Facile and Regioselective Synthesis of Substituted 1H-Pyrazolo[3,4-b]quinolines from 2-Fluorobenzaldehydes and 1H-Pyrazol-5-amines

Article abstract of DOI:10.1002/jhet.2751

The present article concerns the scope and limitations of the regioselective condensation of 2-fluorobenzaldehydes with 1H-pyrazol-5-amines, leading to the synthesis of substituted 1H-pyrazolo[3,4-b]quinolines (PQ), in the presence of a base catalyst (DAB

Full text of DOI:10.1002/jhet.2751

Month 2016
Facile and Regioselective Synthesis of Substituted 1H-Pyrazolo[3,4-b]
quinolines from 2-Fluorobenzaldehydes and 1H-Pyrazol-5-amines
a
a
a
a
b
*
Paweł Szlachcic, Mateusz Kucharek, Bożena Jarosz, Andrzej Danel, and Katarzyna Stadnicka
aInstitute of Chemistry at Faculty of Food Technology, Agricultural University, ul. Balicka 122, 31-149 Kraków, Poland
bFaculty of Chemistry, Jagiellonian University, ul. Ingardena 3, 30-060 Kraków, Poland
*E-mail: p.szlachcic@ur.krakow.pl
Received March 22, 2016
DOI 10.1002/jhet.2751
Published online 00 Month 2016 in Wiley Online Library (wileyonlinelibrary.com).
The present article concerns the scope and limitations of the regioselective condensation of 2-
fluorobenzaldehydes with 1H-pyrazol-5-amines, leading to the synthesis of substituted 1H-pyrazolo[3,4-b]
quinolines (PQ), in the presence of a base catalyst (DABCO and 2,4,6-trimethylpyridine). A method to
obtain these nitrogen heterocycles with fluorine or trifluoromethyl substituents in different positions in the
carbocyclic ring was developed as a part of a systematic research on the influence of fluorine-containing sub-
stituents on the parameters of PQ. Those compounds, characterized by high-fluorescence intensity, have
been tested as emitters for the organic light-emitting diodes since 1997. The functionalization of PQ causes
changes in various parameters, for example, HOMO and LUMO levels, which are important for the adjust-
ment of fabricated organic light-emitting diodes. One of the easiest methods of PQ preparation, namely, the
condensation of substituted anilines with 5-chloro-1H-pyrazole-4-carbaldehydes, is not regioselective. The
method described in this study allows synthesizing of 1H-pyrazolo[3,4-b]quinolines with good yields and
high selectivity – only the expected isomer is obtained. As various different 2-fluorobenzaldehydes are com-
mercially available, and 1H-pyrazol-5-amines with different substituents are easy to prepare, the method
could be a good alternative to the already known procedures. All possible mechanisms of the reaction were
also thoroughly studied.
J. Heterocyclic Chem., 00, 00 (2016).
INTRODUCTION
additionally, the 5-chloro-1H-pyrazole-4-carbaldehydes
can be easily prepared by the Vilsmeier–Haack
formylation of appropriate 1,3-disubstituted-4H-pyrazol-
5-ones [9]. The method is highly useful for aniline and its
4-substituted derivatives (R6 as substituent). The yields
are good to excellent – 40–96% – almost independently
of the substituent (for examples see [6,8,10]). On the
other hand, for the 3-subtituted anilines, two isomers are
always formed, because the reaction is not regioselective
in its origin. These isomers are structurally similar, and
their parameters which are important for separation, for
example, solubility or time of retention; they are also
comparable, and the isomers could be separated in only a
few cases [10b]. Therefore, our interest was focused on a
search for a regioselective method of the synthesis of PQ.
