Fused quinoline heterocycles I. First example of the 2,4-diazidoquinoline-3-carbonitrile and 1-aryl-1,5-dihydro-1,2,3,4,5,6-hexaazaacephenanthrylenes ring systems

Article abstract of DOI:10.1039/a901521c

4-Alkylamino-2-chloroquinoline-3-carbonitriles 2a-f react with hydrazine hydrate to give, in each case, the corresponding 3-amino-4-hydrazino-1H-pyrazolo[3,4-b]quinoline 7. Diazotization of 7 leads to the formation of 2,4-diazidoquinoline-3-carbonitrile 8, a new heterocyclic ring system. The azidoquinoline 8 can be converted to the corresponding aminoquinolines 14, and 15 and 16, by reaction with morpholine and sodium dithionite, respectively. On the other hand, 3-amino-4-arylamino-1H-pyrazolo[3,4-b]quinolines 4g-j were prepared by reaction of 4-arylamino-2-chloroquinoline-3-carbonitriles 2g-j with hydrazine hydrate at 50-60°C. Diazotization of 4g-j afforded the novel tetracyclic ring system 1-aryl-1,5-dihydro-1,2,3,4,5,6-hexaazaacephenanthrylenes 5g-j.

Full text of DOI:10.1039/a901521c

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Fused quinoline heterocycles I. First example of the 2,4-diazido-
quinoline-3-carbonitrile and 1-aryl-1,5-dihydro-1,2,3,4,5,6-hexa-
azaacephenanthrylenes ring systems
Ramadan A. Mekheimer
Chemistry Department, Faculty of Science, El-Minia University, El-Minia 61519, AR Egypt
Received (in Cambridge) 24th February 1999, Accepted 14th June 1999
4-Alkylamino-2-chloroquinoline-3-carbonitriles 2a–f react with hydrazine hydrate to give, in each case, the
corresponding 3-amino-4-hydrazino-1H-pyrazolo[3,4-b]quinoline 7. Diazotization of 7 leads to the formation of
2,4-diazidoquinoline-3-carbonitrile 8, a new heterocyclic ring system. The azidoquinoline 8 can be converted to
the corresponding aminoquinolines 14, and 15 and 16, by reaction with morpholine and sodium dithionite,
respectively. On the other hand, 3-amino-4-arylamino-1H-pyrazolo[3,4-b]quinolines 4g–j were prepared by reaction
of 4-arylamino-2-chloroquinoline-3-carbonitriles 2g–j with hydrazine hydrate at 50–60 ЊC. Diazotization of 4g–j
afforded the novel tetracyclic ring system 1-aryl-1,5-dihydro-1,2,3,4,5,6-hexaazaacephenanthrylenes 5g–j.
Cl
N3
Introduction
X
X
NaN3
Tetracyclic systems containing the quinoline moiety are
expected to have wide-spectrum biological activity. We are
DMF
N
Cl
N
N
B
exploring methods to construct the tetracyclic pyrazolotri-
azinoquinoline system 5. In previous work we prepared novel
heterocyclic ring systems, containing the quinoline skeleton,
with potential pharmaceutical activity.1–5 Pyrazoloquinoline
derivatives have useful biological properties as antitumor
reagents6,7 and are active agents for the treatment of herpes
virus infections.8 Pyrazolotriazines also have considerable
biological and medicinal activities as antitumor,9 antiinflam-
matory,10 and antiviral agents.11 We therefore wanted to develop
an efficient procedure for the synthesis of new heterocyclic
systems containing both pyrazole and triazine moieties con-
densed with a quinoline nucleus, with the expectation that they
would be of potential biological interest. A literature search
revealed that pyrazolotriazinoquinolines have been largely
ignored. We envisaged that the reaction of 4-amino-2-
chloroquinoline-3-carbonitriles 2a–f with hydrazine hydrate
might afford the corresponding pyrazolo[3,4-b]quinolines 4
and subsequent reaction with sodium nitrite in a solution
of H2SO4 (70%) at Ϫ5 ЊC would lead to the formation of the
hitherto unknown tetracyclic system 5. Interestingly, however,
a new compound, 2,4-diazidoquinoline-3-carbonitrile 8, was
obtained. To the best of our knowledge, there are no reports
on the synthesis of 2,4-diazidoquinolines. Steinschifter and
Stadlbauer12 showed that the reaction of 2,4-dichloroquin-
olines A with sodium azide in DMF gave the azido-
tetrazolo[1,5-a]quinoline structure B (Fig. 1). The presence of
the tetrazolo moiety in structure B was demonstrated by
chemical and spectroscopic methods.12 Their attempts to
obtain diazidoquinolines, with electron-donor substituents in
the 3-position, by raising the temperature and using a larger
excess of sodium azide or catalysts such as Cryptofix 5 failed.
The present investigation describes the synthesis of the first
number of a novel heterosystem, 2,4-diazidoquinoline-3-carb-
onitrile 8, and 1-aryl-1,5-dihydro-1,2,3,4,5,6-hexaazaacephen-
anthrylenes 5.
