On the chemistry of cinnoline I. synthesis and reactions of (4-Amino-cinnolin-3-yl)-p-tolyl-methanones

Article abstract of DOI:10.1007/PL00010201

The synthesis of a series of (4-Amino-cinnolin-3-yl)-p-tolyl-methanones from aryl-hydrazonomalononitrile in a one step procedure is reported. The (4-amino-cinnolin-3-yl)-p-tolyl-methanones could be annelated to the corresponding 1,2-dihydro-4-(p-tolyl)-2-oxopyrido[3,2-c]cinnoline derivatives via (4-acetamido-cinnolin-3-yl)-p-tolyl-methanones. Treatment of 1,2-dihydro-9-methyl-4-(p-tolyl)-pyrido[3,2-c]cinnoline-2-one with POCl₁ and P₂S₅ gave 2-chloro-9-methyl-4-(p-tolyl)-pyrido[3,2-c]cinnoline and 1,2-dihydro-9-methyl-4-(p-tolyl)-pyrido[3,2-c]cinnoline-2-thione. Treatment of the ketone with malononitrile afforded 2-amino-3-cyano-9-methyl-4-(p-tolyl)-pyrido[3,2-c]cinnoline. Using these ketones, a facile and convenient route towards substituted pyrimidino[5,4-c]-cinnolines was developed. Chemical and spectroscopic evidences for the structures of the new compounds are presented.

Full text of DOI:10.1007/PL00010201

Monatshefte fuÈr Chemie 130, 1409±1418 (1999)
On the Chemistry of Cinnoline I. Synthesis and
Reactions of (4-Amino-cinnolin-3-yl)-p-tolyl-
methanones
Atef M. Amer1;Ã, Mohamed A. El-Bermaui2, Ahmed F. S. Ahmed1,
and Somya M. Soliman1
1
Chemistry Department, Faculty of Science, Zagazig University, Zagazig, Egypt
2
Organic Chemistry Department, Faculty of Pharmacy, Zagazig University, Zagazig, Egypt
Summary. The synthesis of a series of (4-Amino-cinnolin-3-yl)-p-tolyl-methanones from aryl-
hydrazonomalononitrile in a one step procedure is reported. The (4-amino-cinnolin-3-yl)-p-tolyl-
methanones could be annelated to the corresponding 1,2-dihydro-4-(p-tolyl)-2-oxopyrido[3,2-
c]cinnoline derivatives via (4-acetamido-cinnolin-3-yl)-p-tolyl-methanones. Treatment of 1,2-
dihydro-9-methyl-4-(p-tolyl)-pyrido[3,2-c]cinnoline-2-one with POCl3 and P2S5 gave 2-chloro-9-
methyl-4-(p-tolyl)-pyrido[3,2-c]cinnoline and 1,2-dihydro-9-methyl-4-(p-tolyl)-pyrido[3,2-c]cinno-
line-2-thione. Treatment of the ketone with malononitrile afforded 2-amino-3-cyano-9-methyl-4-(p-
tolyl)-pyrido[3,2-c]cinnoline. Using these ketones, a facile and convenient route towards substituted
pyrimidino[5,4-c]-cinnolines was developed. Chemical and spectroscopic evidences for the
structures of the new compounds are presented.
Keywords. Cycloadditions; Hydrazones; Cinnolines; Pyridines; Pyrimidines.
Zur Chemie der Cinnoline, 1. Mitt. Synthese und Reaktionen von
(4-Amino-cinnolin-3-yl)-p-tolyl-methanonen
Zusammenfassung. Die Synthese einer Reihe von (4-Amino-cinnolin-3-yl)-p-tolyl-methanonen aus
Arylhydrazonomalonitrilen in einem Schritt wird beschrieben. Die Edukte wurden uÈber die (4-
Acetamido-cinnolin-3-yl)-p-tolyl-methanone zu den entsprechenden 1,2-Dihydro-4-(p-tolyl)-2-
oxopyprido[3,2-c]cinnolinderivaten anelliert. Behandlung der 1,2-Dihydro-9-methyl-4-( p-tolyl)-
pyrido[3,2-c]cinnolin-2-one mit POCl3 bzw. P2S5 ergab 2-Chlor-9-methyl-4-(p-tolyl)-pyrido[3,2-
c]cinnolin und 1,2-Dihydro-9-methyl-4-( p-tolyl)-pyrido[3,2-c]cinnolin-2-thion. Umsetzung dieses
Ketons mit Malonitril lieferte 2-Amino-3-cyano-9-methyl-4-( p-tolyl)-pyrido[3,2-c]cinnolin. Mit
Hilfe dieser Edukte wurde eine einfache Route zu substituierten Pyrimidino[5,4-c]cinnolinen
È
È
eroffnet. Chemische und spektroskopische Evidenzen fur die Struktur der neuen Verbindungen
werden mitgeteilt.
