Dipolar cycloaddition reactions with quinazolinones: A new route for the synthesis of several annelated pyrrolo- and pyridazinoquinazoline derivatives

Article abstract of DOI:10.3390/80500401

The novel 2-aryl-3a,4,12,12a-tetrahydropyrrolo[3′,4′:4,3]- pyridazino[6,1-b]-quinazoline-1,3,6-triones (6a-d), 2-aryl-10-oxopyridazino[6,1- b]-quinazoline-3-thio-carboxamides (10a-d) and 2-aryl-3-nitro-1,2,3,4- tetrahydro-pyridazino[6,1-b]quinazolin-10-ones (12a-d) were synthesized via a new, facile one step route involving the reactions of the zwitterion 4, formed in situ, with a variety of N-arylmaleimides 5, 3-aryl-2-cyano-thioacrylamides 8 and ω-nitrostyrenes 11. Dehydrogenation of the tetrahydro derivatives 6a-d and 12a-d in nitrobenzene resulted in the formation of 2-arylpyrrolo[3′, 4′:4,3]-pyridazino[6,1-b]quinazoline-1,3,6-triones (7a-d) and 2-aryl-3-nitropyridazino[6,1-b]quinazolin-10-ones (13a-d), respectively. The structures of the products were confirmed by elemental analysis and spectral data.

Full text of DOI:10.3390/80500401

Molecules 2003, 8, 401-410
molecules
ISSN 1420-3049
http://www.mdpi.org/
Dipolar Cycloaddition Reactions with Quinazolinones: A New
Route for the Synthesis of Several Annelated Pyrrolo- and
Pyridazinoquinazoline Derivatives
†
*
Sami S. Ghabrial and Hatem M. Gaber
National Organization for Drug Control and Research, P.O. Box 29, Cairo, A.R. Egypt.
†
Current address: Department of Chemistry and Biochemistry, Florida Atlantic University, 777
Glades Road, P.O. Box 3091, Boca Raton, FL 33431-0991, U.S.A. E-mail:
hatemgaber@yahoo.com
* Author to whom correspondence should be addressed; e-mail: ssghabrial@hotmail.com
Received: 26 November 2001; in revised form: 6 April 2003 / Accepted: 9 April 2003 / Published: 31
May 2003
Abstract: The novel 2-aryl-3a,4,12,12a-tetrahydropyrrolo[3',4':4,3]-pyridazino[6,1-b]-
quinazoline-1,3,6-triones (6a–d), 2-aryl-10-oxopyridazino[6,1-b]-quinazoline-3-thio-
carboxamides (10a–d) and 2-aryl-3-nitro-1,2,3,4-tetrahydro-pyridazino[6,1-b]quinazolin-
10-ones (12a–d) were synthesized via a new, facile one step route involving the reactions
of the zwitterion 4, formed in situ, with a variety of N-arylmaleimides 5, 3-aryl-2-cyano-
thioacrylamides 8 and ω-nitrostyrenes 11. Dehydrogenation of the tetrahydro derivatives
6a–d and 12a–d in nitrobenzene resulted in the formation of 2-arylpyrrolo[3',4':4,3]-
pyridazino[6,1-b]quinazoline-1,3,6-triones (7a–d) and 2-aryl-3-nitropyridazino[6,1-
b]quinazolin-10-ones (13a–d), respectively. The structures of the products were
confirmed by elemental analysis and spectral data.
Keywords: Quinazolinones; pyrroloquinazolinones; pyridazinoquinazolinones; N-aryl-
maleimides; 3-aryl-2-cyanothioacrylamides; styrenes.

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Introduction
In recent years there has been an increasing interest in the chemistry of 4(3H)-quinazolinones
because of their biological significance. Many of them show antifungal, antibacterial, anticancer, anti-
inflammatory, anticonvulsant, immunotropic, hypolipidemic, antitumor, antiulcer analgesic and
antiproliferative activities as well as inhibitory effects for thymidylate synthase and poly-(ADP-ribose)
polymerase (PARP) [1-13]. On the other hand, heterocycles containing the pyridazine nucleus also
exhibit various pharmacological activities; reduction of blood pressure [14], anticonvulsant activity
[15] and moreover there are pyridazine derivatives that have shown an interesting affinity towards A1-
receptors, and are potentially usable as cerebroprotective agents [16,17]. Because of these established
biological activities, and within the framework of our systematic studies of new heterocyclic
compounds with biological activity [18-21], we became interested in the synthesis of a series of novel
4(3H)-quinazolinone derivatives containing a pyridazine ring, with the aim of obtaining annelated
pyridazinoquinazolines with enhanced biological significance. This contribution represents a follow-up
on our previous work on the chemistry of N-chlorosuccinimide (NCS) [22-24].
