On the chemistry of cinnoline V [1]. Reactions of 4-aminocinnolines with amines

Article abstract of DOI:10.1007/s00706-003-0084-3

We describe the effect of the solvent during the intra-cyclization of the arylhydrazonomalononitrile to obtain new and useful substituted cinnolines, namely 4-amino-3-cyanocinnolines and (4-amino-cinnolin-3-yl)arylmethanones. 4-Amino-3-cyano-5,7-dimethyl-cinnoline was treated with n-hexylamine, cyclohexylamine, and isopropylamine to yield the corresponding cinnoline-3-carboxamidine derivatives. Furthermore, 4-amino-3-cyano-5,7- dimethylcinnoline was reacted with diaminoethane to give 4-amino-5,7-dimethyl-3- (4,5-dihydroimidazol-2-yl)cinnoline. Treatment of 4-amino-3-cyano5,7- dimethylcinnoline with hydrazine hydrate provided 3-amino-7,9-dimethyl-1H- pyrazolo[4,3-c]cinnoline. Moreover, (4-aminocinnolin-3-yl)phenylmethanones were treated with hydrazine hydrate to give 3-phenyl-1H-pyrazolo[4,3-c]cinnolines. Finally, reactions of (4-aminocinnolin-3-yl)phenylmethanone with 3,5-dimethylaniline, phenyl hydrazine, hydroxylamine, and phenyl isothiocyanate are discussed. Chemical and spectroscopic evidence for the structures of the new compounds is presented. Springer-Verlag 2003.

Full text of DOI:10.1007/s00706-003-0084-3

Monatshefte f€ur Chemie 135, 595–604 (2004)
DOI 10.1007/s00706-003-0084-3
On the Chemistry of Cinnoline V ½1ꢀ.
Reactions of 4-Aminocinnolines with Amines
ꢁ
Atef M. Amer , Mathat M. El-Mobayed, and Sherif Asker
Chemistry Department, Faculty of Science, Zagazig University, Zagazig, Egypt
Received June 24, 2003; accepted June 24, 2003
Published online December 30, 2003 # Springer-Verlag 2003
Summary. We describe the effect of the solvent during the intra-cyclization of the arylhydrazonoma-
lononitrile to obtain new and useful substituted cinnolines, namely 4-amino-3-cyanocinnolines and
(4-amino-cinnolin-3-yl)arylmethanones. 4-Amino-3-cyano-5,7-dimethyl-cinnoline was treated with n-
hexylamine, cyclohexylamine, and isopropylamine to yield the corresponding cinnoline-3-carboxami-
dine derivatives. Furthermore, 4-amino-3-cyano-5,7-dimethylcinnoline was reacted with diaminoethane
to give 4-amino-5,7-dimethyl-3-(4,5-dihydroimidazol-2-yl)cinnoline. Treatment of 4-amino-3-cyano-
5,7-dimethylcinnoline with hydrazine hydrate provided 3-amino-7,9-dimethyl-1H-pyrazolo[4,3-c]cin-
noline. Moreover, (4-aminocinnolin-3-yl)phenylmethanones were treated with hydrazine hydrate
to give 3-phenyl-1H-pyrazolo[4,3-c]cinnolines. Finally, reactions of (4-aminocinnolin-3-yl)phenyl-
methanone with 3,5-dimethylaniline, phenyl hydrazine, hydroxylamine, and phenyl isothiocyanate
are discussed. Chemical and spectroscopic evidence for the structures of the new compounds is
presented.
Keywords. Cycloadditions; Hydrazones; Cinnolines; Pyrazoles; Amines.
Introduction
Recent studies have shown that cinnolines and their derivatives exhibit various
biological activities [2–5] such as antihypertensive, antihromobotic, antitumor,
antisecretory, and bactericidal activities. 4-Aminocinnolines have recently become
of importance due to their antibacterial, antihistaminic, antidepressive, and sedative
properties [6–9]. Our group has recently been interested in the synthesis of deri-
vatives containing the cinnoline system, in order to evaluate their antitumor activity
[10–12]. We have continued our investigations by expanding the structure activity
relationship studies of new series of cinnoline derivatives. Now we synthesized a
series of new substituted 4-aminocinnoline derivatives, 4-aminocinnoline-3-car-
boxamidines, 3-(4,5-dihydroimidazol-2-yl)cinnoline, and pyrazolo[4,3-c]cinno-
ꢁ
Corresponding author. E-mail: amer_1eg@yahoo.com

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A. M. Amer et al.
lines with respect to a projected investigation of their utility as pharmacological
agents.