Ã
Corresponding author

1410
A. M. Amer et al.
Introduction
Cinnoline is toxic and shows antibacterial activity towards Escherichia coli [1].
Neither itself not its derivatives have yet been found in nature [2]. Derivatives of
cinnolines and their benzo and heterocyclic analogs exhibit biological activity in
various areas, including antihypertensive, autihrombotic, antitumor, antisecretory,
and bactericidal activities [3±6]. 4-Aminocinnolines recently became important
due to their antibacterial, antihistaminic and insecticidic properties [7]. Moreover,
in recent years these derivatives have been extensively utilized as intermediates for
the synthesis of fused cinnolines of potential biological activity [8±11]. Gewald
et al. [12] have reported that the intramolecular Friedel-Crafts reaction of aryl
hydrazone derivatives yields cinnolines. In connection with these ®ndings and
prompted by our ongoing our interest in the synthetic potential of fused nitrogen
containing heterocyclic compounds [13±16] we now describe a convenient method
for the synthesis of (4-amino-cinnolin-3-yl)-p-tolyl-methanones 4a±h as starting
materials and some substituted fused cinnoline systems like the pyrido[3,2-
c]cinnolines 6±10 and the pyrimidino[5,4-c]cinnolines 11±14 with respect to a
projected investigation of their utility as pharmacological agents.
Results and Discussion
The intention of this investigation was to explore the scope and limitations of the
Gewald procedure as a synthetic method for the formation of (cinnolin-3-yl)-aryl-
methanones 4a±h bearing various substituents as well as to study the effect of the
substituent at the aryl group during the cyclization of the aryl hydrazonomalo-
nonitriles 2a±g. For this purpose, aryl-hydrazonomalononitriles 2a±g were
synthesized in good yield by treatment of malononitrile with diazonium salts
1a±g obtained from the corresponding aniline derivatives (o-, m-, p-toluidine, 4-
1a, 2a: R ˆ 2-CH3
1b, 2b: R ˆ 3-CH3
1c, 2c: R ˆ 4-CH3
4a: R ˆ 8-CH3
4b: R ˆ 7-CH3
4c: R ˆ 6-CH3
1d, 2d: R ˆ 4-Br
4d: R ˆ 6-Br
1e, 2e: R ˆ 4-OCH3 4e: R ˆ 6-OCH3
1f, 2f: R ˆ 4-NO3
4h: R ˆ 6-OH
1g, 2g: R ˆ 4-COOH
Scheme 1

Cinnoline Chemistry
1411
4a±6a
4b±6b
4c±6c
R1 ˆ 8-CH3
R1 ˆ 7-CH3
R1 ˆ 6-CH3
R2 ˆ H
R2 ˆ COCH3
R2 ˆ COCH3
Scheme 14102
bromoaniline, 4-methoxyaniline, 4-nitroaniline, 4-aminobenzoic acid). It was
found that the (4-amino-cinnolin-3-yl)-p-tolyl-methanones 4a±h could be readily
obtained via cyclization of 2a±g in the presence of AlCl3 and toluene under re¯ux
(Scheme 1). As to the mechanism, we propose that an intramolecular Friedel-
Crafts cyclization ®rst gives 3a±h. Then, condensation of the cyano group at
position 3 of 3a±h with toluene in the presence of the Lewis acid leads to the
corresponding ketones 4a±h in a reaction of the Hoesch type [17]. We found that
only ketone 4h could be isolated in the case of 2e instead of 4e due to a
1
demethylation by AlCl3. The structure of 4h was deduced from its H NMR
spectrum where the signal corresponding to the methoxy group was absent.