N
N
A
Fig. 1
4-alkylamino-2-chloroquinoline-3-carbonitrile 2a–f, where the
nucleophilic substitution first takes place at position 4. This
was confirmed chemically by acid hydrolysis of 2a–f with
a mixture of acetic acid and water, resulting in the form-
ation of the corresponding quinolin-2-ones. For example, acid
hydrolysis of 2d produced, in one step, 4-benzylamino-3-
cyanoquinolin-2(1H)-one 3d. The structure of the isomeric
quinolin-4-one for compound 3d could be excluded because the
IR spectrum showed significantly an amide carbonyl function
at 1650 cmϪ1,13,14 whereas 4-quinolinones are known to have
carbonyl absorptions below 1600 cmϪ1.15–17 Refluxing these
amines with excess of hydrazine hydrate (80%) did not afford
the 4-alkylamino-3-amino-1H-pyrazolo[3,4-b]quinoline deriv-
atives 4a–f, but rather gave one of the two unexpected isomeric
structures 7 or 10. Spectral data could not unequivocally dif-
ferentiate these isomers. Therefore, 3-amino-4-hydrazine-1H-
pyrazolo[4,3-c]quinoline 10 was prepared separately to chem-
ically verify the structure of its isomer 7. The reaction of 1 with
hydrazine hydrate according to ref. 2 gave 11 and reaction of 11
with excess of hydrazine hydrate in DMF at reflux yielded 10.
The structural assignment for 7 was established on the basis
of consistent elemental and spectral data. The IR spectrum
showed no cyano absorption at 2200 cmϪ1, but absorption
bands at 3400, 3330, 3300 and 3150 cmϪ1 were assigned as NH
1
and NH2 amino functions. Moreover, the H NMR spectrum
revealed the absence of alkyl protons and the presence of
signals for hydrazino protons at C-4, two amino protons at C-3,
and a pyrazole NH proton in addition to aromatic protons in
their expected positions. The mass spectrum showed a molecu-
lar ion at m/z 214 (100%). Formation of the pyrazoloquinol-
ine 7 can be rationalized as follows: both the alkylamino group
at position 4 and the chloro atom at position 2 of 4-alkylamino-
2-chloroquinoline-3-carbonitriles 2a–f undergo a nucleophilic
substitution reaction with two molecules of hydrazine. Sub-
sequent intramolecular cyclization via the attack of the NH2 of
the hydrazino group at position 2 on the nitrile carbon yields the
pyrazolo-fused compound 7. Reaction of compound 7 with
Results and discussion
2,4-Diazidoquinoline-3-carbonitrile 8 was obtained in three
steps starting from 2,4-dichloroquinoline-3-carbonitrile 1.2
Reaction of 1 with an excess of the appropriate alkylamine in
DMF solution at room temperature gave the corresponding
J. Chem. Soc., Perkin Trans. 1, 1999, 2183–2188
2183

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N
R
N
N
N
N
N
H
NHR
NHR
N
NH2
N
CN
O
5g-j
(67-76 %)
2g-j
HNO2
N
H
N
N
R
NH
H
N
3d,g
( 90-94 %)
4g-j
(58-67 %)
N
N
N
H3O+
6
2d,g
N3
N
N3
N
NHR
CN
CN
N3
CN
N2H4
NHNH2
NH2
N
N
N
Cl
N
HNO2
N
(70 %)
8
N
N
2a-j
(96-98 %)
H
N
7 (65-77 %)
2a-f
RNH2
Cl
N3
N
-RNH2
N
//
N
HN
N
NH2
N
CN
9
//
N
NHNH2
N
Cl
2, 3, 4, 5
R
(75 %)
10
1
a
Me
b
c
Et
N
HN
Cyclohexyl
NH2
N2H4
N2H4
d
e
PhCH2
Bui
N
Cl
f
Pri
11
g
Ph
h
i
4-CH3-C6H4
4-CH3O-C6H4
j
3-CH3-C6H4
Scheme 1
sodium nitrite in a 70% solution of H2SO4 at Ϫ5 ЊC gave a solid
product for which the two possible isomeric structures 8 and
9 can be written (see Scheme 1). Between these two possible
structures, the previously unreported 2,4-diazidoquinoline
structure 8 was assigned to the product isolated on the basis of
its elemental analysis and spectral data. The IR spectra showed
no absorption for amino and diazo groups but absorption
bands for the N3 and CN groups were observed at 2140 and
ination of water to give the final product 8 (Scheme 2). The
presence of the two azide groups at C-2 and C-4 was confirmed
by conversion to the corresponding aminoquinolines 15 and 16.