Results and Discussion
We previously have described the synthesis of (4-aminocinnolin-3-yl)-p-tolylme-
thanones from arylhydrazone derivatives [11]. We now report the results of experi-
ments designed to explore the scope and the limitations of this procedure as a
synthetic method for the formation of (4-aminocinnolin-3-yl)arylmethanones bear-
ing various substitutents. In addition, we studied the effect of the solvent on the
cyclization of the arylhydrazonomalononitriles 1a and 1b to obtain new and useful
substituted cinnolines at position three 3a–3h. For this purpose, arylhydrazonoma-
lononitriles 2a and 2b were synthesized in good yield by treatment of malononitrile
with diazonium salts obtained from the corresponding aniline or 3,5-dimethylaniline
as shown in Scheme 1.
It was found that 4-amino-3-cyanocinnoline 2a and 2b and (4-amino-cinnolin-
3-yl)phenylmethanone 3a and 3b were readily obtained via intracyclization of 1a
and 1b in the presence of AlCl3 and benzene under reflux. Only compound 2a was
obtained under similar conditions by Gewald [13]. The structure of 3a was eluci-
dated on the basis of its spectral data. The IR spectrum of 3a showed no absorption
band due to a cyano group, the 13C NMR spectrum gave a signal at ꢀ ¼ 196.43 for
the carbonyl group, and the mass spectra of 3a gave m=z ¼ 249.3 (100%) [M]þ and
172.2 [M-Ph]þ. Compound 3a was only obtained when the reaction time was
increased to 5 h. From the mechanistic standpoint, intramolecular Friedel-Craft
cyclization first gives 2a and 2b. Then, condensation of the cyano group at position
3 of 2a and 2b with benzene in the presence of the Lewis acid leads to the
Scheme 1

On the Chemistry of Cinnoline V
597
corresponding ketones 3a and 3b by a Hoesch type [14] reaction. Other solvents
instead of benzene, such as toluene, ethylbenzene, o-xylene, m-xylene, p-xylene
and 1,3,5-trimethylbenzene under the same conditions via intracyclization of 1a
gave 3c–3h in excellent yields, but 2a was not detected (Scheme 1). Furthermore,
we found that in certain solvents such as carbon disulfide, dichloromethane, carbon
tetrachloride, pyridine, or without solvent the cyclization of 1a at lower or higher
temperature did not occur. In most of all these cases compound 1a could be par-
tially recovered.
It seemed to be of interest to study the reactivity of the cyano group in 2b
towards amines. The cyano group at position 3 in the cinnoline derivatives exhibits
the normal characteristic of this group [15]. Thus 2b condensed with n-hexylamine,
cyclohexylamine, and isopropylamine afforded 4-aminocinnoline-3-carbox-
amidines 4–6. When 2b was treated with diaminoethane the sole product was 7.
The formation of the product is accounted for by a stepwise nucleophilic attack of
the cyanide followed by cyclization and elimination of ammonia to give 7 as shown
in Scheme 2.
Treatment of 2b with hydrazine hydrate gave 3-amino-7,9-dimethyl-1H-pyr-
azolo[4,3-c]cinnoline 10. The mass spectrum of 10 exhibits a strong molecular ion
peak Mþ at m=e ¼ 213.2 which represents also the base peak. The mechanism
illustrated in Scheme 3 is proposed: hydrazine adds to the cyano group, then the
amino group of the hydrazone unit initiates an addition-elimination of the ring
amino-group.
Scheme 2
Scheme 3

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A. M. Amer et al.
Scheme 4
Scheme 5
Furthermore, the carbonyl group at position 3 in the cinnoline derivatives 3a
and 3b exhibits the normal characteristics of this group. Thus, the reaction of 3b
with 3,5-dimethylaniline or phenylhydrazine gave 11 and 12.
Finally, the reaction of 3a and 3b with hydrazine hydrate in ethanol and few
drops of concentrated hydrochloric acid under reflux condition afforded 13a and
13b. The first step is the nucleophilic attack at the carbonyl group rather than
substitution of the amino group [16] followed by cyclization to give the pyr-
azolo[4,3-c]cinnoline (Scheme 5). Similarly, the reaction of 3a and 3b with hydro-
xylamine hydrochloride afforded isoxazolo[4,3-c]cinnoline derivatives 15a and
15b in 20% yield via the oximes 14a and 14b. Treatment of 3a and 3b with phenyl
isothiocyanate at reflux temperature gave the corresponding N,N0-disubstituted
thioureas 16a and 16b.
Most of the compounds were tested in vitro at the national cancer institute using
their panel of 60 human tumor cell lines [17]. (4-Aminocinnoline-3-yl)arylmetha-
nones 3 demonstrated considerable cytotoxicity against a number of human cancer
cell lines.