Results and Discussion
The starting material 3-amino-2-methyl-4(3H)-quinazolinone (2) was prepared by condensation of
2-methyl-3,1-benzoxazin-4-one (1) with hydrazine hydrate as described in the literature [25]. It was
then reacted with NCS to yield in situ the respective 3-amino-2-chloromethyl-4(3H)-quinazolinone (3),
which was isolated and its structure confirmed on the basis of analytical and spectral data. This
reaction constitutes a new and facile procedure for the synthesis of this reactive compound [26].
Compound 3 was then treated with triethylamine (TEA) to afford the zwitterion 4, created by the loss
of HCl (Scheme 1). This zwitterionic species 4 was used as the key intermediate for the present study.
Thus, the behavior of 4 towards the N-arylmaleimides 5a-d was investigated with regards to the
synthesis of annelated quinazolines. It was found that compound 2 reacted with N-phenylmaleimide
(5a) in the presence of NCS and TEA in dry chloroform with stirring for 1 h at room temperature to
give a reaction product of molecular formula C19H14N4O3 which corresponds to the addition of one
molecule of 2 to one molecule of 5a, with subsequent elimination of a HCl molecule. The IR spectrum
of this product showed the presence of NH (3340 cm-1), C=O (1680 cm-1), saturated CH2 and CH
(2980 cm-1) and C=N groups (1635 cm-1), in addition to the CO-NAr-CO group, which appears as two
1
widely separated bands [27] at 1780 and 1710 cm-1. Its H-NMR spectrum revealed the presence of
signals for the pyridazine H-3 and H-4, pyridazine-CH2, NH and aromatic protons in their proper
positions (cf. Experimental). Based on the above data, this product was formulated as 2-phenyl-
3a,4,12,12a-tetrahydropyrrolo[3',4':4,3]-pyridazino[6,1-b]quinazoline-1,3,6-trione (6a). The formation
of 6a is assumed to proceed via the initial reaction of 2 with NCS to yield 3-amino-2-chloromethyl-
4(3H)-quinazolinone (3), which is not isolated, but rather reacts in situ with TEA to give the
zwitterionic intermediate 4, which in turn reacts with 5a via a dipolar cycloaddition to yield the final
isolable pyrrolopyridazinoquinazoline derivative 6a. This constitutes a simple and easy one pot

Molecules 2003, 8
403
reaction leading to a fused heterocyclic derivative which otherwise is difficult to obtain. A similar
reaction with maleimides has been described in our earlier communications [23, 24]. Similarly, the
diionic species 4 reacted with each of the N-arylmaleimides 5b-d, under the same experimental
conditions, to afford the corresponding tetrahydropyrrolo[3',4':4,3]pyridazino[6,1-b]quinazolinetrione
derivatives 6b-d, respectively, whose structure was based also on correct elemental analyses and
spectroscopic data studies (cf. Experimental).
Scheme 1
O
O
NH2
CH3
O
N
N2H4.H2O
-H2O
N
1
CH3
N
2
dry CHCl3 / py.
NCS
O
O
-
NH2
N
NH
TEA
-HCl
N
+
N
CH2Cl
N
CH2
3
4
O
N
Ar
5a-d
O
O
O
N
O
O
H
N
N
PhNO2
-4H
/
N
N
N Ar
N Ar
N
O
O
6a-d
7a-d
a, Ar=C H
5-7
b, Ar=C66H54Cl-p
c, Ar=C6H4OCH3-p
d, Ar=C6H4CH3-p
Additional confirmation of the structures
of
6a-d
came
from
their
dehydrogenation using boiling nitrobenzene to yield the corresponding pyrrolo[3',4':4,3]-
pyridazino[6,1-b]quinazoline-1,3,6-triones 7a-d, respectively (Scheme 1). The structure of the latter
products was also confirmed by their elemental analyses and spectral data. Thus, the IR spectra of
1
compounds 7a-d displayed bands assignable to NH and saturated CH2 groups, while their H-NMR
spectra revealed only the presence of signals for pyridazine H-5 and aromatic protons (and for CH3 or
OCH3 if present). No pyridazine H-3 or H-4 signals were detected in these spectra which were found

Molecules 2003, 8
404
to be in accordance with the expected outcome of the proposed dehydrogenation reaction (cf.