Reduction of the two azido groups at positions 2 and 4 of 8,
utilizing sodium dithionite as reducing agent, gave the cor-
responding 2,4-diaminoquinoline-3-carbonitrile 16.18 On the
other hand, reaction of compound 8 with excess of morpholine
in DMF solution at room temperature yielded 2-azido-4-
morpholinoquinoline-3-carbonitrile 14, via nucleophilic attack
at position 4. Reduction of the azido group at position 2 of 14
with sodium dithionite afforded the corresponding amino
compound 15, in high yield (Scheme 3). Acid hydrolysis of 15
yielded the aminoquinolines 18, presumably via nucleophilic
attack of water at C-4 followed by elimination of a morpholine
molecule to give 18. Overnight hydrolysis of 18 in 48% hydro-
bromic acid followed by basification yielded 17.19 The latter
compound 17 was synthesized to emphasize chemically that the
nucleophilic substitution, i.e. the replacement of the azido
group with a morpholine moiety in 8, first takes place at posi-
tion 4. On the basis of these results, it may be concluded that
1
2190 cmϪ1, respectively. The H NMR spectrum showed no
amino protons and the presence of only four aromatic protons
at δ 7.70–8.28. Furthermore, 13C NMR gave strong evidence for
the formation of compound 8, which confirmed the presence of
a CN carbon at δ 118.54. If the reaction product was the isomer
9, it would be difficult to assign this signal and consequently the
other possible structure 9 was eliminated. Other signals have
also been found at the expected field for compound 8 (see
Experimental section). The reaction mechanism of formation
of 8 is assumed to proceed via the reaction of 7 with nitrous
acid to give the N-nitroso intermediate 12. A proton shift to
afford intermediate 13 was followed by ring opening and elim-
2184
J. Chem. Soc., Perkin Trans. 1, 1999, 2183–2188

View Article Online
isolation of 2,4-diazidoquinolines 8 is attributed to the acidic
medium. An azido–tetrazolo isomerization shifted the equilib-
rium towards the azido form, i.e., in this case the azido form is
more stable in the acidic medium. Our interest in developing
synthetic approaches to the interesting heterocyclic pyrazolo-
triazinoquinoline ring system 5 led us to investigate the reac-
tion of 4-arylamino-2-chloroquinoline-3-carbonitriles 2g–j with
hydrazine hydrate, which gave pyrazoloquinolines 4g–j, good
precursors for the preparation of tetracycles 5. Thus, the
required starting material 3-amino-4-arylamino-1H-pyrazolo-
quinoline derivatives 4g–j were prepared from 1. Replacement
of the chloro atom at position 4 in 1 by aromatic amines was
achieved when the reaction was performed in DMF solution at
50–60 ЊC, giving the corresponding amines 2g–j. Beside the
analytical and spectroscopic confirmation of the structure of
compounds 2g–j (see Experimental section), it was confirmed
chemically by their conversion into the corresponding quinolin-
2-ones, via hydrolysis with aq. acetic acid. For example, acid
hydrolysis of 2g yielded the corresponding quinolin-2-one 3g
(Scheme 1). Refluxing of amines 2g–j with excess of hydra-
zine hydrate (80%) gave 3-amino-4-arylamino-1H-pyrazolo-
quinolines 4g–j. The IR spectrum showed the absence of a
cyano absorption. The 1H NMR spectrum revealed the
presence of signals for an amino group at C-3 and C-4 and
there was a pyrazole NH as well as aromatic protons in their
expected positions. When compounds 4g–j reacted with sodium
nitrite in a 70% solution of H2SO4 at Ϫ5 ЊC they yielded a
solid product which was identified as a 1-aryl-1,5-dihydro-
1,2,3,4,5,6-hexaazaacephenanthrylenes 5 (Scheme 1). The other
possible structure 6 was readily ruled out for the reaction prod-
ucts on the basis of spectral data. Thus, the lack of a diazo
absorption at 2160 cmϪ1 20 in the IR spectrum of the reaction
product supported the assigned structure 5 and allowed us to
discard the other possible structure 6. Moreover, the structure
1
of 5 has been established by its H NMR-spectrum which dis-
played the absence of an amino group (NH) signal for the
quinoline C-4 at δ 10.64–10.83, present in the spectra of 4g–j,
and the presence of singlets at about δ ≈ 14.2, assignable to the
pyrazole NH. It would be difficult to rationalize for this absorp-
tion if the reaction product was 6, or to rationalize signals due
to aryl protons. Several attempts were made to confirm the
structures of 4g–j and 5g–j by mass spectrometry. However,
the compounds decomposed under both electron-impact-
ionization and fast-atom bombardment.
Conclusions
The work described in this paper shows for the first time a novel
and general route to pyrazoloquinolines 7, via nucleophilic
substitution of the alkylamino group at C-4 in quinolines 2a–f
by hydrazine hydrate as a nucleophile, and also to 1-aryl-1,5-
dihydro-1,2,3,4,5,6-hexaazaacephenanthrylenes 5. This method
utilizes diazide compounds, which provide an excellent syn-
thesis of the sensitive 2,4-diazidoquinolines. Currently we are
working on an extension of this approach to prepare new tetra-
cyclic ring systems from pyrazolo[4,3-c]quinolines.
NH2
N3
NH
N
..
NH
N
NH2
2HNO2
N
NO
−H2O
N
N
N
Experimental
H
H
Mps (uncorrected) were obtained on a Gallenkamp melting
point apparatus. Microanalyses were performed by the Micro-
analytical Data Unit at Cairo University. Mass spectra were
recorded on GCMS-QP 1000EX or Finnigan Mat 8430 (ioniz-
ation energy 70 eV). IR spectra (KBr) were recorded on a
Shimadzu 470 spectrophotometer. 1H NMR spectra were
recorded on a Varian Gemini 200, a Bruker AC270 or a Bruker
AM400 spectrometer at 200, 270 or 400 MHz, respectively,
using [2H6]dimethyl sulfoxide as solvent with tetramethylsilane
as internal standard. J-Values are given in Hz. 13C NMR spectra
were measured on Bruker AM 400 (400 MHz) spectrometer.
Analytical TLC was performed with silica gel plates using silica
gel 60 PF254 (Merck). 2-Amino-4-hydroxyquinoline 17 was
prepared from 2-amino-4-hydroxyquinoline-3-carbonitrile 18
according to ref. 19.