Experimental
Melting points were measured on a Kofler hot stage microscope (Reichert, Vienna) and are uncor-
1
rected. H (200 MHz) and 13C NMR (50 MHz) spectra were recorded on a Bruker DPX 200 spectro-

On the Chemistry of Cinnoline V
599
meter; chemical shifts are given in ppm relative to internal TMS at 295 K. IR spectra were obtained on
a Biorad FT-IR-45 instrument. The mass spectra were measured on a Hewlett Packard 5989 AMS
instrument (79 eV, direct probe inlet). For all novel compounds satisfactory elemental analyses were
obtained.
Preparation of Arylhydrazonomalononitriles 1
To a well stirred solution of 6.66 g of malononitrile (100mmol) in 130cm3 of EtOH and 20cm3 of H2O
containing 10 g of CH3COONa, the diazonium salt (100 mmol) prepared in the usual way from the
corresponding aniline was added gradually with stirring during 20min at 0–5ꢂC. The product was
filtered, washed with H2O, dried, and recrystallized from the given solvent.
Phenylhydrazonomalononitrile (1a, C9H6N4)
Prepared from aniline; crystallization from benzene gave fine yellow crystals (87%); mp 143ꢂC [18];
1H NMR (CDCl3): ꢀ ¼ 7.30–7.42 (m, Ph), 10.24 (br, NH) ppm; 1H NMR (DMSO-d6): ꢀ ¼ 7.15–7.48
(m, Ph), 12.9 (br, NH) ppm; 13C NMR (CDCl3): ꢀ ¼ 86.42 (CH), 108.34, 112.21, 116.03, 126.82,
129.91, 139.70 (phenyl, 2CN) ppm.
3,5-Dimethylphenylhydrazonomalononitrile (1b, C11H10N4)
Prepared from 3,5-dimethylaniline; crystallization from EtOH gave fine yellow crystals (92%); mp
1
158–160ꢂC; IR (KBr): ꢁꢀ¼ 3212, 3162, 3082, 2916, 2228, 1622, 1595, 1562, 1487cmꢃ1; H NMR
(CDCl3): ꢀ ¼ 2.67 (s, 2CH3), 7.21 (s, 1Har), 7.26 (s, 2Har), 10.25 (br, NH) ppm.
General Procedure for the Preparation of 4-Aminocinnolin-3-carbonitrile
and (4-Aminocinnolin-3-yl)arylmethanone Derivatives
A mixture of 10 mmol of 1 and 2.50 g of AlCl3 (0.04 mmol) in 150 cm3 of a nonpolar aromatic solvent
(benzene, toluene, ethylbenzene, o-xylene, m-xylene, p-xylene, 1,3,5-trimethylbenzene) was heated
under reflux for 3 h with stirring and then allowed to cool to room temperature. The resulting product
was poured on 500 cm3 of cold H2O and left for 2 h. The resulting solid product was collected by
filtration, washed with petroleum ether (40–60ꢂC), and crystallized from the solvent given.
4-Aminocinnolin-3-carbonitrile (2a, C9H6N4)
Prepared from 1a; crystallization from CH3COOH gave greenish yellow crystals (36%); mp 312–
318ꢂC; IR (KBr): ꢁꢀ¼ 3371, 3341, 3102, 3081, 2227, 1681, 1616, 1571, 1516 cmꢃ1; 1H NMR (DMSO-
d6): ꢀ ¼ 7.74 (t, J ¼ 7.5 Hz, 1Har), 8.17 (br, NH2), 8.21 (d, J ¼ 8.4 Hz, 1Har), 8.41 (d, J ¼ 8.4 Hz, 1Har)
ppm; 13C NMR (DMSO-d6): ꢀ ¼ 114.26, 115.52, 116.90, 122.27, 128.75, 129.75, 132.96, 146.08,
147.61 (aryl, CN) ppm.
4-Amino-5,7-dimethylcinnolin-3-carbonitrile (2b, C11H10N4)
Prepared from 1b; crystallization from CHCl3 gave fine yellow crystals (52%); mp 270–275ꢂC; IR
(KBr): ꢁꢀ¼ 3498, 3308, 3214, 2895, 2217, 1612, 1561, 1495 cmꢃ1; 1H NMR (DMSO-d6): ꢀ ¼ 2.40 (s,
CH3), 2.78 (s, CH3), 7.20 (br, NH2), 7.28 (s, 1Har), 7.77 (s, 1Har) ppm; 13C NMR (DMSO-d6):
ꢀ ¼ 20.98 (CH3), 23.00 (CH3), 111.99, 116.83, 116.94, 125.99, 133.96, 134.49, 142.78, 146.81,
149.77 (aryl, CN) ppm.