Experimental).
As a continuation of our studies aimed at synthesizing pyridazinoquinazoline derivatives with
potential biological activity, the behavior of the zwitterionic species 4 towards a variety of 3-aryl-2-
cyanothioacrylamides 8a-d was also examined. Thus, 4 reacted in chloroform with 3-phenyl-2-
cyanothioacrylamide (8a) to give the respective 10-oxopyridazino[6,1-b]quinazoline-3-
thiocarboxamide structure 10a (Scheme 2).
Scheme 2
O
O
H
N
N
Ar
Ar
N
-HCN
-2H
N
CSNH2
CSNH2
N
N
CN
10a-d
9a-d
CSNH2
CN
Ar
dry CHCl3 / py.
8a-d
4
ArCH=CHNO2
dry CHCl3 / py.
11a-d
O
O
N
H
N
Ar
N
Ar
N
PhNO2
/
N
-4H
NO2
N
NO2
12a-d
13a-d
8-13
a, Ar=C6H5
b, Ar=C6H4Cl-p
c, Ar=C6H4OCH3-p
d, Ar=C6H4NO2-p
Formation of 10a is assumed to proceed via addition of the NH in 4 to the activated α,β-
unsaturated center in 8a, affording the cyclic adduct 9a which spontaneously aromatizes to the final
product 10a via elimination of a HCN molecule and subsequent dehydrogenation. The IR spectrum of
1
this product showed the bands of NH2, C=O and C=S groups. Moreover, its H-NMR spectrum
revealed the presence of signals corresponding to the presence of NH2 function, in addition to the

Molecules 2003, 8
405
pyridazine CH and aromatic protons in their proper positions (cf. Experimental). In the same way,
each of 8b-d also reacted with 4 to yield the corresponding pyridazinoquinazolines 10b-d, respect-
ively, whose structures was similarly established based on elemental analysis and spectral data.
As an extension of this synthetic route, the behavior of 4 towards various ω-nitrostyrenes 11a-d
was also studied. Thus, compound 2 and NCS in chloroform and TEA (i.e. 4) reacted with 11a-d to
yield the corresponding 3-nitrotetrahydropyridazino[6,1-b]quinazolin-10-ones 12a-d, respectively
(Scheme 2). Both elemental analyses and spectral data of the latter products were consistent with the
assigned structures. Bands of NH and saturated CH2 groups appeared in their IR spectra, while their
1H-NMR spectra confirmed the presence of these groups, in addition to two pyridazine-CH and
aromatic protons, in each case (cf. Experimental).
The 1,2,3,4-tetrahydro derivatives 12a-d could also be dehydrogenated by the action of boiling
nitrobenzene to afford the corresponding 2-aryl-3-nitropyridazino[6,1-b]quinazolin-10-ones 13a-d
(Scheme 2). No absorption bands for NH groups were detected in the IR spectra of 13a-d.
Additionally, their 1H-NMR spectra revealed the complete absence of pyridazine-CH, pyridazine-CH2
and NH signals while they revealed only the presence of signals for pyridazine H-5 and aromatic
protons (and for OCH3 if present).
Acknowledgements
Thanks are due to Department of Chemistry and Biochemistry, Florida Atlantic University, Boca
Raton, Florida, USA, for providing some facilities during the progress of this work.
Experimental
General
All melting points are uncorrected. IR (KBr discs) were recorded on Perkin Elmer FT–IR type 4
1
spectrophotometer. H-NMR Spectra were recorded on Gemini 200 MHz Spectrometer using TMS as
an internal standard. 13C-NMR spectra were recorded using a Varian Mercuy 300 NMR Spectrometer.