Friedländer condensation of an o-aminobenzaldehyde
(anthranilic aldehyde) with 1,3-disubstituted-4H-pyrazol-
5-ones is regioselective (by that method, PQ was
introduced in chemistry for the first time by Musierowicz
et al. in 1928 [1]), but only the unsubstituted anthranilic
aldehyde is commercially available, and fluorine
substituted aldehydes have to be prepared prior to the
condensation. Additionally, o-aminobenzaldehydes are
1H-Pyrazolo[3,4-b]quinolines (PQ, Fig. 1) are tricyclic,
heterocyclic compounds known since 1928, when they
were obtained for the first time [1]. Various nitrogen
heterocycles are commonly used in fabrication of organic
light-emitting diodes (OLEDs) [2] – the first one was
fabricated on the base of a 8-hydroxyquinoline complex
by Tang and Van Slyke in 1987 [3]. In 1997, 4-methyl-
1,3-diphenyl-1H-pyrazolo[3,4-b]quinoline
luminophor
was used for the fabrication of an OLED cell by He et al.
[4]. Since then, many different PQ have been used as
emitters in OLED (see examples [5,6]).
As part of the study on the influence of fluorine
substitution on the parameters of PQ-based emitters [7],
we considered the preparation of PQ derivatives with the
fluorine atom (or trifluoromethyl group) located in all
four positions of the carbocyclic ring of PQ (Fig. 1,
R5ÀR8 = F, CF3). The most common method of 4-H-PQ
(Fig. 1, R4 = H) synthesis is the condensation of
substituted anilines with different 5-chloro-1H-pyrazole-
4-carbaldehydes, introduced by Brack in 1965 [8]. Many
substituted anilines are available commercially;
© 2016 Wiley Periodicals, Inc.

P. Szlachcic, M. Kucharek, B. Jarosz, A. Danel, and K. Stadnicka
Vol 000
non-solvent conditions at 220–240°C. They only proved
the structures of the products by using elemental analysis
1
of nitrogen (with no apparatus details), neither H-NMR
nor 13C-NMR spectra were present, and the melting point
of the suggested product, 1,3,5,7-tetraphenyl-4-
(pentafluorophenyl)-bis-pyrazolo[3,4-b,4′,3′-e]pyridine, is
similar to that found for the 5,6,7,8-tetrafluoro-1H-
pyrazolo[3,4-b]quinoline by Abramov. It is possible that
Joshi obtained not BPP, but the same PQ as Abramov.
Figure 1. The structure of substituted 1H-pyrazolo[3,4-b]quinoline, PQ.
not very stable compounds and have a limited shelf life
[11]. If 2-aminobenzaldehyde is replaced by 2-
nitrobenzaldehyde, PQ could be obtained in a two-step
procedure [12], but in this case, the substrates
(substituted 2-nitrobenzaldehydes) also have to be
prepared before the condensation. Substituted anthranilic
acids could be regioselectively transformed into 4-chloro-
1H-pyrazolo[3,4-b]quinolines, but the procedure is a
multistep reaction [13]. The procedure of Neelima et al.
requires the substituted 2-chloro-3-ketoquinolines to be
prepared and reacted with hydrazines to produce the
expected PQ [14], but 2-chloro-3-ketoquinolines with
fluorine atoms or the trifluoromethyl group have not
been obtained yet. Finally, we have found a promising
paper by Abramov et al., concerning the condensation
of pentafluorobenzaldehyde with 1H-pyrazol-5-amines
in xylene/acetic acid solution [15]. As a result, the
RESULTS AND DISCUSSION
Abramov et al. did not perform a systematic research on
the scope and limitations of their method, so we decided to
continue the research and expand on their findings, and
investigate the range of possible applications of that
reaction for the synthesis of 1H-pyrazolo[3,4-b]
quinolines, PQ.
First, we have condensed benzaldehydes containing a
halogen atom in the ortho position with 1,3-diphenyl-1H-
pyrazol-5-amine, 2a (Table 1).