Strong electron withdrawing substituents, such as the nitro and the carboxylic
group in 2, retarded cyclization of 2 considerably, even at higher temperatures. In
these cases, 2 could be partially recovered.
Having now available the ketones 4 as starting materials, we continued our
efforts directed towards the synthesis of bi- and tricyclic systems containing a
pyridazine subunit [18±19]. The method described provides a possible starting
point for the synthesis of many new fused cinnoline derivatives. Treatment of the
(4-amino-cinnolin-3-yl)-p-tolyl-methanones 4a±c with acetic anhydride under
re¯ux readily afforded the 4N-acetylated ketones 5a±c which underwent
cyclization to the pyrido[3,2-c]cinnoline derivatives 6a±c in dimethylformamide
solution in the presence of potassium carbonate at re¯ux temperature.
Treatment of 6c with POCl3 and P2S5 under re¯ux afforded the corresponding
2-chloro-pyrido[3,2-c]cinnoline 7 and pyrido[3,2-c]cinnoline-2-thione 8. Interest-
ingly enough, 6c was regioselectively methylated in position 1 upon treatment with
CH3I/KOH to yield 9 (Scheme 3).
Scheme 3

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A. M. Amer et al.
Scheme 4
Scheme 5
The reaction of 4c with malononitrile was carried out under basic conditions to
give the corresponding cyclic product 10. Finally, our study was extended to
prepare the pyrimido[5,4-c]cinnoline derivatives 11±14 with the aim to improve
the antibacterial activity relative to the same systems prepared earlier [8]. When 4c
was reacted with formamide, urea, or potassium isothiocyanate, the cinnolines 11,
12, and 13 were obtained (Scheme 4).
Treatment of cinnoline 5c with ammonium acetate in presence of NH3 afforded
2,9-dimethyl-4-(p-tolyl)-pyrimido[5,4-c]cinnoline 14 (Scheme 5). The structures
of all novel compounds were con®rmed by their elemental and spectroscopic data.
Experimental
Melting points were measured on a Ko¯er hot stage microscope (Reichert, Vienna) and are
uncorrected. 1H and 13C NMR spectra were recorded on a Bruker DPX 200 spectrometer; chemical
shifts are given in ꢀ units relative to internal TMS at 295 K. IR spectra were obtained on Biorad FT-
IR-45 instrument. All experiments were carried out with exclusion of moisture. For all newly
synthesized compounds, satisfactory elemental analyses were obtained.
Preparation of aryl-hydrazonomalononitriles 2; general procedure
To a well stirred solution of 6.60 g malononitrile (100 mmol) in 130 cm3 ethanol and 20 cm3 H2O
containing 10 g CH3COONa, the diazonium salt (100 mmol) prepared in the usual way from the

Cinnoline Chemistry
1413
corresponding anilines was added gradually with stirring during 20 min at 0±5ꢀC. The product was
®ltered, washed with water, dried, and recrystallized from the given solvent.
2-Tolyl-hydrazonomalononitrile (2a; C10H8N4)
Prepared from o-toluidine; crystallization from ethanol gave ®ne orange crystals (95%); m.p.: 96ꢀC;
1
IR (KBr): 3350 br, 3199, 2920 br, 2218, 1610, 1532, 1480 cm 1; H NMR (CDCl3): 2.42 (s, CH3),
7.18±7.32 (m, 3Har), 7.51±7.55 (d, 1Har), 9.65 (br, NH) ppm.
3-Tolyl-hydrazonomalononitrile (2b; C10H8N4)
Prepared from m-toluidine; crystallization from ethanol gave ®ne yellow crystals (98%); m.p.:
198ꢀC; IR (KBr): 3350 br, 3198, 2920 br, 2218, 1608, 1474 cm 1; 1H NMR (CDCl3): 2.41 (s, CH3),
7.10±7.16 (m, 3Har), 7.32 (s, 1Har), 9.85 (br, NH) ppm; 13C NMR (CDCl3): 31.01 (CH3), 95.75 (CH),
117.97, 122.23, 122.51, 126. 74, 137.28, 141.84. 154.00, 154.59 (aryl, 2CN) ppm.