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A. M. Amer et al.
(4-Aminocinnolin-3-yl)phenylmethanone (3a, C15H11N3O)
Prepared from 1a and benzene; crystallization from EtOH gave yellow crystals (34%); mp 150–153ꢂC;
IR (KBr): ꢁꢀ¼ 3563br, 3381, 3033, 1617, 1600, 1570, 1416cmꢃ1; 1H NMR (DMSO-d6): ꢀ ¼ 7.50–7.64
(m, 3Har), 7.77–7.98 (m, 4Har), 8.26 (d, J ¼ 8.0 Hz, 1Har), 8.58 (d, J ¼ 8.3 Hz, 1Har), 8.94 (br, NH2)
ppm; 13C NMR (DMSO-d6); ꢀ ¼ 115.95, 122.94, 127.59, 128.72, 128.97, 130.30, 131.26, 132.66,
132.99, 139.32, 145.62, 147.24 (aryl), 196.43 (C¼O) ppm; MS: m=z ¼ 249.3 (100%) [Mþ], 172.2
[Mþ-Ph], 171.2, 122.2, 105.05, 91.15, 63.13, 57.20, 55.20.
(4-Amino-5,7-dimethylcinnolin-3-yl)phenylmethanone (3b, C17H15N3O)
Prepared from 1b and benzene; crystallization from ethyl acetate gave yellow crystals (18%); mp
1
168ꢂC; IR (KBr): ꢁꢀ¼ 3445, 3251, 3190, 2900, 1620, 1587, 1515, 1431cmꢃ1; H NMR (DMSO-d6):
ꢀ ¼ 2.48 (s, CH3), 2.91 (s, CH3), 7.36 (s, 1Har), 7.46 (m, 3Har), 7.78 (d, J ¼ 7.7 Hz, 2Har), 7.87 (s, 1Har),
8.53 (br, NH2) ppm; 13C NMR (DMSO-d6): ꢀ ¼ 20.97 (CH3), 23.24 (CH3), 113.20, 126.26, 127.49,
130.17, 131.05, 133.20, 133.48, 135.43, 139.68, 142.69, 147.39, 149.21 (aryl), 196.95 (C¼O) ppm.
(4-Aminocinnolin-3-yl)-p-tolylmethanone (3c, C16H13N3O)
Prepared from 1a and toluene; crystallization from ethyl acetate gave white crystals (53%); mp 208–
218ꢂC [13]; IR (KBr): ꢁꢀ¼ 3310, 3228, 3030, 2920, 1635, 1590, 1550, 1530 cmꢃ1; 1H NMR (DMSO-
d6): ꢀ ¼ 2.40 (s, CH3), 7.30 (d, J ¼ 8.0 Hz, 2Har), 7.79 (m, 3Har), 7.90 (t, J ¼ 7.6 Hz, 1Har), 8.22 (d,
J ¼ 8.5 Hz, 1Har), 8.53 (d, J ¼ 8.0 Hz, 1Har), 9.19 (br, NH2) ppm; 13C NMR (DMSO-d6): ꢀ ¼ 21.10
(CH3), 115.93, 122.78, 128.17, 128.70, 128.87, 130.65, 132.53, 133.20, 136.41, 141.56, 145.38, 147.28
(aryl), 195.76 (C¼O) ppm.
(4-Aminocinnolin-3-yl)(4-ethylphenyl)methanone (3d, C17H15N3O)
Prepared from 1a and ethylbenzene; crystallization from MeOH gave fine yellow crystals (77%); mp
1
220–221ꢂC; IR (KBr): ꢁꢀ¼ 3344, 3284, 3131, 3032, 2932, 1630, 1616, 1560, 1528cmꢃ1; H NMR
(DMSO-d6): ꢀ ¼ 1.25 (t, J ¼ 7.5 Hz, CH3), 2.70 (q, J ¼ 7.5 Hz, CH2), 7.35 (d, J ¼ 7.8 Hz, 2Har), 7.86
(m, 3Har), 7.97 (t, J ¼ 7.8 Hz, 1Har), 8.25 (d, J ¼ 8.2, 1Har), 8.55 (d, J ¼ 8.2 Hz, 1Har), 8.87 (br, NH2)
ppm; 13C NMR (DMSO-d6): ꢀ ¼ 15.40 (CH3), 26.20 (CH2), 115.95, 122.82, 127.04, 128.74, 128.94,
130.73, 132.61, 133.20, 136.71, 145.41, 147.29, 147.71 (aryl), 196.00 (C¼O) ppm.