7
12
N3
N
N3
N
CN
N3
C
H
−H2O
N
N
H
NO
8
13
Scheme 2
O
O
N3
N
N
O
CN
CN
CN
N3
2
2
4
HN
N
N3
N
NH2
N
(97 %)
14
15 (92 %)
8
H3O+
2
2
4
NH2
N
OH
Et
CN
CN
HBr (48 %)
NH2
N
NH2
N
NH2
18 (80 %)
17
16 (90 %)
Scheme 3
J. Chem. Soc., Perkin Trans. 1, 1999, 2183–2188
2185

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WARNING: Compound 8 is an explosive. A detonation
occurred at its mp.
4-Anilino-2-chloroquinoline-3-carbonitrile 2g. Yield 1.8 g
(98%) as yellowish needles, mp 199–201 ЊC (Found: C, 68.59; H,
3.47; Cl, 12.52; N, 15.19. C16H10ClN3 requires C, 68.69; H, 3.60;
Cl , 12.69; N, 15.02%); νmax/cmϪ1 3400 (NH), 3050 (arom CH)
and 2200 (CN); δ 7.28 (m, 5 H, ArH), 7.80 (m, 3 H, ArH), 8.45
(d, J 8, 1H, ArH) and 10.15 (s, 1H, NH).
General procedure for the synthesis of 4-alkyl (or 4-aryl)amino-
2-chloroquinoline-3-carbonitriles 2a–j
For 2a–f. The appropriate alkylamine (5.4 mmol) was added
to a solution of 1 (0.2 g, 0.9 mmol) in DMF (3 mL). The
reaction mixture was stirred for 10 min at room temperature
and was than poured into water (10 mL). The precipitated solid
product was isolated by suction and recrystallized from EtOH.
2-Chloro-4-[(4-methylphenyl)amino]quinoline-3-carbonitrile
2h. Yield 1.94 g (98%) as yellowish needles, mp 207–209 ЊC
(Found: C, 69.56; H, 4.17; Cl, 11.97; N, 14.33. C17H12ClN3
requires C, 69.50; H, 4.12; Cl, 12.08; N, 14.30%); νmax/cmϪ1 3400
(NH), 3050 (arom CH), 2900 (aliph CH) and 2200 (CN); δ 2.36
(s, 3H, CH3), 7.26 (m, 4H, ArH), 7.68 (m, 1H, ArH), 7.87 (m,
2 H, ArH), 8.50 (d, J 8, 1H, ArH) and 10.09 (s, 1H, NH).
For 2g–j. The appropriate aromatic amine (13.44 mmol) was
added to a solution of 1 (6.73 mmol) in DMF (15 mL). The
reaction mixture was stirred at 50–60 ЊC for 4 h, during which
time yellow crystals separated out. After cooling to room
temperature the reaction mixture was worked up as described
for 2a–f. In the case of 2j, the crude product was purified by
preparative TLC using silica gel plates (toluene–acetone, 10:3
v/v), followed by recrystallization from EtOH.
2-Chloro-4-[(4-methoxyphenyl)amino]quinoline-3-carbonitrile
2i. Yield 2 g (96%) as yellowish needles, mp 216–218 ЊC (Found:
C, 65.83; H, 4.0; Cl, 11.66; N, 13.50. C17H12ClN3O requires C,
65.91; H, 3.90; Cl, 11.46; N, 13.56%); νmax/cmϪ1 3320 (NH),
3050 (arom CH), 2950 and 2850 (aliph CH) and 2200 (CN);
δ 3.81 (s, 3H, OCH3), 7.01 (d, J 8, 2H, ArH), 7.33 (d, J 8, 2H,
ArH), 7.65 (m, 1H, ArH), 7.84 (m, 2H, ArH), 8.51 (d, J 8, 1H,
ArH) and 10.06 (s, 1H, NH).
2-Chloro-4-(methylamino)quinoline-3-carbonitrile 2a. Yield
0.190 g (97%) as colorless needles, mp 220–222 ЊC (Found: C,
60.74; H, 3.76; Cl, 16.20; N, 19.33. C11H8ClN3 requires C, 60.69;
H, 3.70; Cl, 16.31; N, 19.30%); νmax/cmϪ1 3350 (NH), 3050
(arom CH), 2930 (aliph CH) and 2200 (CN); δ 3.33 (d, J 4, 3H,
NCH3), 7.55–7.83 (m, 3H, 2 × ArH and NH), 8.27 (d, J 8, 1H,
ArH) and 8.48 (d, J 8, 1H, ArH).
2-Chloro-4-[(3-methylphenyl)amino]quinoline-3-carbonitrile
2j. Yield 1.909 g (96%) as yellowish needles, mp 165–166 ЊC
(Found: C, 69.39; H, 4.16; Cl, 12.27; N, 14.38. C17H12ClN3
requires C, 69.50; H, 4.12; Cl , 12.08; N, 14.30%); νmax/cmϪ1
3250 (NH), 3050 (arom CH), 2800 (aliph CH) and 2200 (CN);
δ 2.35 (s, 3H, CH3), 7.14 (m, 3H, ArH), 7.33 (m, 1H, ArH), 7.69
(m, 1H, ArH), 7.85 (m, 2H, ArH), 8.50 (d, J 8, 1H, ArH) and
10.11 (s, 1H, NH).