4-Tolyl-hydrazonomalononitrile (2c; C10H8N4)
Prepared from p-toluidine; crystallization from methanol gave ®ne yellow crystals (98%); m.p.: 158±
1
160ꢀC; IR (KBr): 3350 br, 3198, 2921, 2218, 1608, 1480 cm 1; H NMR (CDCl3): 2.37 (s, CH3),
7.22 (s, 4Har), 9.90 (br, NH) ppm; 13C NMR (CDCl3): 30.55 (CH3), 95.30 (CH), 118.09, 121.97,
125.58, 140.01, 146.58, 147.10 (aryl, 2CN) ppm.
4-Bromophenyl-hydrazonomalononitrile (2d; C9H5BrN4)
Prepared from 4-bromoaniline; crystallization from ethyl acetate gave ®ne crystals (80%); m.p.:
1
190ꢀC; IR (KBr): 3343 br, 3195, 2218, 1610, 1480, 1450 cm 1; H NMR (CDCl3): 7.19±7.23 (d,
1
2Har), 7.54±7.58 (d, 2Har), 9.75 (br, NH) ppm; H NMR (CDCl3/DMSO-d6): 7.29±7.42 (m, 4Har),
12.76 (br, NH) ppm; 13C NMR (CDCl3/DMSO-d6): 94.82 (CH), 119.23, 123.31, 127.95, 128.23,
141.87, 150.33 (aryl, 2CN) ppm.
4-Methoxyphenyl-hydrazonomalononitrile (2e; C10H8N4O)
Prepared from 4-methoxyaniline; crystallization from petroleum ether gave greenish yellow crystals
(93%); m.p.: 136±138ꢀC; IR (KBr): 3353 br, 3194, 2950 br, 2220, 1610, 1477, 1410 cm 1; 1H NMR
(CDCl3): 3.85 (s, OCH3), 6.94±6.98 (d, 2Har), 7.27±7.32 (d, 2Har), 10.08 (br, NH) ppm; 13C NMR
(CDCl3): 55.63 (OCH3), 84.67 (CH), 109.00, 112.76, 115.05, 117.58, 129.32, 158.49 (aryl,
2CN) ppm.
4-Nitrophenyl-hydrazonomalononitrile (2f; C9H5N5O2)
Prepared from 4-nitroaniline; crystallization from ethanol gave ®ne yellow crystals (75%); m.p.:
1
180ꢀC; IR (KBr): 3329 br, 3198, 2223, 1610, 1527, 1478 cm 1; H NMR (CD3OD): 7.61±7.65 (d,
2Har), 8.29±8.33 (d, 2Har) ppm; 1H NMR (DMSO-d6): 7.58±7.62 (d, 2Har), 8.22±8.27 (d, 2Har) ppm;
13C NMR (DMSO-d6): 98.51 (CH), 119.48, 123.84, 126.71, 135.52, 153.91, 156.84 (aryl, 2CN) ppm.
4-Phenyl-hydrazonomalononitrile-carboxylic acid (2g; C10H6N4O2)
Prepared from 4-amino-benzoic acid; crystallization from acetic acid gave ®ne yellow crystals
(87%); m.p.: 260±262ꢀC; IR (KBr): 3330 br, 3197, 2950 br, 2222, 1610, 1480, 1450 cm 1; 1H NMR

1414
A. M. Amer et al.
(DMSO-d6): 7.49±7.53 (d, 2Har), 7.93±7.97 (d, 2Har), 13.00 (br, OH) ppm; 13C NMR (DMSO-d6):
96.63 (CH), 119.64, 124.04, 126.13, 140.96, 154.81, (aryl, 2CN), 176.65 (C=O) ppm.
Preparation of (4-Amino-cinnolin-3-yl)-p-tolyl-methanones 4; general procedure
A mixture of 10 mmol aryl hydrazonomalononitrile 2 and 2.50 g AlCl3 (0.04 mmol) in 150 cm3
toluene was heated under re¯ux for 5 h with stirring and then allowed to cool to room temperature.
The resulting product was poured on 500 cm3 cold water and left for 2 h. The resulting solid product
was collected by ®ltration, washed with petroleum ether (40±60ꢀ), and crystallized from the solvent
given.