(4-Aminocinnolin-3-yl)(3,4-dimethylphenyl)methanone (3e, C17H15N3O)
Prepared from 1a and o-xylene; crystallization from EtOH gave yellowish white crystals (78%); mp
265ꢂC (dec); IR (KBr): ꢁꢀ¼ 3320, 3180, 3030, 2917, 1636, 1610, 1516, 1430cmꢃ1; 1H NMR (DMSO-
d6): ꢀ ¼ 2.27 (s, CH3), 2.29 (s, CH3), 7.10 (m, 1Har), 7.25 (d, J ¼ 7.8 Hz, 1Har), 7.65 (s, 1Har), 7.80–
8.00 (m, 1Har), 8.20 (d, J ¼ 7.8 Hz, 1Har), 8.60 (d, J ¼ 8.4 Hz, 1Har), 9.15 (br, NH2) ppm; 13C NMR
(DMSO-d6): ꢀ ¼ 19.40 (CH3), 19.57 (CH3), 116.23, 123.20, 126.55, 128.31, 128.85, 129.06, 131.43,
133.31, 133.40, 135.65, 136.29, 140.94, 145.51, 146.36 (aryl), 195.12 (C¼O) ppm.
(4-Aminocinnolin-3-yl)(2,4-dimethylphenyl)methanone (3f, C17H15N3O)
Prepared from 1a and m-xylene; crystallization from CH3COOH and H2O gave pale yellow crystals
1
(66%); mp 268–269ꢂC; IR (KBr): ꢁꢀ¼ 3310, 3200, 2920, 1641, 1612, 1425 cmꢃ1; H NMR (DMSO-
d6): ꢀ ¼ 2.26 (s, CH3), 2.37 (s, CH3), 7.13 (m, 2Har), 7.33 (d, J ¼ 7.6 Hz, 1Har), 7.87 (t, J ¼ 7.8 Hz,
1Har), 8.10–8.18 (m, 2Har), 8.71 (d, J ¼ 8.2 Hz, 1Har), 9.70 (s, NH2) ppm; 13C NMR (DMSO-d6):

On the Chemistry of Cinnoline V
601
ꢀ ¼ 19.64 (CH3), 20.92 (CH3), 116.69, 123.68, 124.24, 125.38, 129.26, 130.95, 133.00, 134.28, 135.84,
136.34, 139.63, 143.41, 147.69 (aryl), 198.42 (C¼O) ppm.
(4-Aminocinnolin-3-yl)(2,5-dimethylphenyl)methanone (3g, C17H15N3O)
Prepared from 1a and p-xylene; crystallization from ethyl acetate gave pale yellow crystals (49%); mp
260ꢂC (dec); IR (KBr): ꢁꢀ¼ 3274, 3155, 3029, 2910, 1637, 1602, 1514, 1416cmꢃ1; 1H NMR (DMSO-
d6): ꢀ ¼ 2.07 (s, CH3), 2.28 (s, CH3), 7.05 (m, 2Har), 7.16 (s, 1Har), 7.81 (t, J ¼ 7.6 Hz, 1Har), 7.98 (t,
J ¼ 7.6 Hz, 1Har), 8.08 (d, J ¼ 8.4 Hz, 1Har), 8.65 (d, J ¼ 8.4 Hz, 1Har), 9.75 (br, NH), 11.30 (br, NH)
ppm; 13C NMR (DMSO-d6): ꢀ ¼ 18.90 (CH3), 20.47 (CH3), 116.73, 120.45, 124.06, 127.82, 129.06,
129.77, 130.95, 132.64, 134.37, 135.20, 139.50, 149.79 (aryl), 187.63 (C¼O) ppm.
(4-Aminocinnolin-3-yl)(2,4,6-trimethylphenyl)methanone (3h, C18H17N3O)
Prepared from 1a and 1,3,5-trimethylbenzene; crystallization from DMF and EtOH gave orange
crystals (82%); mp 250–255ꢂC; IR (KBr): ꢁꢀ¼ 3384br, 3179, 2919, 1616, 1510, 1430cmꢃ1
;
1H
NMR (DMSO-d6): ꢀ ¼ 2.05 (s, 2CH3), 2.31 (s, CH3), 6.96 (s, 2Har), 7.90 (t, J ¼ 8.0 Hz, 1Har), 8.01
(m, 2Har), 8.65 (d, J ¼ 8.4 Hz, 1Har), 9.77 (br, NH), 11.29 (br, NH) ppm; 13C NMR (DMSO-d6):
ꢀ ¼ 19.82 (2CH3), 21.15 (CH3), 117.08, 120.6, 124.18, 128.33, 129.97, 133.10, 134.24, 136.16, 138.00,
138.09, 140.42, 150.34 (aryl), 188.36 (C¼O) ppm.