2-Chloro-4-(ethylamino)quinoline-3-carbonitrile 2b. Yield
0.202 g (97%) as colorless needles, mp 202–203 ЊC (Found: C,
62.18; H, 4.31; Cl, 15.53; N, 18.22. C12H10ClN3 requires C,
62.20; H, 4.35; Cl, 15.32; N, 18.13%); νmax/cmϪ1 3330 (NH),
3050 (arom CH), 2980, 2920 (aliph CH) and 2220 (CN); δ 1.33
(t, J 6, 3H, CH3), 3.87 (q, J 6, 2H, CH2), 7.56–7.85 (m, 3H,
2 × ArH and NH) and 8.34–8.41 (m, 2H, ArH).
General procedure for the synthesis of 4-benzyl (or phenyl)amino-
2-oxo-1,2-dihydroquinoline-3-carbonitrile 3d, g
A solution of 2d or 2g (1.7 mmol) in a mixture of acetic acid (10
mL) and water (2 mL) was refluxed for 6 h. The solvent was
then removed under reduced pressure and the resulting solid
product was collected by filtration, dried and recrystallized
from DMF.
2-Chloro-4-(cyclohexylamino)quinoline-3-carbonitrile
2c.
Yield 0.245 g (96%) as colorless needles, mp 137–138 ЊC (Found:
C, 67.19; H, 5.79; Cl, 12.58; N, 14.62. C16H16ClN3 requires C,
67.23; H, 5.64; Cl, 12.42; N, 14.70%); νmax/cmϪ1 3350 (NH),
3050 (arom CH), 2900 and 2850 (aliph CH) and 2200 (CN);
δ 1.13–2.05 (m, 11H, aliph H), 7.55–7.80 (m, 3H, 2 × ArH and
NH), 8.25 (d, J 8, 1H, ArH) and 8.45 (d, J 8, 1H, ArH).
4-Benzylamino-2-oxo-1,2-dihydroquinoline-3-carbonitrile 3d.
Yield 0.440 g (94%) as colorless needles, mp 252–253 ЊC (Found:
C, 74.01; H, 4.95; N, 15.18. C17H13N3O requires C, 74.17; H,
4.76; N, 15.26%); νmax/cmϪ1 3300 and 3200 (NH), 2200 (CN)
and 1650 (CO); δ 5.20 (d, J 6, 2H, CH2), 7.30–7.40 (m, 5H,
ArH), 7.62–8.49 (m, 4H, ArH), 9.01 (br s, 1H, NH) and 11.62
(s, 1H, quinoline NH).
4-Benzylamino-2-chloroquinoline-3-carbonitrile 2d. Yield
0.257 g (97%) as colorless needles, mp 205–207 ЊC (Found: C,
69.36; H, 4.29; Cl, 12.19; N, 14.23. C17H12ClN3 requires C,
69.50; H, 4.12; Cl, 12.08; N, 14.30%); νmax/cmϪ1 3380 (NH),
3050 (arom CH), 2950 (aliph CH) and 2200 (CN); δ 5.10 (d, J 6,
2H, CH2), 7.28–7.38 (m, 5H, ArH); 7.61–8.48 (m, 4H, ArH)
and 8.99 (br s, 1H, NH).
4-Anilino-2-oxo-1,2-dihydroquinoline-3-carbonitrile 3g. Yield
0.40 g (90%) as yellowish needles, mp 332–334 ЊC (Found: C,
73.68; H, 4.35; N, 16.02. C16H11N3O requires C, 73.55; H, 4.24;
N, 16.08%); νmax/cmϪ1 3300 and 3200 (NH), 2200 (CN) and
1650 (CO); δ 7.30 (m, 5H, ArH), 7.83 (m, 3H, ArH), 8.48 (d, J 8,
1H, ArH), 10.19 (s, 1H, NH) and 11.67 (s, 1H, quinoline NH).
2-Chloro-4-(isobutylamino)quinoline-3-carbonitrile 2e. Yield
0.280 g (96%) as colorless needles, mp 149–150 ЊC (Found: C,
64.89; H, 5.58; Cl, 13.53; N, 16.29. C14H14ClN3 requires C,
64.73; H, 5.43; Cl, 13.67; N, 16.18%); νmax/cmϪ1 3350 (NH),
3050 (arom CH), 2950 (aliph CH) and 2200 (CN); δ 0.96 (d, J 6,
6H, 2 × CH3), 2.10 (m, 1H, CH), 3.59 (t, J 6, 2H, CH2), 7.56–
7.84 (m, 3H, 2 × ArH and NH), 8.32 (d, J 8, 1H, ArH) and 8.51
(d, J 8, 1H, ArH).
Reaction of 2a–j and 8 with hydrazine hydrate
Synthesis of 3-amino-4-arylamino-1H-pyrazolo[3,4-b]quino-
lines 4g–j. A mixture of an arylamine 2g–j (1.36 mmol) and
hydrazine hydrate (5 ml; 80%) was refluxed for 3 h, until TLC
showed the disappearance of the starting compounds. After
cooling, the mixture was evaporated to dryness in vacuo.
Methanol (3 mL) was added to the remaining oily residue with
stirring. The solution was neutralized with acetic acid and the
precipitated solid product was collected by filtration, washed
with methanol, dried and recrystallized from DMF–EtOH.
3-Amino-4-anilino-1H-pyrazolo[3,4-b]quinoline 4g. Yield
0.251 g (67%) as orange needles, mp 290–292 ЊC (decomp.)