(4-Amino-8-methyl-cinnolin-3-yl)-p-tolyl-methanone (4a; C17H15N3O)
Prepared from 2a; crystallization from methanol gave greenish white crystals (89%); m.p.: 160ꢀC;
1
IR (KBr): 3340 br, 3131, 2974, 1631, 1606, 1566, 1526, 1474 cm 1; H NMR (CDCl3): 2.41 (s,
CH3), 3.00 (s, CH3), 7.24±7.27 (d, 2Har), 7.51±7.58 (t, 1Har), 7.66±7.69 (d, 1Har), 7.80±7.84 (d, 1Har)
7.98±8.02 (d, 2Har) ppm; 13C NMR (CDCl3): 27.79 (CH3), 31.21 (CH3), 125.40, 127.53, 137.77,
138.10, 138.54, 140.70, 142.28, 143.14, 145.67, 148.20, 151.89, 154.86 (aryl), 206.59 (C=O) ppm.
(4-Amino-7-methyl-cinnolin-3-yl)-p-tolyl-methanone (4b; C17H15N3O)
Prepared from 2b; crystallization from methanol gave white crystals (89%); m.p.: 270±272ꢀC; IR
;
1H NMR
1
(KBr): 3337 br, 3125, 2973, 2920, 1630, 1566, 1526, 1474, 1422, 1410, 1385 cm
(DMSO-d6): 2.40 (s, CH3), 2.57 (s, CH3), 7.30±7.34 (d, 2Har), 7.60±7.65 (d, 1Har), 7.78±7.82 (d,
2Har), 8.03 (s, 1Har), 8.43 (d, 1Har), 8.47 (br, NH2) ppm; 13C NMR (DMSO-d6): 31.16 (CH3), 31.36
(CH3), 123.87, 132.70, 137.34, 138.22, 140.66, 140.93, 143.13, 146.46, 151.57, 153.24, 155.55,
157.33 (aryl), 205.70 (C=O) ppm.
(4-Amino-6-methyl-cinnolin-3-yl)-p-tolyl-methanone (4c; C17H15N3O)
Prepared from 2c; crystallization from ethanol gave faint yellowish white crystals (89%); m.p.: 288±
1
290ꢀC; IR (KBr): 3344, 3131, 3032, 2932, 1630, 1610, 1560, 1528, 1474 cm 1; H NMR (DMSO-
d6): 2.39 (s, CH3), 2.54 (s, CH3), 7.28±7.32 (d, 2Har), 7.77±7.80 (d, 3Har), 8.12±8.16 (d, 1Har), 8.34
(s, 1Har), 8.80 (br, NH2) ppm; 13C NMR (DMSO-d6): 31.16 (CH3), 31.52 (CH3), 125.92, 131.57,
135.44, 138.22, 138.63, 140.68, 143.01, 146.53, 149.12, 151.56, 155.11, 156.12 (aryl), 205.91
(C=O) ppm.
(4-Amino-6-bromo-cinnolin-3-yl)-p-tolyl-methanone (4d; C16H12BrN3O)
Prepared from 2d; crystallization from ethanol gave yellow crystals (89%); m.p.: >360ꢀC; IR (KBr):
3310, 3228, 3030, 2920, 1635, 1590, 1550, 1530 cm 1; 1H NMR (CD3OD): 2.46 (s, CH3), 7.37±7.41
(d, 2Har), 7.55±7.68 (m, 5Har) ppm; 1H NMR (DMSO-d6): 2.39 (s, CH3), 7.35±7.39 (d, 2Har), 7.56±
7.74 (m, 5Har), 8.34 (s, 1Har), 8.80 (br, NH2) ppm.
(4-Amino-6-hydroxy-cinnolin-3-yl)-p-tolyl-methanone (4h; C16H13N3O2)
Prepared from 2e; crystallization from ethanol gave orange yellow crystals (89%); m.p.: 208±210ꢀC;
IR (KBr): 3563 br, 3380, 3030, 1637, 1600, 1570, 1520, 1416 cm 1; 1H NMR (CDCl3): 2.46 (s, CH3),
5.18 (br, NH2), 6.89±6.93 (d, 2Har), 7.33±7.37 (d, 2Har), 7.41 (br, OH), 7.67±7.71 (m, 3Har) ppm.

