3-(4-fluorophenyl)-1H-pyrazole-4-carbaldehyde in the synthesis of aza- and diazaphenanthrene derivatives

Article abstract of DOI:10.1134/S1070428007020157

Condensation of 3-(4-fluorophenyl)-1H-pyrazole-4-carbaldehyde with 2-naphthyl-or 6-quinolylamine and CH-acids (acetone, acetophenone, cyclic mono-and β-diketones) provided new derivatives of benzo[f]quinoline, benzo[a]phenanthridine, benzo[a]acridine, and

Full text of DOI:10.1134/S1070428007020157

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2007, Vol. 43, No. 2, pp. 241−248. © Pleiades Publishing, Ltd. 2007.
Original Russian Text © N.G. Kozlov, K.N. Gusak, 2007, published in Zhurnal Organicheskoi Khimii, 2007, Vol. 43, No. 2, pp. 249−256.
3-(4-Fluorophenyl)-1H-pyrazole-4-carbaldehyde in the Synthesis
of Aza- and Diazaphenanthrene Derivatives
N. G. Kozlov and K. N. Gusak
Institute of Physical Organic Chemistry, Nathional Academy of Sciences of Belarus’, Minsk, 220072 Belarus’
e-mail: loc@ifoch.bas-net.by
ReceivedAugust 9, 2005
Abstract—Condensation of 3-(4-fluorophenyl)-1H-pyrazole-4-carbaldehyde with 2-naphthyl- or 6-quinolylamine
and CH-acids (acetone, acetophenone, cyclic mono- and β-diketones) provided new derivatives of benzo[f]quino-
line, benzo[a]phenanthridine, benzo[a]acridine, and 4,7-phenanthroline. The arising in the course of the reaction
[3-(4-fluorophenyl)-1H-pyrazole-4-ylmethylene]-2-naphthyl-(or 6-quinolyl)amines, [3-(4-fluorophenyl)-1H-pyrazole-
4-ylmethylene]-1,3-indandione, and octahydro-1,8-xanthenedione derivatives were isolated.
DOI: 10.1134/S1070428007020157
High and versatile biological activity of benzo[f]quino-
line and 4,7-phenanthroline derivatives [1–6] calls for the
search of new synthons for preparation of previously
unknown compounds of these classes. New synthetic
approaches that we develop for the preparation of fused
nitrogen-containing heterocycles of aza- and diaza-
phenanthrene series, namely, benzo[a]phenanthridines,
benzo[f]quinolines, benzo[a]acridines, and 4,7-phen-
anthrolines [1, 7, 8], are based on involvement of a wide
range of aromatic aldehydes in condensation with
2-naphthyl-, 6-quinolylamines, and CH-acids. The
aldehyde contributing a methine fragment and a phenyl
ring with attached pharmacophore moieties into the
structure of azaheterocycles plays an exceptional part in
the synthesis of biologically active compounds: analogs
of bactericides, cardioprotectors, enzyme inhibitors,
analgesics, and alkaloids [1–6, 9, 10].
with 2-naphthyl- or 6-quinolylamines (II and III), and
with CH-acids of various classes: methyl ketones [acetone
(IV) and acetophenone (V)], cyclopentanone (VI), cyclo-
hexanone (VII), 4-methylcyclohexanone (VIII),
1,3-cyclohexanedione (IX), dimedone (X), and 1,3-indan-
dion (XI).
The condensation of aldehyde I with amines II and
III and methyl ketones IV and V was performed by boiling
a solution of the reagents in an aliphatic alcohol in the
presence of a catalytic quantity of hydrochloric acid.
Based on the data of [1, 8] we believe that in the three-
component reagents mixture first the aldehyde reacts with
arylamine to give azomethine XII and XIII whose
condensation with CH-acid occurs via a sequence of
stages: addition of the CH-acid to the C=N bond of the
azomethine, cyclocondensation of the arising amine-
ketone A into a dihydro derivative of the azaphen-
anthreneseries B, and dehydrogenation of the latter into
a completely aromatic benzo[f]quinoline or 4,7-phen-
anthroline. In the condensation under study of pyr-
azolecarbaldehyde I with amines II and III and ketones
IV and V under the above conditions we did not detect
any intermediate compounds.As a result the reaction led
to the selective formation in 39–55% yield of individual
1-methyl- (or phenyl)-3-[3-(4-fluorophenyl)-1H-pyrazol-
4-yl]benzo[f]quinolines XIVa and XIVb and 1-phenyl-3-
[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-4,7-phenanthroline
(XV).
The condensation of heterocyclic aldehydes with
2-naphthyl-, 6-quinolylamines and CH-acids was studied
mainly on pyridine- and quinolinecarbaldehydes [1, 11,
12]. No published data are known on the use in the syn-
thesis of aza- and diazaphenanthrenes of aldehydes from
the pyrazole series. At the same time it is expectable that
introduction of a pyrazole ring into the molecule of aza-
phenanthrene can endow the compounds with new
properties and extend the opportunities of their application
as drugs, reagents for biochemical investigations, and for
medicinal diagnostics.