In the case of 2-chloro, 2-bromo, and 2-
iodobenzaldehydes (1b–d), the main product was a
corresponding 1,3,5,7-tetraphenyl-4-(2′-halophenyl)-bis-
5,6,7,8-tetrafluoro-1H-pyrazolo[3,4-b]quinolines
were
synthesized, applying the reaction used earlier for the
preparation of substituted acridines [16]. The results of
the Abramov et al. study on the reaction of
pentafluorobenzaldehyde with 1H-pyrazol-5-amines seem
to be different from those found earlier by Joshi et al.
[17], who obtained bis-pyrazolo[3,4-b,4′,3′-e]pyridines
(BPP), rather than PQ, in a similar reaction performed in
1H,7H-pyrazolo[3,4-b,4′,3′-e]pyridine,
BPP
(4b–d,
Table 1), as expected, and as observed earlier in similar
conditions (for 2-chloro- and 2-bromobenzaldehyde, 1b
and 1c) by other authors [8,18]. However, for the 2-
fluorobenzaldehyde (1a), 1,3-diphenyl-1H-pyrazolo[3,4-
b]quinoline, PQ (3a), was obtained as a major product
Table 1
Synthesis of 1,3-diphenyl-1H-pyrazolo[3,4-b]quinoline, PQ (3), and 1,3,5,7-tetraphenyl-4-(2′-halophenyl)-bis-pyrazolo[3,4-b,4′,3′-e]pyridine, BPP (4)
by the reaction of 2a (R1,R3 = Ph) with 2-halobenzaldehydes, 1.
Products
Entry
Aldehyde
PQ
Yields (%)
BPP
Yields (%)
1
2
3
4
1a (X = F)
1b (X = Cl)
1c (X = Br)
1d (X = I)
3a*
3b*
3c*
3d*
29
2.5
2
4a
4b
4c
4d
10
51
45
37
1.5
*3a–d are the same compound, 1,3-diphenyl-1H-pyrazolo[3,4-b]quinoline.
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(proved by the elemental analysis and 1H-NMR/13C-NMR
spectra). In all the cases, the products were initially
separated by column chromatography, followed by a
centrifugally accelerated, radial, thin layer preparative
chromatograph (Chromatotron) separation [19]. Our
results seem to be different to those found earlier by
Quiroga et al., who obtained 5,7-dimethyl-1,3-diphenyl-
4-(2′-fluorophenyl)-bis-1H,7H-pyrazolo[3,4-b,4′,3′-e]
pyridine in 80% yield in microwave irradiation reaction
conditions [20]. However, the authors used 3-methyl-1-
phenyl-1H-pyrazol-5-amine, 2b, in the reaction, instead
of a 1,3-diphenyl-1H-pyrazol-5-amine, 2a. The possible
reasons for the different results, and the importance of the
substituent type in the position 3 of 1H-pyrazol-5-amine
(R3 in 2), will be discussed later.
compared with 2-chlorobenzaldehyde (3b and 4b in
Table 1). The use of 2,4-difluorobenzaldehyde (1i)
results in the PQ (3i) as the major product, but for the
2,4-dichlorobenzaldehyde (1j), the major product
appears to be the BPP, 4j (similarly as for 2-
chlorbenzaldehyde, 3b and 4b, Table 1). It is worth
noting here that the yield of 7-fluoro-1,3-diphenyl-1H-
pyrazolo[3,4-b]quinoline (3i, 49%) and 5-fluoro-1,3-
diphenyl-1H-pyrazolo[3,4-b]quinoline
(3e,
65%),
obtained separately from different substrates, is better
than the results of the reaction between 3-fluoroaniline
and 1,3-diphenyl-5-chloro-1H-pyrazole-4-carbaldehyde.
In the second case, a mixture of 5-fluoro- and 7-fluoro-
1,3-diphenyl-1H-pyrazolo[3,4-b]quinoline was obtained.
7-Fluoro
isomer
was
isolated
by
fractional
The results we obtained encouraged us to investigate a
wider group of reagents. We started with 2,6-dihalogen-
substituted and 2,4-dihalogen-substituted benzaldehydes
in the same reaction conditions (Table 2).
crystallization, followed by column chromatography at
39% yield, but the attempts to obtain pure 5-fluoro
isomer, free from 7-fluoro, failed.