Cinnoline Chemistry
1415
Acetylation of (4-amino-cinnolin-3-yl)-p-tolyl-methanones 4; general procedure
A solution of 2.77 g of 4a±c (10 mmol) in 15 cm3 acetic anhydride was heated to boiling, which
resulted a dark yellow solution. Within 5 min, needles began to form. After cooling in ice, the
product was ®ltered off to give pure 5a or a mixture of the 4-diacetylaminocinnolines 5b,c,
respectively. The latter crude product was used for the next step without further puri®cation.
(4-Acetamido-8-methyl-cinnolin-3-yl)-p-tolyl-methanone (5a: C21H20N3O2)
Prepared from 4a; crystallization from acetic acid and H2O gave yellowish crystals (85%); m.p.:
160ꢀC; IR (KBr): 3446, 3130, 2932, 1712, 1690, 1625, 1580, 1490 cm 1; 1H NMR (CDCl3): 2.29 (s,
COCH3), 2.43 (s, CH3), 2.70 (s, CH3), 7.29±7.82 (m, 5Har), 8.01 (d, 2Har) ppm.
(4-Diacetamido-7-methyl-cinnolin-3-yl)-p-tolyl-methanone (5b; C23H22N3O3)
Prepared from 4b; crystallization from ethanol gave yellowish crystals (57%); m.p.: 130ꢀC; IR
(KBr): 3130, 2940, 1737, 1698, 1623, 1580, 1474 cm 1; 1H NMR (CDCl3): 2.32 (s, 2COCH3), 2.47
(s, CH3), 2.73 (s, CH3), 7.30 (d, 2Har), 7.79±7.83 (m, 3Har), 8.52 (s, Har), 8.80 (d, Har) ppm.
(4-Diacetamido-6-methyl-cinnolin-3-yl)-p-tolyl-methanone (5c; C23H22N3O3)
Prepared from 4c; crystallization from ether gave faint reddish crystals (65%); m.p.: 125ꢀC; IR
1
(KBr): 3130, 2932, 1739, 1697, 1624, 1580, 1490 cm 1; H NMR (CDCl3): 2.32 (s, 2COCH3),
2.43 (s, CH3), 2.66 (s, CH3), 7.29 (d, 2Har), 7.63 (s, Har), 7.78 (m, 3Har), 8.61 (d, Har) ppm;
13C NMR (CDCl3): 31.42 (CH3), 32.16 (CH3), 36.03 (2COCH3), 129.07, 134.38, 138.56, 138.78,
140.06, 140.81, 142.73, 142.85, 144.48, 154.78, 159.57, 160.82 (aryl), 181.85 (2C=O), 201.59
(C=O) ppm.
Preparation of 1,2-dihydro-4-(p-tolyl)-2-oxopyrido[3,2,c]cinnolines 6; general procedure
To a solution of 3.20 g of crude amide 5a±c (10 mmol) in 25 cm3 dry DMF, 1.4 g K2CO3 were added
and the mixture was heated for 2 h. After concentration, the residue was treated with 30 cm3 H2O.
The pH was adjusted to 3±4 by addition of 2 N HCl, and the precipitated solid was collected, washed
with H2O, and recrystallized from the given solvent.
1,2-Dihydro-7-methyl-4-(p-tolyl)-2-oxopyrido[3,2-c]cinnoline (6a; C19H15N3O)
Prepared from 5a; crystallization from ethanol gave yellowish white crystals (89%); m.p.: >350ꢀC;
IR (KBr): 3402, 3083, 2926, 1655, 1554, 1492 cm 1; 1H NMR (CDCl3): 2.44 (s, CH3), 3.01 (s, CH3),
7.07 (s, Har), 7.29±7.82 (m, 5Har), 8.01 (d, 2Har), 13.20 (br, NH) ppm.
1,2-Dihydro-8-methyl-4-(p-tolyl)-2-oxopyrido[3,2-c]cinnoline (6b; C19H15N3O)
Prepared from 5b; crystallization from DMF/H2O gave yellowish white crystals (89%); m.p.: 348±
350ꢀC; IR (KBr): 3400, 3144, 3082, 2926, 1656, 1552, 1491 cm 1; 1H NMR (CDCl3): 2.49 (s, CH3),
2.69 (s, CH3), 7.07 (s, Har), 7.35±7.39 (d, 2Har), 7.77±7.81 (d, 3Har), 8.34 (s, 1Har), 8.85±8.89 (d,
1Har), 13.50 (br, NH) ppm; 13C NMR (CDCl3): 31.02 (CH3), 31.57 (CH3), 121.93, 130.74, 131.39,
138.62, 138.74, 139.92, 141.49, 141.82, 143.36, 149.32, 152.06, 158.06, 163.61 (aryl), 174.02
(C=O) ppm.

