was isolated by column chromatography or
crystallization.
2-{2-[6-Methoxy-4-(2-methoxyphenyl)-1-oxo-1H-phthalazin-2-yl]-
ethyl}-isoindole-1,3-dione (3c)
Yield: 50%; mp 180–184 °C; Rf ¼ 0.72 (AcOEt–toluene 1:1); IR (KBr, cmꢁ1):
1
=
n ¼ 1710, 1653 (C O); H NMR (200 MHz, DMSO-d6, ppm): d ¼ 8.21 (d, 1H, 8-
ArH, J ¼ 8.9 Hz), 7.88–7.79 (m, 4H, ArH), 7.47–7.37 (m, 2H, ArH), 7.10 (d, 1H,
ArH, J ¼ 8.4 Hz), 6.77 (m, 1H, ArH), 6.58 (dd, 1H, ArH, J ¼ 7.4, 1.7 Hz), 6.47
(d, 1H, 5-ArH, J ¼ 2.4 Hz), 4.72–4.63 (m, 1H, CH2), 4.14–4.03 (m, 3H, CH2),
3.73 (s, 3H, OMe), 3.63 (s, 3H, OMe); 13C NMR (50 MHz, DMSO-d6, ppm): d
¼ 167.6, 162.5, 158.1, 156.8, 144.3, 134.4, 131.4, 131.1, 130.8, 130.2, 128.3, 123.1,
120.3, 120.0, 111.3, 108.1, 55.5, 55.2, 48.4, 36.1. Anal. calcd. for (C26H21N3O5): C,
68.56; H, 4.65; N, 9.23%. Found: C, 68.54; H, 4.76; N, 9.21%.
Synthesis of Amines 4
Hydrazine monohydrate (98%, 4.04 × 10ꢁ3 mol, 0.2 cm3) was added to a sol-
ution of phthalimido- derivative of phthalazinone 3 (1.49 × 10ꢁ3 mol) in dry EtOH
(15 cm3). The mixture was heated to boiling until TLC analysis (CHCl3=MeOH
19=1) indicated the absence of a starting lactam. After the reaction was completed,
the mixture was cooled to ambient temperature and acidified by addition of a
hydrochloric acid and next all was again heated to boiling for 30 min. After this time,
the mixture was again cooled to ambient temperature and the separated product was
filtrated off. The filtrate was alkalized by a solution of 40% KOH. In next step the
solution was extracted with CH2Cl2 (3 × 50 cm3). The combined extracts were dried
over MgSO4 and concentrated under vacuum. The amine was isolated by column
chromatography.
Amines 4b and 4c were unstable and their full analysis was difficult. For these
compounds only IR, NMR, and MS spectra were recorded.
2-(2-Aminoethyl)-2H-phthalazin-1-one (4a)[14]
Yield: 50% (oil) (mp 84–88 °C[14]); Rf ¼ 0.04 (AcOEt–MeOH 3:1, next MeOH);
1
IR (KBr, cmꢁ1): n ¼ 3330, 3290 (NH), 1656 (C O); H NMR (200 MHz, CDCl3,
=
ppm): d ¼ 8.50–8.40 (m, 1H, ArH), 8.20 (s, 1H, 4-pyridH), 7.90–7.70 (m, 3H,
ArH), 4.33 (t, 2H, CH2, J ¼ 6.2 Hz), 3.19 (t, 1H, CH2, J ¼ 6.2 Hz), 1.40 (s, 2H,
NH2) ppm; 13C NMR (50 MHz, CDCl3, ppm): d ¼ 157.0, 138.1, 133.3, 131.9,
129.8, 128.0, 126.9, 126.2, 53.8, 41.0.

1748
Z. MALINOWSKI, D. SROCZYŃSKI, AND A. K. SZCZEŚNIAK
Preparation of 4-Methyl-N-[2-(1-oxo-1H-phthalazin-2-yl)-ethyl]-
benzenesulfonamide (5)
To a solution of sodium methoxide (1.52 × 10ꢁ2 mol) in dry MeOH (40 cm3)
was added 2H-phthalazin-1-one 2 (0.0137 mol). The mixture was heated under reflux
for 30 min. Afterward, N-tosylaziridine (1.64 × 10ꢁ2 mol) was added and heating was
continued for another 10 h. Then the mixture was cooled to ambient temperature and
neutralized by solution of hydrochloric acid (1:1). The separated product was
filtrated, washed with dry MeOH, and purified by recrystallization from AcOEt.