The interesting effect of using 2,6-dichlorbenzaldehyde
(1g) was that much more PQ (3g) was formed, in
contrast to the reaction of 2-chlorobenzaldehyde and 2,4-
dichlorobenzaldehyde (1b and 1j) – this could be
explained by a mechanism proposed earlier by Abramov
et al. [15]. The tendency of 2-fluorobenzaldehyde (1a) to
form PQ rather than BPP possibly means that the first
stage of the reaction could be the addition of the amine
group of the 1H-pyrazol-5-amine to the carbon atom
linked with fluorine (Scheme 1) – SNAr (addition–
elimination) mechanism.
For comparison, we also performed the reaction with
pentafluorobenzaldehyde, 1k (used by Abramov et al.
[15]). As can be seen from Table 2, 2-fluoro-6-halogen-
benzaldehydes (1e,f,h) predominantly form the
corresponding 5-halogen-1,3-diphenyl-1H-pyrazolo[3,4-
b]quinoline, PQ (3e,f,h), and in all cases, the fluorine
atom is substituted. The highly reactive 1k forms
practically only PQ, as expected (84% yield). 2,6-
Dichlorbenzaldehyde (1g) forms more BPP (4g) than
PQ (3g), but the amount of PQ is still very high, when
Table 2
Synthesis of substituted 1,3-diphenyl-1H-pyrazolo[3,4-b]quinoline, PQ (3), and 1,3,5,7-tetraphenyl-4-(substituted-phenyl)-bis-pyrazolo[3,4-b,4′,3′-e]
pyridine, BPP (4) by the reaction of 2a (R1,R3 = Ph) with substituted benzaldehydes, 1.
Products
Entry
Aldehyde
PQ
Yields (%)
BPP
Yields (%)
1
2
3
4
5
6
7
1e (X,Y = F, Z = H)
3e
3f*
3g*
3h
3i
65
57
22
68
49
6
4e
4f
4g
4h
4i
2.5
9
38
9
7
1f (X = F, Y = Cl, Z = H)
1g (X,Y = Cl, Z = H)
1h (X = F, Y = I, Z = H)
1i (X,Z = F, Y = H)
1j (X,Z = Cl, Y = H)
1k (pentafluorobenzaldehyde)
3j
3k
4j
4k
49
traces
84
*3f and 3g are the same compound, 6-chloro-1,3-diphenyl-1H-pyrazolo[3,4-b]quinoline.
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Scheme 1. The proposed mechanism of the formation of PQ (3) in the reaction of 2-fluorobenzaldehydes (1) and 1H-pyrazol-5-amine 2. [Color figure can
be viewed in the online issue, which is available at wileyonlinelibrary.com.]
The fluorine atom is the most electronegative of all
elements and stabilizes the transition state better than the
other halogens [21]. The fluorine is also the smallest one
and causes the lowest steric hindrance. The elimination of
halogen is the easiest for iodine, but as the elimination
stage is not rate-determining, 2-iodobenzaldehyde (1d)
forms mostly BPP (4d in Table 1). That elimination step
ends with the formation of o-[(1,3-disubstituted-1H-
pyrazol-5-yl)amino]benzaldehyde, 5, with subsequent
intramolecular electrophilic substitution (SE) and the
formation of 4-hydroxy-4,9-dihydro-1,3-disubstituted-1H-
pyrazolo[3,4-b]quinoline, 6 (Scheme 1, solid arrows,
black). This compound could easily eliminate a water
molecule, forming PQ (3). At this stage, an alternative
reaction route is also possible: 5 reacts with 2 (dotted
arrows, red) and, after losing a water molecule, forms
Schiff’s base of 5 and 2: N-{o-[(1,3-disubstituted-1H-
pyrazol-5-yl)amino]benzylideno}-1,3-disubstituted-1H-
pyrazol-5-amine, 7. It could also undergo the
intramolecular SE reaction and form 4-[(1,3-
disubstituted-1H-pyrazol-5-yl)amino]-4,9-dihydro-1,3-
disubstituted-1H-pyrazolo[3,4-b]quinoline, 8, with
subsequent elimination of 2. As a result, PQ is formed.