1416
A. M. Amer et al.
1,2-Dihydro-9-methyl-4-(p-tolyl)-2-oxopyrido[3,2-c]cinnoline (6c; C19H15N3O)
Prepared from 5c; crystallization from ethanol gave white crystals (89%); m.p.: >350ꢀC; IR (KBr):
1
3402, 3143, 3082, 2926, 1656, 1552, 1492 cm 1; H NMR (CDCl3): 2.49 (s, CH3), 2.75 (s, CH3),
7.07 (s, 1Har), 7.36±7.40 (d, 2Har) 7.77±7.84 (d, 3Har), 8.51±8.56 (d, 1Har), 8.68 (s, 1Har), 13.10 (br,
NH) ppm.
2-Chloro-9-methyl-4-(p-tolyl)-pyrido[3,2-c]cinnoline (7; C19H14ClN3)
A mixture of 0.30 g 6c (1 mmol) and 10 cm3 POCl3 was re¯uxed for 3 h. Excess of POCl3 was
removed under reduced pressure, and the residue was poured on crushed ice and 25% NH3 under
vigorous stirring. The green solid thus obtained was washed with water and recrystallized from
acetic acid to give green crystals.
1
Yield: 55%; m.p.: >360ꢀC; IR (KBr): 3085, 2927, 1628, 1552, 1489 cm 1; H NMR (CDCl3):
2.49 (s, CH3), 2.75 (s, CH3), 7.05 (s, 1Har), 7.33±7.40 (d, 2Har), 7.75±7.84 (d, 3Har), 8.51±8.56 (d,
1Har), 8.66 (s, 1Har) ppm.
1,2-Dihydro-9-methyl-4-(p-tolyl)-pyrido[3,2-c]cinnoline-2-thione (8; C19H15N3S)
A mixture of 0.30 g 6c (1 mmol), 0.15 g P2S5, and 20 cm3 pyridine was re¯uxed for 3 h. Excess of
pyridine was removed under reduced pressure, and the residue was poured on crushed ice and 15%
HCl under vigorous stirring. The yellow solid thus obtained was washed with water and
recrystallized from acetic acid to give yellow crystals.
Yield: 42%; m.p.: >350ꢀC; IR (KBr): 3420, 3085, 2927, 1628, 1563, 1500, 1210 cm 1; 1H NMR
(DMSO-d6): 2.42 (s, CH3), 2.57 (s, CH3), 6.91 (s, 1Har), 7.35 (d, 2Har), 7.81±7.85 (d, 3Har), 8.15 (d,
1Har), 8.40 (s, 1Har) ppm.
1,9-Dimethyl-4-(p-tolyl)-pyrido[3,2-c]cinnoline-2-one (9; C20H17N3O)
A mixture of 0.30 g 6c (1 mmol), 3 cm3 KOH (7%), and 0.30 cm3 CH3I was stirred overnight at room
temperature. The resulting precipitate was washed with H2O and recrystallized from acetonitrile to
give red crystals.
Yield: 32%; m.p.: >350ꢀC; IR (KBr): 3080, 2933, 1682, 1625, 1550, 1492 cm
;
1H NMR
1
(CDCl3): 2.49 (s, CH3), 2.75 (s, CH3), 4.36 (s, NCH3), 7.15 (s, 1Har), 7.35±7.40 (d, 2Har), 7.73±7.83
(d, 3Har), 8.50 (d, 1Har), 8.67 (s, 1Har) ppm.
2-Amino-9-methyl-4-(p-tolyl)-pyrido[3,2-c]cinnoline-3-nitrile (10; C20H15N5)
A mixture of 0.28 g 4c (1 mmol), 0.07 g malononitrile (1 mmol), and 15 cm3 pyridine was re¯uxed
for 6 h. Excess pyridine was removed under reduced pressure, and the residue was poured on crushed
ice and HCl under vigorous stirring. The solid obtained was washed with H2O and crystallized from
acetic acid to give colourless crystals.