In this study we investigated for the first time reactions
of 3-(4-fluorophenyl)-1H-pyrazole-4-carbaldehyde (I)
From reaction carried out under milder conditions (20–
50°C) both in the presence and absence of HCl we isolated
241

KOZLOV, GUSAK
242
R1
O
NH
N
NH
N
R1
NH
N
R1
N
NH
NH
X
X
X
F
F
F
А
B
R1
XIVа, XIVb, XV
R2
F
O
IV, V
R2
(CH2)n
NH
N
R2
O
(CH2)n
N
H
N
N
N
H
(CH2)n
_
NH2
O
O
X
II, III
NH
NH
N
VI VIII
N
N
X = CH
D
H
X
F
F
C
F
XII, XIII
I
R3
O
R2
NH
O
(CH2)n
N
R3
N
O
O
IX, X
XI
F
F
_
R3
O
XVIа XVIc
R3
R3
O
NH
N
O
NH
N
R3
N
O
O
N
NH
NH
H
X
X
F
F
E
XX
F
F
II
F
R3
R3
O
F
O
N
HN
R3
R3
O
N
O
N
H
HN
O
N
NH2
NH
I + IX, X
X
H
G
XXI
II, III
R3
R3
F
R3
R3
F
O
O
F
O
R3
R3
R3
R3
R3
R3
O
O
O
N
N
O
KOH
HN
HN
NH
O
O
N
N
NH
N
N
H
X
XVIIа, XVIIb, XVIIIа, XVIIIb
F
I
XXII
XIXа, XIXb
R1 = Me (IV, XIVa), Ph (V, XIVb, XV); R2 = H (VI, VII, XVIà, XVIb), 4-Me (VIII), 3-Me (XVIc); R3 = H (IX, XVIIa–XIXa), Me
(X, XVIIb–XIXb);X=CH(II, XII, XIVà, XVIb, XVIIà, XVIIb), N(III, XIII, XV, XVIIIà, XVIIIb); n=1(VI, XVIa), 2(VII,VIII,
XVIb, XVIc).
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3-(4-FLUOROPHENYL)-1H-PYRAZOLE-4-CARBALDEHYDE
243
of the vibronic structure of α-band was observed
apparently caused by the presence of nitrogen atoms of
the pyrazole ring. Bands at shorter waves in the region
283–291 and 224–263 nm are r- and β-bands (‘La and
‘Bb) respectively, and the r-band is more intensive than
the β-band in conformity to the spectral pattern of
compounds with angular structure (phenanthrene and its
heterocyclic analogs).
In the 1H NMR spectra of compounds XIVa, XIVb,
and XV the signals from aromatic protons appear in the
region 7.61–8.84 ppm. The proton of NH group and
methine proton of the pyrazole ring appear respectively
as a singlet at 11.02–13.30 ppm and a multiplet in the
region 8.70–8.80 ppm. In the spectrum of benzoquinoline
XIVa the methyl group protons give rise to a singlet at
3.00 ppm.
azomethines XII and XIII. The nitrogen atoms in the
heteroaromatic ring of the aldehyde molecule activate
the carbonyl group owing to the –I-effect in the stage of
condensation with amine. In the arising azomethine
molecule the effect of the nitrogens of the pyrazole ring
on the activity of C=N bond is apparently less pronounced,
and in the stage of methyl ketone addition the crucial
importance belongs to sterical hindrances due to the
presence of a fluorophenyl substituent in the pyrazole
ring. Therefore the boiling of reagents and the use of
catalyst to activate both azomethine and CH-acid becomes
necessary. Therewith a fast cyclization occurs of amino-
ketones Aand oxidation of 1,2-dihydropyridine derivatives
B into the most thermodynamically feasible hetero-
aromatic reaction products XIVa, XIVb, and XV. In the
presence of the catalyst (HCl) formed aza- and diaza-
phenanthrene hydrochlorides which when treated with
ammonium hydroxide provide free bases XIVa, XIVb,
and XV.
The condensation of aldehyde I and amine II or
azomethine XII with cyclic ketones VI–VIII was carried
out under the same conditions as used with methyl ketones
IV and V. Therewith cyclopentanone VI and cyclohexa-
none VII formed products of dehydrocyclization of
aminoketones C, 4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-
2,3-dihydro-1H-benzo[f]cyclopenta[c]quinoline (XVIa)
and 5-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-1,2,3,4-tetra-
hydrobenzo[a]phenanthridine (XVIb) in 43–52% yield,
and 4-methylcyclohexanone (VIII) gave according to
1H NMR spectra a mixture of 3-methyl-5-[3-(4-fluoro-
phenyl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydrobenzo[a]-
phenanthridine (XVIc) and its precursor, 1,2,3,4,5,6-
hexahydro derivative D in approximately equal amounts.
The spectrum of reaction products obtained from ketone
VIII alongside the signals from cycloaliphatic protons in
the range 1.70–3.65 ppm, methyl group protons (0.95–
1.17 ppm), aromatic protons (6.84–8.80 ppm), and the
proton from NH of pyrazole ring at 13.30 ppm contained
a broadened singlet of NH group proton at 4.20 ppm and
a singlet of the methine proton at 5.34 ppm, both latter
resonances characterisic of 1,2-dihydropyridine ring [13].
Inasmuch as we failed to isolate from the mixture
individual compounds D and XVIc, we further performed
the reaction in the presence of an oxidant (nitrobenzene)
to convert completely intermediate D into final reaction
product XVIc.
Azomethines XII and XIII previously unknown were
synthesized by condensation of aldehyde I with amines
II and III by boiling in ethanol without catalyst. Reacting
with acetone (IV) and acetophenone (V) under the given
conditions of the theree-component condensation com-
pounds XII and XIII formed benzoquinolines XIVa, XIVb
and phenanthroline XV in 42–48% yield.
In the IR spectra of compounds XIVa, XIVb, and XV
absorption bands are present in the region 3070–
3030 cm–1 (C–H) and 875–865, 840–835, 770–755 cm–1
[δ(C–H)]. NH group in the pyrazole ring gives rise to
a strong band at 3200 cm–1.