That second route was proposed by Abramov as an
explanation of PQ formation in the reactions between
1k and 1H-pyrazol-5-amines, 2 [15]. That mechanism
readily explains the tendency of 2-fluorobenzaldehydes to
form PQ, but does not explain why small amounts of
BPP are formed as well. Moreover, our attempts to
obtain 5 from 2-halogenbenzaldehydes (1a–d) and 2a,
using Buchwald catalysts [22], failed to produce
expected products. In the examined cases, we have
obtained only Schiff’s bases of 1 and 2a.
Considering the previous statement, it is safe to assume
that another mechanism is probably more correct – the
one proposed earlier by Hennig et al. as an explanation
for the formation of BBP in the reaction of 1H-pyrazol-5-
amines with benzaldehydes [23]. The authors observed
that performing the reaction in boiling ethanol produced a
Schiff’s base, 9, as the main product. In higher
temperatures, and with the excess of the 1H-pyrazol-5-
amine, BPP is formed (Scheme 2).
The mechanism proposed by Hennig and developed here
explains not only the formation of PQ and BPP but also
the formation of another product found by us: the
4-(1,3-disubstituted-1H-pyrazolo[3,4-b]quinolin-4-yl)-1,3-
disubstituted-1H-pyrazol-5-amine, 13. The first stage,
described in Scheme 2, after the formation of Schiff’s
base, 9, is its reaction with another 2 molecule and the
formation of a by-product, 4-{[(1,3-disubstituted-1H-
pyrazol-5-yl)amino](phenyl)methyl}-1,3-disubstituted-
1H-pyrazol-5-amine, 10. That molecule could reversibly
lose molecule 2 and again react with 2 forming a
4,4′-(phenylmethanediyl)bis(1,3-disubstituted-1H-pyrazol-5-
amine), 12 (dashed/dotted arrows, pink). Finally, after
losing a NH3 molecule and being oxidized, the BPP (4) is
formed (dotted arrows, blue). But in some cases, other
paths are also possible. When fluorine in the ortho
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Scheme 2. “Hennig’s” mechanism of the formation of PQ, BBP, and 13 in the reaction of 2-fluorobenzaldehydes 1 and 1H-pyrazol-5-amine 2. [Color
figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
position (in respect to formyl group) is present, its high
electronegativity causes the free amine group of 10 to
attack the carbon atom linked with fluorine and, after
losing a HF molecule, to form 8 (proposed also in
Scheme 1). In the next stage, 2 is eliminated from 8, and
PQ (3) is formed (solid arrows, green on Scheme 2). The
formation of PQ is also possible at the stage of 11 –
nitrogen of imine group could attack the carbon atom
linked to fluorine, and after dehydrofluorination, the PQ is
formed (solid arrow, violet). We have also found another
product, 13: yellow compound exhibiting very weak
fluorescence in the solution, with Rf much lower than
those of PQ (3) and BPP (4). This yellow, nonfluorescent
compound was observed on the chromatographic column
or the chromatotron plate in most of the studied reactions,
but because of its strong affinity to the stationary phase, it
remained unisolated, or the amounts were too small to
identify the compound (<1 mg). The reaction between 1a
and 2a was repeated several times, and all collected
samples of 13 (13a in that case) were mixed together and
purified by crystallization, and the structure of 13a was
confirmed. The 1H-NMR/13C-NMR spectra were
complex, suggesting a molecule with 29 non-equivalent
carbon atoms, 24 aromatic hydrogens, and an amine
group. To unambiguously determine the structure of that
molecule, single crystal X-ray diffraction experiment was
performed. The shape of the molecule with the atom
numbering scheme is presented in Figure 2 [24].