Reaction of 4-Amino-5,7-dimethylcinnoline-3-carbonitrile (2b) with Aliphatic Amines
A mixture of 1.00 g of 2b (5mmol) and 6 mmol of an aliphatic amine in 10cm3 of CH3OH was heated
at reflux temperature for 5 h. Then the solvent was removed under reduced pressure to give a yellow
orange solid which was recrystallised from the given solvent.
4-Amino-5,7-dimethyl-N-hexylcinnoline-3-carboxamidine (4, C17H25N5)
Prepared from n-hexylamine; crystallization from ethyl acetate gave buff crystals (85%); mp 102–
105ꢂC; IR (KBr): ꢁꢀ¼ 3533, 3443, 3348, 2922, 2800, 1628, 1496 cmꢃ1; 1H NMR (DMSO-d6): ꢀ ¼ 0.85
(t, J ¼ 12Hz, CH3), 1.30 (m, 3CH2), 1.64 (m, CH2), 2.42 (s, CH3), 2.85 (s, CH3), 3.15–3.32 (m, CH2
and NH2), 6.77 (br, NH2), 7.16 (s, 1Har), 7.71 (s, 1Har) ppm; 13C NMR (DMSO-d6): ꢀ ¼ 13.97 (CH3),
20.83 (CH3), 23.49 (CH3), 22.16, 26.98, 30.82, 31.22, 47.19 (5CH2), 113.65, 125.55, 129.24, 132.06,
134.60, 142.77, 145.01, 150.29, 156.87 (aryl and C¼N) ppm; MS: m=z ¼ 299 [Mþ], 228, 199, 169,
144, 115, 91, 77, 43 (100%).
4-Amino-5,7-dimethyl-N-cyclohexylcinnoline-3-carboxamidine (5, C17H23N5)
Prepared from cyclohexylamine; crystallization from EtOH gave yellow crystals (77%); mp 180–182ꢂC;
1
IR (KBr): ꢁꢀ¼ 3522, 3431, 3277, 3150, 1620, 1530 cmꢃ1; H NMR (DMSO-d6): ꢀ ¼ 1.28–1.81 (m,
5CH2), 2.42 (s, CH3), 2.85 (s, CH3), 3.32 (s, CH), 6.82 (br, NH2), 7.16 (s, 1Har), 7.71 (s, 1Har), 12.15
(br, NH) ppm; 13C NMR (DMSO-d6): ꢀ ¼ 20.88 (CH3), 23.54 (CH3), 24.28, 25.69, 33.34, 53.19 (cyclo-
hexane), 113.68, 125.58, 129.33, 132.10, 134.66, 140.11, 145.19, 150.30, 155.16 (aryl and C¼N) ppm.
4-Amino-5,7-dimethyl-N-isopropylcinnoline-3-carboxamidine (6, C14H19N5)
Prepared from isopropylamine; crystallization from ethyl acetate gave orange yellow crystals (46%);
mp 170–173ꢂC; IR (KBr): ꢁꢀ¼ 3530, 3440, 3320, 1628, 1510 cmꢃ1; 1H NMR (DMSO-d6): ꢀ ¼ 1.46 (d,
J ¼ 7.0 Hz, CH3), 2.44 (s, CH3), 2.86 (s, CH3), 3.25 (m, CH), 7.17 (s, 1Har), 7.73 (s, 1Har) ppm;

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13C NMR (DMSO-d6): ꢀ ¼ 13.96 (2CH3), 20.89 (CH3), 23.55 (CH3), 40.32 (CH), 113.60, 125.57,
129.25, 132.12, 134.65, 140.16, 145.07, 150.33, 157.43 (aryl and C¼N) ppm.
4-Amino-5,7-dimethyl-3-(4,5-dihydroimidazol-2-yl)cinnoline (7, C13H15N5)
Prepared from 1,2-diaminoethane; crystallization from MeOH gave white crystals (54%); mp 228–
1
230ꢂC; IR (KBr): ꢁꢀ¼ 3417, 3395, 3107, 1621, 1494 cmꢃ1; H NMR (DMSO-d6): ꢀ ¼ 2.46 (s, CH3),
2.88 (s, CH3), 3.18 (s, CH2), 3.94 (t, J ¼ 9.4 Hz, CH2), 7.24 (s, NH2), 7.41 (s, 1Har), 7.79 (s, 1Har),
10.48 (br, NH); signals at 7.24 and 10.48 disappear by addition of D2O; 13C NMR (DMSO-d6):
ꢀ ¼ 20.94 (CH3), 23.48 (CH3), 43.01 (CH2), 55.05 (CH2), 113.07, 125.81, 128.19, 132.49, 134.70,
140.72, 143.98, 150.10, 165.52 (aryl and C¼N) ppm.