The mass spectra of azaphenanthrenes XIVa, XIVb,
and XV contain molecular ion peaks [M]+ corresponding
to maximal abundance (100%), peaks of ions [M – H]+
(Irel 38–43%), and peaks of low intensity (Irel 10–12%)
of ions [M – HCN]+ and [M – H – HCN]+ whose
presence is characteristic of nitrogen-containing hetero-
aromatic compounds.
Electron absorption spectra of compounds XIVa,
XIVb, and XV are located in UV region (224–367 nm)
and possess a structure characteristic of benzo[f]quinoline
and 4,7-phenanthrolines [1, 11, 12]. The long-wave band
(338–367 nm) was interpreted as Clar α-band (‘Lb
according to Platt), and it suffers a red shift compared to
the previously studied spectra of azaphenanthrenes [1,
11]. This shift apparently originates from the longer
conjugation chain due to introducing p-fluoro-
phenylpyrazole substituent. At the same time in the
spectra of compounds XIVa, XIVb, and XV a smoothing
In the IR spectra of compounds XVIa–XVIc alongside
the group of absorption bands of aromatic C–H bonds in
the region 3060–3040 cm–1 and a stretching vibrations
band of NH group in the pyrazole ring at 3210 cm–1
additionally appear characteristic bands of the stretching
vibrations of cycloaliphatic C–H bonds in the range 2930–
2855 cm–1.
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KOZLOV, GUSAK
244
In the mass spectra of azaphenanthrenes XVIa–XVIc
that undergoes dehydrocyclization into a system of benzo-
[a]acridinone XVIIa and XVIIb, and benzo[b]-[4,7]-
phenanthrolinone XVIIIa and XVIIIb.
molecular ion peaks [M]+ (Irel 100%) are the most
abundant, also appear peaks of ions [M – FC6H4C3H2N2]+
(Irel 30–38%) and weak peaks (Irel 5–10%) originating
from CH2 group elimination from the molecular ion
(MeCH for compound XVIc).
The attempt to prepare 2-[3-(4-fluorophenyl)pyrazol-
4-yl]methylene-1,3-cyclohexanediones H by heating an
equimolar mixture of aldehyde I and diones IX and X
aiming at further reaction of the product with amines II
and III led to the formation of bis-dicarbonyl derivatives
J like in reaction of substituted benzaldehydes with cyclic
diketones [15]. The heating with alkali solution converted
bisdiketones J into octahydroxanthene derivatives XIXa
and XIXb, and at treating with amines II and III
compounds J eliminated cyclohexanedione and through
intermediates H and G transformed into aza- and diaza-
phenanthrenes XVIIa, XVIIb, XVIIIa, and XVIIIb.
UV spectra of compounds XVIa–XVIc are similar to
those of benzoquinolines XIVa and XIVb, only the
β-band (221–249 nm) undergoes a notable blue shift
apparently due to introduction into the molecule of a fuzed
carbocycle.
In the 1H NMR spectra of compounds XVIa–XVIc
the signals of cycloaliphatic protions were observed in
the region 1.78–3.78 ppm that were lacking in the spectra
of azaphenanthrenes XIVa and XIVb; in the spectrum
of benzoquinoline XVIc appeared a doublet from the
protons of a methyl group at 0.96 ppm.
The IR spectra of compounds XVIIa, XVIIb, XVIIIa,
and XVIIIb contain characteristic bands of stretching
and bending vibrations of NH groups of pyrazole and
dihydropyridine rings at 3130–3250 and 1635–1630
cm–1. The stretching vibrations of the keto group conjugat-
ed to the enamine fragment appeared at 1605–1595 cm–1.
The stretching vibrations bands of cycloaliphatic CH
bonds were observed in the region 2960–2870 cm–1, those
of CH bonds in the aromatic rings, at 3080–3045 cm–1.
The three-component condensation of aldehyde I,
amines II and III, and β-diketones IX and X proceeded
in 1-butanol without catalysts whose role played the
proton of the dissociated enol form of the β-dicarbonyl
compound. In keeping with the above scheme of reaction
between aldehyde I, amines II and III, and monoketones
VI–VIII it was presumable that the cyclization of the
adduct formed from diones IX and X and azomethines
XII and XIII, aminodiketone E, would let to the formation
of pyrazolyl derivatives of hexahydrobenzo[a]phenanthri-
dine and 4,7-phenanthroline F or to products of their
aromatization. However it was established by means of
1H NMR spectroscopy that the reaction products were
compounds isomeric to structure F, aza- and diazaphenan-
threnes with a stable against oxidation 1,4-dihydropyridine
ring, 12-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-7,8,9,10,11,12-
hexahydrobenzo[a]acridin-11-ones XVIIa and XVIIb
and their benzo[b][4,7]-phenanthroline analogs XVIIIa
and XVIIIb (yield 72–90%) whose formation may be
regarded as a result of intermediate E transformation
analogous to Hofmann–Martius rearrangement (migration
of N-alkyl substituents of aniline into the aromatic ring
[14]) followed by cyclocondensation of aminodi-
ketone G.
The mass spectra of azaphenanthrenes XVIIa,
XVIIb, XVIIIa, and XVIIIb contain molecular ion peaks
[M]+ (Irel 25–38%). The most abundant (100%) peak in
the spectra is that of ion [M – FC6H4C3H2N2]+ (m/z 248
for compound XVIIa, 249 for phenanthroline XVIIIa,
276 and 277 for dimethyl derivatives XVIIb and XVIIIb).