(Found: C, 69.74; H, 4.92; N, 25.38. C16H13N5 requires C, 69.80;
H, 4.76; N, 25.44%); νmax/cmϪ1 3400–2700 (NH, NH2) and 1640
2-Chloro-4-(isopropylamino)quinoline-3-carbonitrile 2f. Yield
0.212 g (96%) as colorless needles, mp 224–225 ЊC (Found: C,
63.76; H, 5.08; Cl, 14.29; N, 16.93. C13H12ClN3 requires C,
63.53; H, 4.92; Cl, 14.45; N, 17.10%); νmax/cmϪ1 3350 (NH),
3080 (arom CH), 2980 (aliph CH) and 2200 (CN); δ 1.37 (d, J 6,
6H, 2 × CH3), 4.74 (m, 1H, CH), 7.55–8.26 (m, 4H, 3 × ArH
and NH) and 8.46 (d, J 8, 1H, NH).
2186
J. Chem. Soc., Perkin Trans. 1, 1999, 2183–2188

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(C᎐N); δ 5.69 (br s, 2H, NH ), 7.19–8.71 (m, 9H, ArH), 10.83 (s,
1,5-Dihydro-1-phenyl-1,2,3,4,5,6-hexaazaacephenanthrylene
᎐
2
1H, NH) and 12.52 (s, 1H, pyrazole NH).
5g. Yield 0.380 g (73%), as brownish needles, mp 312–314 ЊC
(decomp.) (Found: C, 66.94; H, 3.70; N, 29.22. C16H10N6
requires C, 67.12; H, 3.52; N, 29.36%); νmax/cmϪ1 3400 (NH),
3-Amino-4-[(4-methylphenyl)amino]-1H-pyrazolo[3,4-b]-
quinoline 4h. Yield 0.237g (60%) as orange needles, mp 248–
250 ЊC (decomp.) (Found: C, 70.46; H, 5.26; N, 24.14. C17H15N5
requires C, 70.57; H, 5.23; N, 24.21%); νmax/cmϪ1 3400–2700
1670 (N᎐N) and 1640 (C᎐N); δ 7.69–8.85 (m, 9H, ArH) and
᎐
᎐
14.18 (s, 1H, NH).
(NH, NH ) and 1640 (C᎐N); δ 2.37 (s, 3H, CH ), 6.04 (br s, 2H,
NH2), 7.11–8.66 (m, 8H, ArH), 10.65 (s, 1H, NH) and 12.45
(s, 1H, pyrazole NH).
3-Amino-4-[(4-methoxyphenyl)amino]-1H-pyrazolo[3,4-b]-
quinoline 4i. Yield 0.266 g (60%) as orange needles, mp 276–
278 ЊC (decomp.) (Found: C, 66.67; H, 5.02; N, 22.89.
C17H15N5O requires C, 66.87; H, 4.95; N, 22.94%); νmax/cmϪ1
1,5-Dihydro-1-(4-methylphenyl)-1,2,3,4,5,6-hexaazaacephen-
anthrylene 5h. Yield 0.388 g (71%) as brownish needles,
mp > 360 ЊC (Found: C, 67.89; H, 4.14; N, 27.85. C17H12N6
requires C, 67.99; H, 4.03; N, 27.98%); νmax/cmϪ1 3200 (NH),
᎐
2
3
2800 (aliph CH), 1670 (N᎐N) and 1630 (C᎐N); δ 2.38 (s, 3H,
᎐
᎐
CH3), 7.64–8.81 (m, 8H, ArH) and 14.16 (s, 1H, NH).
1,5-Dihydro-1-(4-methoxyphenyl)-1,2,3,4,5,6-hexaaza-
acephenanthrylene 5i. Yield 0.437 g (76%) as brownish needles,
mp > 360 ЊC (Found: C, 64.38; H, 3.79; N, 26.39. C17H12N6O
requires C, 64.55; H, 3.83; N, 26.57%); νmax/cmϪ1 3200 (NH),
3400–2700 (NH, NH ) and 1640 (C᎐N); δ 3.83 (s, 3H, OCH ),
᎐
2
3
5.72 (br s, 2H, NH2), 7.16–8.63 (m, 8H, ArH), 10.64 (s, 1H,
NH) and 12.44 (s, 1H, pyrazole NH).
3-Amino-4-[(3-methylphenyl)amino]-1H-pyrazolo[3,4-b]-
quinoline 4j. Yield 0.230 g (58%) as orange needles, mp 308–
310 ЊC (decomp.) (Found: C, 70.41; H, 5.40; N, 24.12 C17H15N5
requires C, 70.57; H, 5.23; N, 24.21%); νmax/cmϪ1 3400–2700
2850 (aliph CH), 1670 (N᎐N) and 1630 (C᎐N); δ 3.82 (s, 3H,
᎐ ᎐
OCH3), 7.66–8.80 (m, 8H, ArH) and 14.15 (s, 1H, NH).
1,5-Dihydro-1-(3-methylphenyl)-1,2,3,4,5,6-hexaazaacephen-
anthrylene 5j. Yield 0.366 g (67%) as brownish needles,
mp > 360 ЊC (Found: C, 67.78; H, 4.21; N, 28.15. C17H12N6
requires C, 67.99; H, 4.03; N, 27.98%); νmax/cmϪ1 3200 (NH),
(NH, NH ) and 1640 (C᎐N); δ 2.36 (s, 3H, CH ), 5.71 (br s, 2H,
᎐
2
3
NH2), 7.18–8.68 (m, 8H, ArH), 10.81 (s, 1H, NH) and 12.50 (s,
1H, pyrazole NH).