Mass spectra were recorded on AEI MS 30 mass spectrometer operating at 70eV. Compounds 1 [28], 2
[25], 5 [29] and 11 [30] were prepared according to the reported literature procedures.
Synthesis of 3-amino-2-chloromethyl-4(3H)-quinazolinone (3) [26].
A solution of 2 (0.01 mol) in dry chloroform (10 mL) containing pyridine (2 drops) was stirred
with NCS (0.01 mol) for 20 min. Removal of the solvent gave a residue which was recrystallized from
ethanol to give the title compound as colorless crystals, yield 98%, m.p. 156°C; Anal. Calcd. for
C9H8ClN3O: C, 51.56; H, 3.84; N, 20.04; Cl, 16.91%; Found: C, 51.8; H, 3.9; N, 20.3; Cl, 17.1%; IR: ν
= 3400, 3350 (NH2), 2980 (sat. CH2), 1680 (C=O), 1630 (C=N) cm-1; 1H-NMR (CDCl3): δ = 4.51 (s,
2H, CH2), 5.90 (br s, 2H, NH2), 7.30-7.92 (m, 4H, H-arom.) ppm.

Molecules 2003, 8
406
General Procedure for the Synthesis of 2-aryl-3a,4,12,12a-tetrahydropyrrolo[3',4':4,3]-pyridazino-
[6,1-b]quinazoline-1,3,6-triones (6a–d), 2-aryl-10-oxopyridazino[6,1-b]quinazoline-3-thio-
carboxamides (10a–d) and 2-aryl-3-nitro-1,2,3,4-tetrahydropyridazino[6,1-b]quinazolin-10-ones
(12a–d).
To a solution of NCS (0.01 mol) in dry chloroform (30 mL) and pyridine (2 drops), compound 2
(0.01 mol) was added and stirred for 20 min. To this solution, each of the appropriate N-aryl-
maleimides 5a–d, 3-aryl-2-cyanothioacrylamides 8a–d or ω-nitrostyrenes 11a–d (0.015 mol) was
added and the reaction mixture was stirred for additional 10 min. at room temperature. A solution of
TEA (0.12 mol) in dry chloroform (5 mL) was added dropwise over ca. 30 min. Stirring was continued
for an extra 60 min. then the solution was washed with water (2x15 mL), dried and evaporated in
vacuo. The residues were triturated and recrystallized from ethanol to yield 6a-d, 10a-d and 12a–d,
respectively.
6a: Brown crystals, yield 90%, m.p. 168°C; Anal. Calcd. for C19H14N4O3: C, 65.89; H, 4.07; N,
16.17%; Found: C, 66.1; H, 4.2; N, 16.4%; IR: ν = 3340 (NH), 2980 (sat. CH2 and CH), 1780, 1710
(CO-NAr-CO), 1680 (C=O), 1635 (C=N) cm-1; 1H-NMR (CDCl3): δ = 3.61 (m, 1H, pyridazine H-4),
4.22 (d, 1H, J = 6.4 Hz, pyridazine H-3), 4.50 (d, 2H, J = 6.0 Hz, pyridazine-CH2), 7.01-7.81 (m, 9H,
H-arom.), 9.92 (br s, 1H, NH) ppm; MS: m/z = 346 (M+, 18%).
6b: Brown crystals, yield 92%, m.p. 185°C; Anal. Calcd. for C19H13ClN4O3: C, 59.93; H, 3.44; N,
14.71%; Cl, 9.31; Found: C, 60.1; H, 3.6; N, 14.8; Cl, 9.5%; IR: ν = 3350 (NH), 2985 (sat. CH2 and
1
CH), 1770, 1720 (CO-NAr-CO), 1685 (C=O), 1630 (C=N) cm-1; H-NMR (DMSO-d6): δ = 3.62 (m,
1H, pyridazine H-4), 4.13 (d, 1H, J = 6.5 Hz, pyridazine H-3), 4.55 (d, 2H, J = 6.0 Hz, pyridazine-
CH2), 7.19-7.87 (m, 8H, H-arom.), 10.14 (br s, 1H, NH) ppm.