A sufficiently intensive (18–28%) ion peak (m/z 192 for
acridones XVIIa and XVIIb and 193 for
phenanthrolinones XVIIIa and XVIIIb) corresponds to
elimination from the ion [M – FC6H4C3H2N2]+ of a frag-
ment CH2CH2CO for compounds XVIIa and XVIIIa,
and Me2CCH2CO for dimedone derivatives XVIIb and
XVIIIb.
UV spectra of compounds XVIIa, XVIIb, XVIIIa,
and XVIIIb have a pronounced vibronic structure. The
molecules of partially hydrogenated acridones XVIIa and
XVIIb and benzophenanthrolinones XVIIIa and XVIIIb
contain three independent chromophore fragments:
p-fluorophenylpyrazole substituent, carbonyl group, and
naphthalene or quinoline ring. The latter contribute most
Intermediate E transformation may also occur via its
hydramine cleavage into amine II or III and α,β-un-
saturated ketone H which contains a strongly activated
double bond due to its conjugation with two contiguous
carbonyl groups and reacts with the aromatic ring of
amine II or III at the carbon possessing the highest
electron density and located in the α-position with respect
to the amino group. As a result forms aminodiketone G
*
into the system of π−π -electronic transitions. Therefore
the bands with λmax 216–218, 245–250, 290–292 nm in
the spectra of acridones XVIIa and XVIIb may be related
to the 2-naphthylamine (II) system [UV spectrum, λmax
,
nm (log ε): 204 (4.06), 246 (4.35), 280 (3.63)], and in
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3-(4-FLUOROPHENYL)-1H-PYRAZOLE-4-CARBALDEHYDE
245
spectra of phenanthrolinones XVIIIa and XVIIIb, to the
system of 6-quinolylamine (III) [UV spectrum, λmax,nm
(log ε): 206 (4.08), 247 (4.35), 279 (3.59)]. The
considerable red shift and increased intensity of the first
and the third bands in the spectra of compounds XVIIa,
XVIIb, XVIIIa, and XVIIIb are caused apparently by
overlapping with absorption bands of p-
fluorophenylpyrazolyl substituent. Long-wave absorption
bands (331–340, 370–388 nm) according to [15] are due
to the presence of a carbonyl group.
1H NMR spectra of compounds XVIIa, XVIIb,
XVIIIa, and XVIIIb in the position and multiplicity of
the signals of aromatic and cycloaliphatic protons are
identical to previously published spectra of acridones and
4,7-phenanthrolinones [7, 15]. The structure of com-
pounds XVIIa, XVIIb, XVIIIa, and XVIIIb is confirmed
by the lack of the coupling between the proton of NH
group from the azaphenanthrene skeleton and the proton
at C12 atom linked to the fluorophenylpyrazolyl substituent
that is expected in the alternative structure F. These
proton signals appear as singlets at 9.80–9.87 and 5.70–
5.82 ppm.
XXII in this region a single band cor-responding to the
amino group of the pyrazole ring is conserved.
In the mass spectra of compounds XXI and XXII
peaks of molecular ions [M]+ are of high intensity
(65 and 100%).Also peaks of ions [M – FC6H4C3H2N2]+
(100% for compound XXI and 28% for oxidation product
XXII) are observed. In the spectrum of compound XXII
double-charged ions are present: molecular ion [M]2+ and
ion [M – FC6H4C3H2N2]2+.
UV spectrum of dihydro derivative XXI is identical in
the number of bands to the spectra of benzoacridones
XVIIa and XVIIb. In the spectrum of compound XXI
a significant shift is observed of a long-wave maximum
(476 nm) to the visible region originating apparently from
the presence of the fused indenone structure in the
molecule of the azaphenanthrene. In the UV spectrum
of the dehydrogenation product XXII a strong band
appeared at 285 nm and a less stong band with a vibronic
structure at 225–253 nm. The presence of these bands
(Clar β- and r-bands) endows the spectrum of compound
XXII with a likeness to the spectra of benzoquinolines
XIVa and XIVb. The long-wave band at 338–370 nm
present in the spectrum of indenoquinoline XXII cor-
responds to the α-band in the spectra of benzoquinolines
XIVa and XIVb but is shifted to red as compared to the
latter.
1H NMR spectra of compouns XXI and XXII contain
aromatic protons signals in the region 7.29–8.60 ppm,
signal of the proton from NH group, and the methine
proton of the pyrazole ring at 12.89–13.04 and 8.73–
8.79 ppm respectively. The signals present in the spectrum
of dihydro compound XXI at 9.84 and 5.80 ppm
corresponding respectively to the protons of groups NH
and H12 of dihydropyridine ring disappeared in the oxidized
product XXII indicating the aromatization of the
azaphenanthrene ring in the latter.
We established that in condensation of aldehyde I with
amine II and 1,3-indandione (XI) in ethanol without
catalyst before formation of the target product from the
benzoidenoquinoline series 2-[3-(4-fluorophenyl)pyrazol-
4-yl]methylene-1,3-indandione (XX) is present in the
reaction mixture. This compound was obtained in an
individual state by boiling an ethanol solution of an
equimolar mixture of aldehyde I and dione XI. This
compound with amine II under conditions of the three-
component condensation (aldehyde I + amine II +
diketone XI) gave 13-[3-(4-fluorophenyl)-1H-pyrazol-4-
yl]-7,13-dihydro-12H-benzo[f]indeno[1,2-b]-quinolin-12-
one (XXI). The synthesis of indenoquinoline XXI
obviously proceeds through stages of dione XX addition
to amine II at the electron-rich α-position of the naph-
thalene ring, and of cyclization of the intermediate amino-
diketone similar to intermediate E. Dihydro compound
XXI underwent dehydrogenation at boiling in nitrobenzene
to yield 13-[3-(4-fluorophenyl)-1H-pyrazol-4-yl], 12H-
benzo[f]indeno-[1,2-b]quinolin-12-one (XXII).