3-Amino-7,9-dimethylpyrazolo[4,3-c]cinnoline (10, C11H11N5)
A solution of 1.94 g of 2b (10 mmol) in 5 cm3 of hydrazine hydrate (99%) was kept at room tempera-
ture for one day. The solid product obtained was filtered off and crystallized from ethyl acetate to give
yellow crystals (82%); mp 306–308ꢂC; IR (KBr): ꢁꢀ¼ 3460, 3380, 3138, 2932, 1630, 1580,
1
1490 cmꢃ1; H NMR (CDCl3): ꢀ ¼ 2.43 (s, CH3), 2.87 (s, CH3), 5.34 (br, NH), 7.17 (s, 1Har), 7.71
(s, 1Har) ppm; MS: m=z ¼ 213.2 (100%) [Mþ], 196.05 [Mþ-NH3], 170.15 [Mþ-(CH3 þ CNꢃ)], 157.15,
142.15, 128.15, 115.2, 77.05, 51.15.
Reaction of 3b with Dimethylaniline or Phenylhydrazine
A solution of 2.78 g of 3b (10 mmol) and 1.21g of 3,5-dimethylaniline (10 mmol) or 1.05g of
phenylhydrazine (10 mmol) was refluxed for 8 h by using a Dean Stark apparatus and allowed to cool.
The solid product was filtered off and crystallized from DMF=H2O to give 11 and 12.
4-Amino-5,7-dimethyl-N-(3,5-dimethylphenyl)cinnoline-3-carboxamidine (11, C25H24N4)
Prepared from 3,5-dimethylaniline; crystallization from DMF=H2O gave a yellow powder (75%); mp
1
171ꢂC; IR (KBr): ꢁꢀ¼ 3438, 3239, 3185, 2977, 1590, 1549, 1519, 1428cmꢃ1; H NMR (DMSO-d6):
ꢀ ¼ 2.60 (s, 2CH3), 2.93 (s, CH3), 2.98 (s, CH3), 7.38 (s, 1Har), 7.50 (m, 5Har and NH), 7.88 (s, 1Har),
8.34 (s, 1Har), 8.45 (br, NH), 8.62 (d, J ¼ 7.5 Hz, 2Har) ppm.
(4-Amino-5,7-dimethylcinnolin-3-yl)phenylmethanphenylhydrazone (12, C23H21N5)
Prepared from phenylhydrazine; crystallization from DMF=H2O gave buff crystals (60%); mp
1
>300ꢂC; H NMR (DMSO-d6): ꢀ ¼ 2.62 (s, CH3), 2.97 (s, CH3), 6.70 (br, NH), 7.50–8.00 (m,
12Har), 8.42 (s, NH2) ppm.
Reaction of 3a or 3b with Hydrazine Hydrate
A solution of 3a or 3b (10 mmol), hydrazine hydrate (99%, 40mmol) and 3 cm3 of HCl in 30cm3 of
EtOH was refluxed for 30 h. After diluting with 20cm3 of H2O it was cooled. The precipitate was
filtered off to give 13a and 13b.
3-Phenyl-1H-pyrazolo[4,3-c]cinnoline (13a, C15H10N4)
Prepared from 3a; crystallization from EtOH gave a yellow powder (64%); mp 295ꢂC; IR (KBr):
ꢁꢀ¼ 3375, 3096, 1619, 1599, 1482 cmꢃ1; 1H NMR (DMSO-d6): ꢀ ¼ 7.47 (m, 3Har), 7.99 (m, 2Har), 8.44
(d, J ¼ 8.5 Hz, 1Har), 8.61 (m, 3Har), 13.65 (br, NH) ppm.

On the Chemistry of Cinnoline V
603
7,9-Dimethyl-3-phenyl-1H-pyrazolo[4,3-c]cinnoline (13b, C17H14N4)
1
Prepared from 3b; crystallization from EtOH gave a yellow powder (72%); mp >300ꢂC; H NMR
(DMSO-d6): ꢀ ¼ 2.60 (s, CH3), 2.95 (s, CH3), 7.58 (m, 5Har), 8.32 (s, 1Har), 8.66 (s, 1Har), 14.12 (br,
NH) ppm; 1H NMR (CDCl3): ꢀ ¼ 2.55 (s, CH3), 2.99 (s, CH3), 7.26 (s, 1Har), 7.46 (m, 3Har), 7.96 (m,
3Har) ppm.