6c: Brown crystals, yield 95%, m.p. 95°C; Anal. Calcd. for C20H16N4O4: C, 63.82; H, 4.28; N, 14.88%;
Found: C, 63.7; H, 4.1; N, 14.7%; IR: ν = 3350 (NH), 2982 (sat. CH2 and CH), 1780, 1710 (CO-NAr-
1
CO), 1670 (C=O), 1635 (C=N) cm-1; H-NMR (CDCl3): δ = 3.60 (m, 1H, pyridazine H-4), 3.82 (s,
3H, OCH3), 4.20 (d, 1H, J = 6.5 Hz, pyridazine H-3), 4.61 (d, 2H, J = 6.1 Hz, pyridazine-CH2), 7.11-
7.80 (m, 8H, H-arom.), 9.83 (br s, 1H, NH) ppm.
6d: Brown crystals, yield 80%, m.p. 170°C; Anal. Calcd. for C20H16N4O3: C, 66.65; H, 4.47; N,
15.54%; Found: C, 66.4; H, 4.6; N, 15.7%; IR: ν = 3330 (NH), 2980 (sat. CH2 and CH), 1770, 1715
(CO-NAr-CO), 1670 (C=O), 1630 (C=N) cm-1; 1H-NMR (CDCl3): δ = 1.60 (s, 3H, CH3), 3.65 (m, 1H,
pyridazine H-4), 4.05 (d, 1H, J = 6.3 Hz, pyridazine H-3), 4.65 (d, 2H, J = 5.9 Hz, pyridazine-CH2),
7.00-7.71 (m, 8H, H-arom.), 9.90 (br s, 1H, NH) ppm.
10a: Brown crystals, yield 80%, m.p. 184°C; Anal. Calcd. for C18H12N4OS: C, 65.04; H, 3.63; N,
16.85; S, 9.64%; Found: C, 65.3; H, 3.8; N, 16.7; S, 9.4%; IR: ν = 3400, 3380 (NH2), 1670 (C=O),

Molecules 2003, 8
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1630 (C=N), 1580 (C=S) cm-1; 1H-NMR (CDCl3): δ = 6.55 (s, 1H, pyridazine H-5), 7.15-7.98 (m, 9H,
H-arom.), 9.99 (br s, 2H, NH2) ppm; MS: m/z = 332 (M+, 15%).
10b: Yellow crystals, yield 75%, m.p. 137°C; Anal. Calcd. for C18H11ClN4OS: C, 58.93; H, 3.02; N,
15.27; S, 8.74; Cl, 9.66%; Found: C, 59.2; H, 3.1; N, 15.6; S, 8.4; Cl, 9.5%; IR: ν = 3410, 3370 (NH2),
1675 (C=O), 1630 (C=N), 1585 (C=S) cm-1; 1H-NMR (DMSO-d6): δ = 6.45 (s, 1H, pyridazine H-5),
7.04-7.86 (m, 8H, H-arom.), 9.97 (br s, 2H, NH2) ppm.
10c: Yellow crystals, yield 95%, m.p. 200°C; Anal. Calcd. for C19H14N4O2S: C, 62.97; H, 3.89; N,
15.46; S, 8.84%; Found: C, 62.7; H, 4.0; N, 15.7; S, 8.6%; IR: ν = 3390, 3350 (NH2), 1670 (C=O),
1630 (C=N), 1600 (C=S) cm-1; 1H-NMR (CDCl3): δ = 3.81 (s, 3H, OCH3), 6.40 (s, 1H, pyridazine H-
5), 7.02-7.80 (m, 8H, H-arom.), 9.91 (br s, 2H, NH2) ppm.
10d: Brown crystals, yield 90%, m.p. 145°C; Anal. Calcd. for C18H11N5O3S: C, 57.29; H, 2.92; N,
18.57; S, 8.49%; Found: C, 57.3; H, 3.1; N, 18.3; S, 8.7%; IR: ν = 3380, 3360 (NH2), 1670 (C=O),
1630 (C=N), 1590 (C=S) cm-1; 1H-NMR (CDCl3): δ = 6.52 (s, 1H, pyridazine H-5), 7.02-7.80 (m, 8H,
H-arom.), 9.95 (br s, 2H, NH2) ppm.