2800 (aliph CH), 1670 (N᎐N) and 1630 (C᎐N); δ 2.39 (s, 3H,
᎐ ᎐
CH3), 7.65–8.84 (m, 8H, ArH) and 14.17 (s, 1H, NH).
2,4-Diazidoquinoline-3-carbonitrile 8. Yield 0.768 g (70%)
as brownish needles, mp 130 ЊC [decomp. (with explosion)]
(Found: C, 51.02; H, 1.59; N, 47.56. C10H4N8 requires C,
50.85; H, 1.71; N, 47.44%); νmax/cmϪ1 2190 (CN) and 2140
(N3); δ 7.70 (t, J 8, 1H, ArH), 7.90 (t, J 8, 1H, ArH), 8.14
(d, J 8, 1H, ArH) and 8.28 (d, J 8, 1H, ArH), δC 104.37
(C-3), 109.33 (C-4a), 118.54 (CN), 122.30 (C-6), 127.16
(C-5), 129.52 (C-7), 130.92 (C-8), 137.91 (C-8a), 147.47 (C-4),
160.94 (C-2); m/z 236 (Mϩ, 27%), 152 (68), 125 (11), 100 (40),
87 (100).
Synthesis of 3-amino-4-hydrazino-1H-pyrazolo[3,4-b]quin-
oline 7. A mixture of an alkylamine 2a–f (4.6 mmol) and hydra-
zine hydrate (80%; 8 mL) was heated under reflux for 15 min
and then left to cool to room temperature, whereupon the
product crystallized as orange needles. The resulting product
was isolated by suction and washed with EtOH. The product
was obtained in 65–77% yield as orange needles, mp 292–294 ЊC
(decomp.) (from EtOH) (Found: C, 55.89; H, 4.79; N, 39.08.
C10H10N6 requires C, 56.06; H, 4.71; N, 39.23%); νmax/cmϪ1
3400, 3330, 3300 and 3150 (NH, NH2), 1650 (δ NH) and 1610
(C᎐N); δ 5.42 (br s, 2H, NH ), 6.04 (br s, 2H, NH ), 7.59–8.41
᎐
2
2
(m, 4H, ArH), 8.91 (br s, 1H, NH) and 11.17 (s, 1H, pyrazole
NH); m/z 214 (Mϩ, 100%), 184 (52), 169 (39), 155 (22), 143
(38), 129 (69) and 102 (41).
2-Azido-4-morpholinoquinoline-3-carbonitrile 14
Morpholine (0.295 g, 3.4 mmol) was added to a solution of 8
(0.2 g, 0.85 mmol) in DMF (3 mL). The mixture was stirred for
10 min at room temperature and then poured into water (10
mL). The precipitated solid product was collected by filtration
and recrystallized from EtOH to give compound 14 as greenish
microcrystals (0.230 g, 97%), mp 230–231 ЊC (decomp.)
(Found: C, 59.87; H, 4.38; N, 29.79. C14H12N6O requires C,
59.99; H, 4.32; N, 29.98%); νmax/cmϪ1 3100 (arom CH), 2970
Synthesis of 3-amino-4-hydrazino-1H-pyrazolo[4,3-c]quinoline
10
A mixture of 112 (0.6 g, 2.74 mmol) and hydrazine hydrate (99%;
0.28 g, 5.6 mmol) in DMF (5 mL) was refluxed for 15 min,
during which time yellow crystals separated out. After cooling
to room temperature, the resulting solid title product was
filtered off, dried, and recrystallized from DMF to give yellowish
crystals (0.440 g, 75%), mp 352–353 ЊC (Found: C, 56.14; H,
4.83; N, 39.15. C10H10N6 requires C, 56.06; H, 4.71; N, 39.23%);
νmax/cmϪ1 3300, 3250 and 3200 (NH, NH ) and 1620 (C᎐N);
and 2850 (aliph CH), 2190 (CN), 2140 (N ) and 1610 (C᎐N); δ
᎐
3
3.84 (br s, 4H, 2 × NCH2), 3.93 (br s, 4H, 2 × OCH2), 7.44 (t, J
8, 1H, ArH), 7.77 (t, J 8, 1H, ArH), 7.90 (d, J 8, 1H, ArH) and
8.26 (d, J 8, 1H, ArH).
᎐
2
δ 5.41 (br s, 2H, NH2), 6.07 (br s, 2H, NH2), 7.65 (m, 2H, ArH),
8.24 (d, J 8, 1H, ArH), 8.40 (d, J 8, 1H, ArH), 9.79 (br s, 1H,
NH) and 13.13 (s, 1H, pyrazole NH).
General procedure for the 2,4-diaminoquinoline-3-carbonitriles
15, 16
Sodium dithionite (0.6 g, 3.45 mmol) was added portionwise to
a stirred suspension of 14 (0.3 g, 1.07 mmol) in a methanol (20
mL)–water (10 mL) mixture. Stirring was maintained at 50–
60 ЊC for 3 h. After cooling, water was added and the resulting
solid product was collected by filtration, washed well with
water, dried, and recrystallized from MeOH to give 15. In the
case of 16, sodium dithionite (1.2 g, 6.90 mmol) was added to
a stirred suspension of 8 (0.3 g, 1.3 mmol) in a methanol
(30 mL)–water (15 mL) mixture. Stirring was maintained at
50–60 ЊC for 5 h. Then, the reaction mixture was worked up as
described for 15.