Thus based on condensation of 3-(4-fluorophenyl)-4-
pyrazolecarbaldehyde with 2-naphthyl- or 6-quinolylamine
and CH-acids we developed new efficient methods of
synthesis of previously unknown polynuclear heterocycles
with a high nuitrogen content and an extended conjugation
system, promising as luminophores, light-sensitive
material, and bioactive substances of versatile effect.
In the IR spectra of compounds XXI and XXII
absorption bands of CO group stretching vibrations appear
at 1660 (XXI) and 1690 cm–1 (XXII). The spectrum of
dihydro derivative XXI contains three bands in the region
3280–3230 cm–1 corresponding to the stretching vibra-
tions of NH groupd from azaphenanthrene skeleton and
pyrazole substituent. In the spectrum of oxidized product
EXPERIMENTAL
IR spectra were recorded on a Fourier spectrometer
Nicolet Protege-460 from samples prepared as KBr
pellets. Mass spectra were measured on Finnigan MAT
INCOS-50 instrument at ionizing electrons energy 70eV,
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 43 No. 2 2007

KOZLOV, GUSAK
246
263 (4.60), 283 (4.78), 338 (3.70), 367 (3.74). 1H NMR
spectrum, δ, ppm: 3.00 s (3H, Me), 6.61–8.05 m (10H,
Harom), 8.35 s (1H, H2), 8.80 m (1H, =CH–NH),
13.30 br.s (1H, =CH–NH). Found, %: N 11.67.
C23H16FN3. Calculated, %: N 11.90.
and on GC-MS instrument Hewlett-Packard HP 5890/
5972 in an electron impact mode at the energy 70 eV;
column HP-5MS [30 m × 0.25 mm, film thickness of the
stationary phase (5% PLMe Silicone) 0.25 μm]; vaporizer
temperature 250°C. UV spectra of solutions in ethanol
(C 10–4 mol l −1) were obtained on a spectrometer Specord
UV-Vis. NMR spectra were registered on spectrometers
BrukerAC-500 (500 MHz) and Tesla BS-567 (100 MHz)
from solutions in DMSO-d6, benzene-d6, and chloroform-
d; internal reference TMS.
1-Phenyl-3-[3-(4-fluorophenyl)-1H-pyrazol-4-
yl]benzo[f]quinoline (XIVb). Yield 49% (a), 55% (b),
mp 256–257°C. UV spectrum, λmax, nm (log ε): 225
(4.66), 260 (4.59), 290 (4.89), 340 (3.92), 362 (3.63).
1H NMR spectrum, δ, ppm: 7.15–8.50 m (16H, Harom),
8.70 s (1H, =CH–NH), 11.02 br.s (1H, =CH–NH). Found,
%: N 9.94. C28H18FN3. Calculated, %: N 10.12.
Melting points were measured on Koeffler heating
block.
[3-(4-Fluorophenyl)-1H-pyrazole-4-ylmethyl-
ene]-2-naphthyl-(or 6-quinolyl)amines XII and XIII.
A solution of 5 mmol of aldehyde I, 5 mmol of 2-naphthyl-
amine (II) [or 6-quinolylamine (III)] in 20 ml of ethanol
was boiled for 1 h. The precipitate separated on cooling
was filtered off and recrystallized from ethanol.
1-Phenyl-3-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-
4,7-phenanthroline (XV) was prepared in a similar
fashion from 6-quinolylamine (III), acetophenone (V),
and aldehyde I (method a) or ketone V and azomethine
XIII (method b) by boiling in 1-butanol in the presence
of HCl for 8–9 h. After neutralization with NH4OH the
reaction product was recrystallized from a mixture
ethanol–benzene, 2:1. Yield 39% (a), 44% (b), mp 251–
252°C. UV spectrum, λmax, nm (log ε): 224 (4.58), 258
[3-(4-Fluorophenyl)-1H-pyrazol-4-ylmethylene]-
2-naphthylamine (XII). Yield 63%, mp 163–164°C. UV
spectrum, λmax, nm (log ε): 207 (4.49), 226 (4.43), 253
1
1
(4.52), 291 (4.90), 338 (3.90), 359 (3.67). H NMR
(4.60), 339 (4.11). H NMR spectrum, δ, ppm: 7.25–
spectrum, δ, ppm: 7.22–8.84 m (16H, Harom, =CH–NH ),
11.10 br.s (1H,=CH–NH). Found, %: N 13.41.
C27H17FN4. Calculated, %: N 13.46.
8.35 m (12H, Harom), 9.35 s (1H, CH=N), 10.60 s (1H,
NH). Found, %: N 13.24. C20H14FN3. Calculated, %:
N 13.33.
4-[3-(4-Fluorophenyl)-1H-pyrazol-4-yl]-2,3-
dihydro-1H-benzo[f]cyclopenta[c]quinoline (XVIa).
A solution of 5 mmol of aldehyde I, 5 mmol of 2-naphthyl-
amine (II), 5 mmol of cyclopentanone (VI) (method a)
or 5 mmol of ketone VI and 5 mmol of azomethine XII
(method b) in 20 ml of ethanol and 0.5 ml of concn. HCl
was boiled for 6 h. Reaction product was isolated as
described for compounds XIVa and XIVb. Yield 49%
(a), 52% (b), mp 277–278°C. UV spectrum, λmax, nm
(log ε): 221 (4.49), 248 (4.62), 287 (4.84), 339 (3.70),
356 (3.68). 1H NMR spectrum, δ, ppm: 2.12 m (2H, CH2),
2.80 t (2H, CH2), 3.78 t (2H, CH2), 7.00–8.104 m (10H,
Harom), 8.70 m (1H, =CH–NH), 13.28 br.s (1H, =CH–
NH). Found, %: N 10.90. C25H18FN3. Calculated, %:
N 11.08.