12a: Brown crystals, yield 81%, m.p. 273°C; Anal. Calcd. for C17H14N4O3: C, 63.34; H, 4.37; N,
17.38%; Found: C, 63.6; H, 4.7; N, 17.7%; IR: ν = 3350 (NH), 2980 (sat. CH2 and CH), 1675 (C=O),
1
1630 (C=N) cm-1; H-NMR (DMSO-d6): δ = 3.62 (m, 1H, pyridazine H-4), 4.16 (d, 1H, J = 6.3 Hz,
pyridazine H-3), 4.55 (d, 2H, J = 5.9 Hz, pyridazine-CH2), 7.19-7.88 (m, 9H, H-arom.), 9.78 (br s, 1H,
NH) ppm; MS: m/z = 322 (M+, 25%).
12b: Colorless crystals, yield 95%, m.p. 205°C; Anal. Calcd. for C17H13ClN4O3: C, 57.22; H, 3.65; N,
15.71; Cl, 9.96%; Found: C, 57.4; H, 3.8; N, 15.5; Cl, 10.1%; IR: ν = 3320 (NH), 2985 (sat. CH2 and
1
CH), 1670 (C=O), 1630 (C=N) cm-1; H-NMR (CDCl3): δ = 3.65 (m, 1H, pyridazine H-4), 4.15 (d,
1H, J = 6.3 Hz, pyridazine H-3), 4.57 (d, 2H, J = 6.0 Hz, pyridazine-CH2), 7.06-7.71 (m, 8H, H-
arom.), 9.69 (br s, 1H, NH) ppm.
12c: Yellow crystals, yield 88%, m.p. 245°C; Anal. Calcd. for C18H16N4O4: C, 61.36; H, 4.57; N,
15.90%; Found: C, 61.6; H, 4.8; N, 15.7%; IR: ν = 3350 (NH), 2980 (sat. CH2 and CH), 1670 (C=O),
1
1630 (C=N) cm-1; H-NMR (CDCl3): δ = 3.61 (m, 1H, pyridazine H-4), 3.82 (s, 3H, OCH3), 4.20 (d,
1H, J = 6.4 Hz, pyridazine H-3), 4.51 (d, 2H, J = 6.0 Hz, pyridazine-CH2), 7.11-7.70 (m, 8H, H-
arom.), 9.92 (br s, 1H, NH) ppm.
12d: Yellow crystals, yield 78%, m.p. 265°C; Anal. Calcd. for C17H13N5O5: C, 55.59; H, 3.54; N,
19.07%; Found: C, 55.8; H, 3.5; N, 19.2%; IR: ν = 3360 (NH), 2985 (sat. CH2 and CH), 1670 (C=O),
1
1630 (C=N) cm-1; H-NMR (DMSO-d6): δ = 3.65 (m, 1H, pyridazine H-4), 4.33 (d, 1H, J = 6.5 Hz,
pyridazine H-3), 4.55 (d, 2H, J = 6.1 Hz, pyridazine-CH2), 7.12-7.80 (m, 8H, H-arom.), 10.10 (br s,
1H, NH) ppm.

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General Procedure for the Synthesis of 2-arylpyrrolo[3',4':4,3]pyridazino[6,1-b]quinazoline-1,3,6-
triones 7a–d and 2-aryl-3-nitropyridazino[6,1-b]quinazolin-10-ones 13a–d
A solution of each of 6a-d and 12a-d (1.0 g) was heated in nitrobenzene (15 mL) for 5 h.
Nitrobenzene was steam distilled and the organic compound was extracted with ether. Removal of
ether gave a residue which was crystallized from ethanol to give 7a-d and 13a-d, respectively.
7a: Brown crystals, yield 85%, m.p. 118°C; Anal. Calcd. for C19H10N4O3: C, 66.66; H, 2.94; N,
16.36%; Found: C, 66.8; H, 3.1; N, 16.6%; IR: ν = 1780, 1720 (CO-NAr-CO), 1670 (C=O), 1630
1
(C=N) cm-1; H-NMR (CDCl3): δ = 6.30 (s, 1H, pyridazine H-5), 7.10-7.91 (m, 9H, H-arom.) ppm;
MS: m/z = 342 (M+, 21%).