Reaction of 4g–j and 7 with nitrous acid
General procedure for the 1-aryl-1,5-dihydro-1,2,3,4,5,6-
hexaazaacephenanthrylenes 5g–j and 2,4-diazidoquinoline-3-
carbonitrile 8. For 5g–j. Aq NaNO2 (5.46 mmol in 3 mL) was
added dropwise to a solution of an arylamine 4g–j (1.82 mmol)
in H2SO4 (10 mL, 70%) cooled in ice–salt to Ϫ10 ЊC, while the
temperature of the reaction mixture was maintained at Ϫ10 to
Ϫ5 ЊC. The reaction mixture was kept at Ϫ5 ЊC for 1 h and then
was poured into ice–water. The precipitated solid product was
collected by filtration, washed well with water, dried, and
recrystallized from DMF to give the corresponding tetracycle
5g–j.
2-Amino-4-morpholinoquinoline-3-carbonitrile 15. Yield 0.250
g (92%) as orange crystals, mp 214–215 ЊC (decomp.) (Found:
C, 66.33; H, 5.52; N, 21.89. C14H14N4O requires C , 66.23; H,
5.55; N, 22.03%); νmax/cmϪ1 3400, 3300 and 3200 (NH2), 2950
For 8. Aq. NaNO2 (0.967 g, 14 mmol in 3 mL) was added
dropwise to a solution of 7 (1 g, 4.7 mmol) in H2SO4 (10 mL;
70%) and then the reaction mixture was worked up as described
for 5g–j.
and 2850 (aliph CH), 2200 (CN) and 1640 (C᎐N); δ 3.87 (br s,
᎐
4H, 2 × NCH2), 3.91 (br s, 4H, 2 × OCH2), 7.30 (t, J 8, 1H,
J. Chem. Soc., Perkin Trans. 1, 1999, 2183–2188
2187

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3 R. Mekheimer, Bull. Soc. Chim. Fr., 1994, 131, 279.
4 R. Mekheimer, J. Chem. Res. (S), 1994, 304.
5 A. A. Hassan, R. Mekheimer and N. K. Mohamed, Pharmazie,
1997, 52, 589.
6 M. P. Wentland, S. C. Aldous, D. M. Gruett, R. B. Perni, R. G.
Powles, D. W. Danz, K. M. Klingbeil, A. D. Peverly and R. G.
Robinson, Bioorg. Med. Chem. Lett., 1995, 5, 405.
7 A. Afonso, J. M. Kelly and S. Chackalamannil, U.S. Pat., 5 608 067,
1997 (Chem. Abstr., 1997, 126, 225297x).
ArH), 7.67 (m, 2H, ArH), 8.37 (d, J 8, 1H, ArH) and 8.52 (br s,
2H, NH2).
2,4-Diaminoquinoline-3-carbonitrile 16. Yield 0.210 g (90%)
as yellowish crystals, mp 302–304 ЊC (lit.,18 303–305 ЊC).
2-Amino-4-hydroxyquinoline-3-carbonitrile 18
A mixture of 15 (0.5 g, 2.7 mmol), acetic acid (7 mL) and water
(2 mL) was refluxed for 4 h. The solvent was removed in vacuo
and the resulting solid product was collected by filtration,
washed with water, dried, and recrystallized from DMF to
afford compound 18 as colorless crystals (0.290 g, 80%),
mp > 360 ЊC (Found: C, 64.76; H, 3.69; N, 22.82. C10H7N3O
requires C, 64.86; H, 3.81; N, 22.69%); νmax/cmϪ1 3400, 3300,
3200 and 3100 (NH) and 2200 (CN); δ 7.15 (s, 2H, NH2), 7.20–
8.0 (m, 4H, ArH) and 11.18 (br s, 1H); m/z 185 (Mϩ, 100%), 157
(16), 129 (7), 120 (49), 92 (18).
8 A. Afonso, J. M. Kelly and S. Chackalamannil, U.S. Pat., 5 506 236,
1996 (Chem. Abstr., 1996, 125, 33629q).
9 R. W. Baldwin, M. W. Partridge and M. F. G. Stevens, J. Pharm.
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10 T. Endre, G. Melinda, F. Odon and J. Judit, Hung. Teljes H U 42 771,
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A. B. Kapustin, N. L. Mitin, M. L. Zhiravetskii and I. A. Vinograd,
Khim-Farm. Zh., 1990, 24, 41 (Russian), (Chem. Abstr., 1991, 114,
143358f).
12 W. Steinschifter and W. Stadlbauer, J. Prakt. Chem., 1994, 336, 311.
13 W. Stadlbauer, Monatsh. Chem., 1986, 117, 1305.
14 Th. Kappe, P. F. Fritz and E. Ziegler, Chem. Ber., 1973, 106,
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Acknowledgements
I am greatly indebted to Professor Dr M. Smith at the
University of Connecticut, USA and to Professor Dr D. Doepp
at Duisburg University, Germany, for helpful discussions.
I thank the staff of the spectroscopic unit at the University of
Connecticut, USA, for their help. I am also grateful to the
Egyptian government for providing a postdoctoral Fellowship
that gave me the opportunity to complete this work in the USA.
18 K. Gewald, U. Hain, G. Schwarzer and M. Gruner, J. Prakt. Chem.,
1992, 334, 89.
19 S. B. Kadin and C. H. Lamphere, Synthesis, 1977, 500.
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Paper 9/01521C
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J. Chem. Soc., Perkin Trans. 1, 1999, 2183–2188