Reaction of 3a or 3b with Hydroxylamine Hydrochloride
A solution of 3a or 3b (10 mmol) and NH2OHꢄ HCl (60 mmol) in 20cm3 of EtOH was refluxed for
20h, left to cool, 20cm3 of H2O were added, and the mixture was cooled. The precipitate formed was
filtered off and dried to give 15a and 15b. The mother liquor was concentrated under reduced pressure
to a volume of 20 cm3, neutralized with solid NaHCO3, extracted with CHCl3, and dried (Na2SO4).
After evaporation of the solvent under vacuum the solid was recrystallized from dioxan to give the
oximes 14a and 14b. Thermal conversion of 14a to 15a occured by heating 15mg of the crude oxime
at 150ꢂC for 3 h under vacuum. Pure 15a (50%) was obtained by sublimation.
(4-Aminocinnolin-3-yl)phenylmethanoxime (14a, C15H12N4O)
Prepared from 3a; crystallization from dioxan gave yellow crystals (61%); mp 210ꢂC; IR (KBr):
1
ꢁꢀ¼ 3310, 2786, 1622, 1565, 1000 cmꢃ1; H NMR (DMSO-d6): ꢀ ¼ 7.50 (m, 5Har), 8.21 (m, 2Har),
8.35 (d, J ¼ 8.6 Hz, 1Har), 8.75 (d, J ¼ 8.6 Hz, 1Har), 9.00 (br, NH2), 12.10 (br, OH) ppm; MS:
m=z ¼ 264 [Mþ], 77 (100%).
3-Phenylisoxazolo[4,3-d]cinnoline (15a, C15H9N3O)
Prepared from 3a; crystallization from ethyl acetate gave faint brown crystals (20%); mp 192ꢂC; IR
(KBr): ꢁꢀ¼ 3098, 1612, 1595, 1552, 1489 cmꢃ1; MS: m=z ¼ 247 [Mþ], 220, 205, 159, 143, 118, 77
(100%), 65.
4,6-Dimethyl-3-phenylisoxazolo[4,3-d]cinnoline (15b, C17H13N3O)
1
Prepared from 3b; crystallization from ethyl acetate gave buff crystals (22%); mp 196ꢂC; H NMR
(DMSO-d6): ꢀ ¼ 2.62 (s, CH3), 3.19 (s, CH3), 7.50 (m, 5Har), 8.32 (s, 1Har), 8.66 (s, 1Har) ppm.
Reaction of 3a or 3b with Phenylisothiocyanate
A solution of 3a or 3b (10 mmol) and phenyl isothiocyanate (12 mmol) in 25cm3 of EtOH, and a few
drops of triethylamine was refluxed for 20 h. Then the solvent was removed under reduced pressure and
the residue was recrystallized from ethyl acetate to give N,N0-disubstituted thioureas 16a and 16b.
N-(3-Benzoylcinnolin-1-yl)-N0-phenylthiourea (16a, C22H16N4OS)
Prepared from 3a; crystallization from ethyl acetate gave yellowish crystals (66%); mp 141ꢂC; IR
(KBr): ꢁꢀ¼ 3443, 3387, 3177, 2887, 1635, 1612, 1596, 1520, 1206cmꢃ1; 1H NMR (CDCl3): ꢀ ¼ 5.89
(br, NH), 7.49–7.52 (m, 5Har), 7.74 (d, J ¼ 7.2 Hz, 2Har), 7.91 (m, 5Har), 8.41 (d, J ¼ 8.6 Hz, 2Har) ppm.
N-(5,7-Dimethyl-3-benzoylcinnolin-1-yl)-N0-phenylthiourea (16b, C24H20N4OS)
1
Prepared from 3b; crystallization from ethylacetate gave yellow crystals (72%); mp 147ꢂC; H NMR
(CDCl3): ꢀ ¼ 2.53 (s, CH3), 2.95 (s, CH3), 4.20 (br, NH), 7.23 (m, 6Har), 7.45 (d, J ¼ 7.4 Hz, 3Har),

604
A. M. Amer et al.: On the Chemistry of Cinnoline V
7.96 (d, J ¼ 7.4 Hz, 3Har) ppm; 1H NMR (DMSO-d6): ꢀ ¼ 2.50 (s, CH3), 2.92 (s, CH3), 3.99 (br, NH),
7.36 (m, 9Har), 7.79 (d, J ¼ 7.0 Hz, 2Har), 7.88 (s, 1Har), 8.55 (br, NH) ppm; 13C NMR (CDCl3):
ꢀ ¼ 20.98 (CH3), 23.30 (CH3), 113.14, 125.81, 126.20, 127.45, 127.84, 129.79, 129.99, 130.25, 130.99,
133.23, 133.36, 135.29, 139.69, 142.56, 147.42, 149.06 (aryl, C¼S), 188.33 (C¼O) ppm.
References
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