[3-(4-Fluorophenyl)-1H-pyrazol-4-ylmethylene]-
6-quinolylamine (XIII). Yield 59%, mp 177–178°C. UV
spectrum, λmax, nm (log ε): 208 (4.41), 229 (4.40), 253
1
(4.65), 339 (4.09). H NMR spectrum, δ, ppm: 7.15–
8.80 m (12H, Harom, CH=N), 10.15 s (1H, NH). Found,
%: N 17.54. C19H13FN4. Calculated, %: N 17.72.
1-Methyl (or phenyl)-3-[3-(4-fluorophenyl)-1H-
pyrazol-4-yl]benzo[f]quinolines XIVa and XIVb. (a)
A mixture of 5 mmol of aldehyde I, 5 mmol of 2-naphthyl-
amine (II), 10 mmol of acetone (IV) [or acetophenone
(V)], 20 ml of ethanol, and 0.5 ml of concn. HCl was
boiled for 12 h. The separated precipitate was filtered
off, treated with 25% water solution of NH4OH, washed
with water, and recrystallized from a mixture ethanol–
benzene, 3:1.
5-[3-(4-Fluorophenyl)-1H-pyrazol-4-yl]-1,2,3,4-
tetrahydrobenzo[a]phenanthridine (XVIb) was
obtained from aldehyde I, 2-naphthylamine (II), and
cyclohexanone (VII) (method a) or ketone VII and
azomethine XII (method b) similarly to compound XVIa.
Yield 44% (a), 43% (b), mp 283–284°C. UV spectrum,
b. A solution of 5 mmol of azomethine XII, 10 mmol
of acetone (IV) [or 5 mmol of acetophenone (V)], 20 ml
of ethanol, and 0.5 ml of concn. HCl was boiled for 11
h. Reaction products XIVa and XIVb were isolated as
described above.
1-Methyl-3-[3-(4-fluorophenyl)-1H-pyrazol-4-yl-
benzo[f]quinoline (XIVa). Yield 52% (a), 54% (b), mp
247–248°C. UV spectrum, λmax, nm (log ε): 225 (4.60),
λ
max, nm (log ε): 224 (4.51), 247 (4.60), 289 (4.83), 341
1
(3.89), 360 (3.80). H NMR spectrum, δ, ppm: 1.78 m
(4H, CH2), 2.65 m (2H, CH2), 3.58 m (2H, CH2), 6.98–
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3-(4-FLUOROPHENYL)-1H-PYRAZOLE-4-CARBALDEHYDE
247
8.20 m (10H, Harom), 8.82 m (1H, =CH–NH), 13.30 br.s
(1H, =CH–NH). Found, %: N 10.47. C26H20FN3.
Calculated, %: N 10.69.
222°C. UV spectrum, λmax, nm (log ε): 216 (4.49), 250
(4.39), 292 (4.26), 338 (3.96), 376 (3.98). 1H NMR spec-
trum, δ, ppm: 1.05 s (3H, Me), 1.10 s (3H, Me), 2.14 m
(2H, CH2), 2.58 m (2H, CH2), 5.80 s (1H, H12), 6.80–
8.24 m (11H, Harom, =CH–NH), 9.80 C (1H, NH),
12.61 br.s (1H, =CH–NH). Found, %: N 9.37.
C28H24FN3O. Calculated, %: N 9.61.
3-Methyl-5-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-
1,2,3,4-tetrahydrobenzo[a]phenanthridine (XVIc)
was obtained from aldehyde I, 2-naphthylamine (II), and
4-methylcyclohexanone (VIII) (method a) or ketone VIII
and azomethine XII (method b) similarly to compound
XVIa, but in the presence of 1 ml of nitrobenzene. Yield
12-[3-(4-Fluorophenyl)-1H-pyrazol-4-yl]-
7 , 8 , 9 , 1 0 , 11 , 1 2 - h e x a h y d r o b e n z o [ b ] [ 4 , 7 ] -
phenanthrolin-11-ones XVIIIa and XVIIIb were
obtained from aldehyde I, 6-quinolylamine (III), and
diketone IX or X (method a) or ketone IX, X and
azomethine XII (method b), and also by boiling a butanol
solution of amine III and the condensation product of
aldehyde I with diketone IX or X (method c) similarly to
compounds XVIIa and XVIIb. Benzophenanthrolinones
XVIIIa and XVIIIb were recrystallized from a mixture
ethanol–benzene, 4:1.
36% (a), 42% (b), mp 220–221°C. UV spectrum, λmax
,
nm (log ε): 225 (4.53), 249 (4.58), 284 (4.85), 340 (3.94),
361 (3.80). 1H NMR spectrum, δ, ppm: 0.96 s (3H, Me),
1.78 m (2H, CH2), 1.94–2.86 m (3H, CH, CH2), 3.62 m
(2H, CH2), 6.80–8.16 m (10H, Harom), 8.80 m (1H, =CH–
NH), 13.34 br.s (1H, =CH–NH). Found, %: N 10.17.
C27H22FN3. Calculated, %: N 10.31.