Yield 55%; mp 209–212 °C (AcOEt); IR (KBr, cmꢁ1): n ¼ 3162 (NH), 1636
(C O); 1H NMR (200 MHz, DMSO-d6, ppm): d ¼ 8.39 (s, 1H, 4-pyridH), 8.23
=
(d, 1H, 5-ArH, J ¼ 7.2 Hz), 7.82–7.74 (m, 3H, 6,7,8-ArH), 7.77 (t, 1H, NH, J ¼
6.3 Hz), 7.61 (d, 2H, TsH, J ¼ 8.0 Hz), 7.28 (d, 2H, TsH, J ¼ 8.0 Hz), 4.17 (t, 2H,
CH2, J ¼ 6.3 Hz), 3.18 (m, 2H, CH2) 2.30 (s, 3H, Me); 13C NMR (50 MHz,
DMSO-d6, ppm): d ¼ 158.3, 142.2, 137.7, 137.3, 133.1, 131.6, 129.2, 129.1, 126.8,
126.5, 126.1, 125.4, 49.8, 20.8. Anal. calcd. for (C17H17N3O3S): C, 59.46; H, 4.99;
N, 12.24; S, 9.34%. Found: C, 59.52; H, 4.97; N, 12.31; S, 9.19%.
General Procedure for Preparation of Benzenesulfonamides 9
Pyridopirydazinone 8 (1.53 × 10ꢁ2 mol) was added to a solution of sodium meth-
oxide (1.65× 10ꢁ2 mol) in dry MeOH (70 cm3). The mixture was heated to boiling for
30 min. Afterward, toluene-4-sulfonic acid 2-[methyl-(toluene-4-sulfonyl)-amino]-ethyl
ester (0.0230 mol) was added and heating was continued for the next 7 h. After this time,
the mixture was cooled to ambient temperature. The separated product was filtrated off,
washed with dry MeOH, and purified by crystallization or column chromatography.
4,N-Dimethyl-N-[2-(1-oxo-1H-pyrido[3,4-d]pyridazin-2-yl)-ethyl]-
benzenesulfonamide (9b)
1
Yield: 50%; mp 157–159 °C (MeOH); IR (KBr, cmꢁ1): n ¼ 1655 (C O); H
=
NMR (200 MHz, CDCl3, ppm): d ¼ 9.15 (s, 1H, ArH), 8.98 (d, 1H, ArH, J ¼
4.9 Hz), 8.28 (s, 1H, ArH), 8.18 (d, 1H, ArH, J ¼ 5.5 Hz), 7.60 (d, 2H, TsH, J ¼
8.0 Hz), 7.20 (d, 2H, TsH, J ¼ 8.0 Hz), 4.42 (t, 2H, CH2, J ¼ 5.8 Hz), 3.51 (t, 2H,
CH2, J ¼ 5.8 Hz), 2.91 (s, 3H, NMe), 2.36 (s, 3H, TsMe); 13C NMR (50 MHz,
CDCl3, ppm): d ¼ 157.9, 150.6, 149.1, 143.1, 135.7, 134.8, 132.5, 129.4, 127.0,
123.9, 118.9, 48.7, 48.0, 35.1, 21.5. Anal. calcd. for (C17H18N4O3S): C, 56.97; H,
5.06; N, 15.63; S, 8.95%. Found: C, 57.01; H, 5.09; N, 15.68; S, 8.95%.
FUNDING
We are grateful to the Polish Ministry of Science and Higher Education (Grant
No. 3 T09A 015 29) and to the University of Łódź for financial support.
SUPPORTING INFORMATION
Full experimental details, 1H and 13C NMR data, and IR spectra for this article
can be accessed on the publisher’s website.

SUBSTITUTED PHTHALAZINONES AND PYRIDOPYRIDAZINONES
1749
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