Yield: 70%; m.p.: >350ꢀC; IR (KBr): 3380, 3300, 2932, 2218, 1625, 1553, 1489 cm 1; 1H NMR
(CDCl3): 2.49 (s, CH3), 2.75 (s, CH3), 5.51 (br, NH2), 7.35±7.40 (d, 2Har), 7.73±7.82 (d, 3Har), 8.50
(d, 1Har), 8.62 (s, 1Har) ppm.
9-Methyl-4-(p-tolyl)-pyrimido[5,4-c]cinnoline (11; C18H14N4)
A suspension of 0.28 g 4c (1 mmol) in 10 cm3 formamide was re¯uxed for 2 h. The solid obtained
was ®ltered, washed with H2O, and recrystallized from acetic acid to give pale green crystals.

Cinnoline Chemistry
1417
Yield: 43%; m.p.: 210ꢀC; IR (KBr): 3085, 2929, 1624, 1610, 1553, 1490 cm
;
1H NMR
1
(DMSO-d6): 2.42 (s, CH3), 2.58 (s, CH3), 7.34 (d, 2Har), 7.83±7.98 (m, 4Har), 8.68 (s, 1Har), 9.62 (s,
1Har) ppm.
1,2-Dihydro-9-methyl-4-(p-tolyl)-pyrimido[5,4-c]cinnoline-2-one (12; C18H14N4O)
A mixture of 0.28 g 4c (1 mmol), 0.09 g urea (1.5 mmol), and 10 cm3 acetic acid was re¯uxed for 2 h.
The solid obtained was ®ltered, washed with water, and recrystallized from acetic acid to give pale
yellow crystals.
1
Yield 82%; m.p.: 178ꢀC; IR (KBr): 3378, 3090, 1672, 1624, 1608, 1552, 1489 cm 1; H NMR
(DMSO-d6): 2.42 (s, CH3), 2.58 (s, CH3), 7.33±7.37 (d, 2Har), 7.82±7.87 (d, 3Har), 8.15±8.20 (d,
1Har), 8.51 (s, 1Har), 11.20 (br, NH, exchangable by D2O) ppm.
1,2-Dihydro-9-methyl-4-(p-tolyl)-pyrimido[5,4-c]cinnoline-2-thione (13; C18H14N4S)
0.28 g 4c (1 mmol) was dissolved in 10 cm3 glacial acetic acid and treated with a ®ltered solution of
0.08 g KSCN in 0.5 cm3 H2O for 1 h under cooling to maintain the reaction temperature below 15ꢀC.
The mixture was stirred overnight, and the precipitate was collected by ®lteration and washed with
H2O and then with acetone. Recrystallization from acetic acid gave pale yellow crystals.
Yield: 37%; m.p.: 170±171ꢀC; IR (KBr): 3310, 2931, 2630, 1622, 1610, 1553, 1490 cm
1
.
2,9-Dimethyl-4-(p-tolyl)-pyrimido[5,4-c]cinnoline (14; C19H16N4)
A suspension of 0.32 g 5c (1 mmol) in 1.52 g molten CH3COONH4 (20 mmol) was maintained at
155±160ꢀC for 3 h, during which time a vigorous stream of NH3 was passed through the mixture.
The resulting yellow solid was diluted with H2O, extracted with ether, and the ethereal solution was
washed with dilute aqueous NaOH and dried. Ether was removed under reduced pressure, and the
residue was recrystallized from methanol to give green crystals.
1
Yield 35%; m.p.: 185±187ꢀC; IR (KBr): 3087, 2933, 1627, 1608, 1582, 1489 cm 1; H NMR
(CDCl3): 2.49 (s, CH3), 2.75 (s, CH3), 2.88 (s, CH3), 7.41 (d, 2Har), 7.75±7.83 (d, 3Har), 8.50 (d,
1Har), 8.67 (s, 1Har) ppm.
Acknowledgements
È
A. M. Amer thanks his colleagues in the Institut fuÈr Chemie, Johannes Kepler Universitat Linz, for
their kind assistance during a fellowship sponsored by the Austrian Academic Exchange Service,
Vienna, Austria.
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Received February 17, 1999. Accepted March 1, 1999