7b: Brown crystals, yield 85%, m.p. 215°C; Anal. Calcd. for C19H9ClN4O3: C, 60.56; H, 2.39; N,
14.87%; Cl, 9.43; Found: C, 60.4; H, 2.4; N, 14.6; Cl, 9.3%; IR: ν = 1785, 1715 (CO-NAr-CO), 1675
1
(C=O), 1640 (C=N) cm-1; H-NMR (CDCl3): δ = 6.42 (s, 1H, pyridazine H-5), 7.00-7.81 (m, 8H, H-
arom.) ppm.
7c: Brown crystals, yield 90%, m.p. 160°C; Anal. Calcd. for C20H12N4O4: C, 64.51; H, 3.25; N,
15.04%; Found: C, 64.7; H, 3.4; N, 15.3%; IR: ν = 1780, 1710 (CO-NAr-CO), 1670 (C=O), 1630
1
(C=N) cm-1; H-NMR (CDCl3): δ = 3.80 (s, 3H, OCH3), 6.41 (s, 1H, pyridazine H-5), 7.10-7.82 (m,
8H, H-arom.) ppm.
7d: Brown crystals, yield 92%, m.p. 209°C; Anal. Calcd. for C20H12N4O3: C, 67.41; H, 3.39; N,
15.72%; Found: C, 67.6; H, 3.7; N, 15.9%; IR: ν = 1770, 1720 (CO-NAr-CO), 1670 (C=O), 1635
1
(C=N) cm-1; H-NMR (DMSO-d6): δ = 1.65 (s, 3H, CH3), 6.42 (s, 1H, pyridazine H-5) 7.28-7.86 (m,
13
8H, H-arom.) ppm; C-NMR (DMSO-d6): δ = 21.5 (CH3), 117.6, 123.2, 125.1, 125.7, 126.2, 126.9,
127.8, 128.1, 129.4, 130.3, 134.5, 136.2, 144.0, 147.7 (C-arom.), 155.5 (C-6), 170.1, 171.3 (C-1, C-3)
ppm.
13a: Brown crystals, yield 84%, m.p. > 300°C; Anal. Calcd. for C17H10N4O3: C, 64.15; H, 3.16; N,
17.60%; Found: C, 64.3; H, 3.4; N, 17.9%; IR: ν = 1670 (C=O), 1630 (C=N) cm-1; 1H-NMR (DMSO-
d6): δ = 6.66 (s, 1H, pyridazine H-5), 7.05-7.80 (m, 9H, H-arom.) ppm; MS: m/z = 318 (M+, 32%);
13C- NMR (DMSO-d6): δ = 117.3, 123.6, 125.4, 125.8, 126.2, 126.7, 127.0, 127.3, 128.3, 129.8, 131.4,
148.5, 151.2, 153.0 (C-arom.), 155.3 (C=O) ppm.
13b: Brown crystals, yield 95%, m.p. 280°C; Anal. Calcd. for C17H9ClN4O3: C, 57.87; H, 2.55; N,
15.89; Cl, 10.07%; Found: C, 57.9; H, 2.3; N, 16.0; Cl, 10.1%; IR: ν = 1675 (C=O), 1630 (C=N) cm-
1; 1H-NMR (DMSO-d6): δ = 6.68 (s, 1H, pyridazine H-5), 7.25-7.91 (m, 8H, H-arom.) ppm.
13c: Brown crystals, yield 77%, m.p. > 300°C; Anal. Calcd. for C18H12N4O4: C, 62.07; H, 3.47; N,
16.08%; Found: C, 62.3; H, 3.7; N, 16.2%; IR: ν = 1670 (C=O), 1630 (C=N) cm-1; 1H-NMR (CDCl3):
δ = 3.85 (s, 3H, OCH3), 6.61 (s, 1H, pyridazine H-5), 7.11-7.80 (m, 8H, H-arom.) ppm.

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13d: Brown crystals, yield 90%, m.p. > 300°C; Anal. Calcd. for C17H9N5O5: C, 56.20; H, 2.48; N,
19.28%; Found: C, 56.1; H, 2.6; N, 19.3%; IR: ν = 1675 (C=O), 1635 (C=N) cm-1; 1H-NMR (CDCl3):
δ = 6.71 (s, 1H, pyridazine H-5), 7.02-7.75 (m, 8H, H-arom.) ppm.
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Sample availability: Not available
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