12-[3-(4-Fluorophenyl)-1H-pyrazol-4-yl]-
7,8,9,10,11,12-hexahydrobenzo[a]acridin-11-ones
XVIIa and XVIIb. a. A mixture of 5 mmol of aldehyde
I, 5 mmol of 2-naphthylamine II, 5 mmol of 1,3-cyclo-
hexanedione (IX) [or 5 mmol of dimedone (X)], and 20
ml of 1-butanol was boiled for 6 h. The solution was
evaporated to 1/2 of volume. The separated precipitate
was filtered off, compound XVIIa was recrystallized from
methanol, acridone XVIIb, from ethanol.
12-[3-(4-Fluorophenyl)-1H-pyrazol-4-yl]-
7 , 8 , 9 , 1 0 , 11 , 1 2 - h e x a h y d r o b e n z o [ b ] [ 4 , 7 ] -
phenanthrolin-11-one (XVIIIa). Yield 80% (a), 79%
(b), 63% (c), mp 283–284°C. UV spectrum, λmax, nm
(log ε): 216 (4.59), 243 (4.36), 290 (4.18), 337 (4.04),
378 (3.90). 1H NMR spectrum, δ, ppm: 1.97 m (2H, CH2),
2.40 m (2H, CH2), 2.74 m (2H, CH2), 5.78 s (1H, H12),
7.07 d.d (1H, H2), 7.28 m (4H, Harom), 7.50 d, 7.78 d (2H,
H5,6), 8.29 m (2H, H1, =CH–NH), 8.60 d (1H, H3),
9.84 s (1H, NH), 13.40 br.s (1H, =CH–NH). Found, %:
N 13.56. C25H19FN4O. Calculated, %: N 13.66.
b.Asolution of 5 mmol of azomethine XII, 5 mmol of
diketone IX of 5 mmol of dimedone (X) in 20 ml of
1-butanol was boiled for 6 h. Reaction products XVIIa
and XVIIb were isolated as described above.
9,9-Dimethyl-12-[3-(4-fluorophenyl)-1H-pyrazol-
4-yl]-7,8,9,10,11,12-hexahydrobenzo[b][4,7]
phenanthrolin-11-one (XVIIIb). Yield 82% (a), 86%
(b), 67% (c), mp 236–237°C. UV spectrum, λmax, nm
(log ε): 217 (4.57), 246 (4.34), 292 (4.19), 338 (4.96),
377 (3.92). 1H NMR spectrum, δ, ppm: 1,04 s (3H, Me),
1.12 s (3H, Me), 2.20 m (2H, CH2), 2.59 m (2H, CH2),
5.82 s (1H, H12), 7.04 d.d (1H, H2), 7.30 m (4H, Harom),
7.52 d, 7.80 d (2H, H5,6), 8.30 m (2H, H1, =CH–NH),
8.61 d (1H, H3), 9.83 s (1H, NH), 13.50 br.s (1H, =CH–
NH). Found, %: N 12.58. C27H23FN4O. Calculated, %:
N 12.79.
c. Asolution of 5 mmol of aldehyde I, 5 mmol of dione
IX or diketone X in 20 ml of 1-butanol was boiled for 1 h,
5 mmol of 2-naphthylamine (II) was added, and the
reaction mixture was boiled for 4 h more. Reaction
products XVIIa and XVIIb were isolated as described
above.
12-[3-(4-Fluorophenyl)-1H-pyrazol-4-yl]-
7,8,9,10,11,12-hexahydrobenzo[a]acridin-11-one
(XVIIa). Yield 72% (a), 76% (b), 52% (c), mp 297–
298°C. UV spectrum, λmax, nm (log ε): 218 (4.52), 249
1
(4.46), 291 (4.21), 339 (3.93), 371 (3.93). H NMR
spectrum, δ, ppm: 1.98 m (2H, CH2), 2.38 m (2H, CH2),
2.76 m (2H, CH2), 5.70 s (1H, H12), 6.80–8.22 m (11H,
Harom, =CH–NH), 9.87 C (1H, NH), 12.58 br.s (1H, =CH–
NH). Found, %: N 10.11. C26H20FN3O. Calculated, %:
N 10.27.
9-[3-(4-Fluorophenyl)-1H-pyrazol-4-yl]-
2,3,4,5,6,7,8,9-octahydro-1H-xanthene-1,8-diones
XIXa and XIXb. Asolution of 5 mmol of aldehyde I and
5 mmol of diketone IX or dimedone (X) in 20 ml of ethanol
or 1-butanol was boiled for 1 h, 1 ml of a saturated
solution of KOH in alcohol was added, and the mixture
was boiled for 2 h more. The precipitate was filtered off,
washed with methanol, with ether, and dried.
9,9-Dimethyl-12-[3-(4-fluorophenyl)-1H-pyrazol-
4-yl]-7,8,9,10,11,12-hexahydrobenzo[a]acridin-11-
one (XVIIb). Yield 86% (a), 90% (b), 66% (c), mp 221–
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 43 No. 2 2007

KOZLOV, GUSAK
248
9-[3-(4-Fluorophenyl)-1H-pyrazol-4-yl]-
tion of 1 mmol of dihydro derivative XXI in 10 ml of
nitrobenzene was boiled for 8 h. The reaction product
was recrystallized from a mixture toluene–nitrobenzene,
2:1. Yield 71%, mp 299–300°C. UV spectrum, λmax, nm
(log ε): 225 (4.42), 253 (4.34), 285 (4.74), 338 (4.00),
378 (3.98). 1H NMR spectrum, δ, ppm: 6.98–8.22 m (15H,
Harom, =CH–NH), 13.55 br.s (1H, =CH–NH). Found, %:
N 9.41. C29H16FN3O. Calculated, %: N 9.52.
2,3,4,5,6,7,8,9-octahydro-1H-xanthene-1,8-dione
(XIXa). Yield 54%, mp 223–224°C. UV spectrum, λmax
,
nm (log ε): 206 (4.69), 252 (4.61), 279 (4.27), 330 (3.84).
1H NMR spectrum, δ, ppm: 1.75–2.60 m (12H, CH2),
4.80 s (1H, CH), 7.02–7.80 m (5H, Harom, =CH–NH),
10.60 br.s (1H, =CH–NH). Found, %: N 7.25.
C22H19FN2O3. Calculated, %: N 7.41.
3,3,6,6-Tetramethyl-9-[3-(4-fluorophenyl)-1H-
pyrazol-4-yl]-2,3,4,5,6,7,8,9-octahydro-1H-
xanthene-1,8-dione (XIXb). Yield 49%, mp 180–181°C.
UV spectrum, λmax, nm (log ε): 207 (4.61), 254 (4.58),
The study was carried out under a financial support
of Belorussian-Russian Foundation for Fundamental
Research (grant no. Kh04P-017).
REFERENCES
1
273 (4.19), 333 (3.76). H NMR spectrum, δ, ppm:
0.99 m (12H, 4Me), 1.80–2.30 m (8H, CH2), 5.60 s (1H,
CH), 6.92–7.40 m (5H, Harom, =CH–NH), 10.50 br.s (1H,
=CH–NH). Found, %: N 6.39. C26H27FN2O3. Calculat-
ed, %: N 6.45.
1. Kozlov, N.S., 5,6-Benzokhinoliny (5,6-Benzoquinolines),
Minsk: Nauka i tekhnika, 1970, p. 28.
2. Monge, A.,Alvarez, E., San, Martin, C., Nadal, E., Ruiz, I.,
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5. Bicsak, T.A., Rann, L.R., Reiter, A., and Chase, T., Arch.
Biochem. Biophys., 1982, vol. 216, p. 605.
2-[3-(4-Fluorophenyl)-1H-pyrazol-4-yl]-
methylene-1,3-indandione (XX). Asolution of 5 mmol
of aldehyde I and 5 mmol of diketone XI in 20 ml of
ethanol was boiled for 3 h, the precipitate formed on
cooling was filtered off, washed with ether, and
recrystallized from a mixture ethanol–benzene, 1:1. Yield
95%, mp 289–290°C. UV spectrum, λmax, nm (log ε):
204 (4.25), 247 (4.15), 259 (4.08), 301 (3.51), 370 (4.26).
6. Husseini, R. and Stretton, R.J., Microbios., 1981, vol. 30,
p. 7.
1H NMR spectrum, δ, ppm: 7.30–7.95 m (9H, Harom
,
7. Kozlov, N.G., Basalaeva, L.I., Firgang, S.I., and Shash-
kov, A.S., Zh. Org. Khim., 2004, vol. 40, p. 549.
8. Kozlov, N.G., Popova, L.A., andYakubovich, L.S., Zh. Org.
Khim., 2000, vol. 36, p. 1716.
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Toxicol., 1993, vol. 6, p. 813.
10. Blache, Y., Benezech, V., Chezal, J.-M., Boule, P., Viols, H.,
Chavignon, O., Teulade, J.C., and Chapat, J.-P.,
Heterocycles, 2000, vol. 53, p. 905.
11. Kozlov, N.S., Gusak, K.N., Serzhanina, V.A., and Shma-
nai, G.S., Dokl. Akad. Nauk BSSR, 1985, vol. 29, p. 336.
12. Kozlov, N.S., Shmanai, G.S., and Gusak, K.N., Dokl. Akad.
Nauk BSSR, 1985, vol. 29, p. 141.
–C=CH), 9.30 m (1H, =CH–NH), 13.8 br.s (1H, =CH–
NH). Found, %: N 8.66. C19H11FN2O2. Calculated, %:
N 8.80.
13-[3-(4-Fluorophenyl)-1H-pyrazol-4-yl]-7,13-
dihydro-12H-benzo[f]indeno[1,2-b]quinolin-12-one
(XXI). A solution of 5 mmol of aldehyde I, 5 mmol of
2-naphthylamine (II), 5 mmol of 1,3-indandione (XI)
(method a) or 5 mmol of amine II and 5 mmol of dione
(XX) (method b) in 20 ml of butanol was boiled for 6 h.
The precipitate was boiled with benzene and washed with
ether. Yield 62% (a), 66% (b), mp 340–341°C. UV
spectrum, λmax, nm (log ε): 204 (4.70), 234 (4.69), 267
(4.67), 349 (4.12), 479 (3.18). 1H NMR spectrum, δ, ppm:
5.75 s (1H, CH), 6.85–8.20 m (15H, Harom, =CH–NH),
10.80 s (1H, NH), 13.8 br.s (1H, =CH–NH). Found, %:
N 9.25. C29H18FN3O. Calculated, %: N 9.48.
13. Kozlov, N.G., Sauts, R.D., and Gusak, K.N., Zh. Org. Khim.,
2000, vol. 36, p. 556.
14. Gauptman, Z., Grefe, Yu., and Remane, Kh.,
Organicheskaya khimiya (Organic Chemistry), Moscow:
Khimiya, 1979, 487.
13-[3-(4-Fluorophenyl)-1H-pyrazol-4-yl]-12H-
benzo[f]indeno[1,2-b]quinolin-12-one (XXII). Asolu-
15. Kozlov, N.G., Gusak, K.N., Tereshko, A.B., Firgang, S.I.,
and Shashkov, A.S., Zh. Org. Khim., 2004, vol. 40, p. 1228.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 43 No. 2 2007