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X,R5,R7 =H), was. The authors emphasized that only the
presented route could explain the formation of that
compound. 14 could also react with another 2 molecule
and form a 4,4′-(phenylmethanediyl)bis(1,3-disubstituted-
1H-pyrazol-5-amine), 12. The proposition of Esteves-
Souza et al. explains the formation of 13 and BPP (4),
as does the mechanism proposed by Hennig [23] – the
same intermediate (12 on Schemes 2 and 3) is observed in
both cases. The course of the reaction proposed on
Scheme 3 could also prove the formation of PQ (3) in
the case of 2-halogensubstituted benzaldehydes: if the
carbinol 14 contains the fluorine substituent in ortho
position, the amine group could intramolecularly attack
the carbon atom linked to fluorine (green on Scheme 3)
and form 4,9-dihydro-1,3-disubstituted-1H-pyrazolo[3,4-b]
quinoline, 6 (compare with Scheme 1), which can easily
lose a water molecule and aromatize to PQ (3). In our
study, we did not obtain any product of type 15, but as
we had used aldehydes containing the halogen atom in
ortho position to the carbonyl group, the main products
were different.
It is difficult to unambiguously determine which of the
presented mechanisms is correct, as we, and other
authors, [15,23,25] have found evidence for all of them.
Nevertheless, the analysis of the reaction products
obtained by us and other authors suggests that the
mechanisms depicted in Schemes 2 and 3 are the most
probable, as they explain the formation of all the
observed compounds. It is also possible that both of them
are correct, and the molecules undergo both reactions,
with specific conditions and reagents determining which
of the routes is preferred.
Figure 2. The conformation of 13a in the crystal structure (ORTEP rep-
resentation). Atom numbering scheme is shown. The atomic displacement
ellipsoids are given at 50% probability level. Significant dihedral angles
are the following: Pyrazole_4-Core = 55.47(6), Phenyl_1-Core = 38.47(7),
Phenyl_3-Core = 41.03(5), Phenyl_5-Pyrazole_4 = 45.15(9), and Phenyl_6-
Pyrazole_4 = 46.87(9)°, where Core is 1H-pyrazolo[3,4-b]quinoline
moiety. The conformation is stabilized by strong intermolecular hydrogen
bond N(45)–H(45B)…N(9), intramolecular and intermolecular interactions
of C–H…π types. [Color figure can be viewed in the online issue, which is
available at wileyonlinelibrary.com.]
The behavior of 2,4- and 2,6-dichlorobenzaldehydes (1j
and 1g on Table 2) seems to confirm both the mechanisms
(Schemes 2 and 3). 2,6-Dichlorobenzaldehyde (1g) forms
BPP (4g) as a major product, but the amount of PQ (3g)
The formation of 13 is possible at the stage of 12, when
the attack of one of the amine groups on the carbon linked
to fluorine is faster than the elimination of ammonia
(Scheme 2, dashed arrows, orange). The obtainment of
13 corroborates the existence of a by-product 12, and as a
consequence, it confirms the so-called Hennig’s
mechanism.
There is also another, slightly different explanation for
the formation of the BPP (4) molecule, proposed by
Esteves-Souza et al [25]. That proposition could explain
the formation of PQ (3), as well as 13 (in their case,
they used 1,3-dimethyl-1H-pyrazol-5-amine, 2d, instead
of 2a, and different benzaldehydes). The authors suggest
that the reaction leading to BPP (4) does not go through
the Schiff’s base 9 (Scheme 2), but through (5-amino-
1,3-disubstituted-1H-pyrazol-4-yl)(phenyl)methanol, 14
(Scheme 3).
is
also
significant
(even
though
the
2-
chlorobenzaldehyde, 1b, gives almost only BPP, 4b).
Two chlorine atoms near the aldehyde group increase the
probability of the attack of the amine group on the
carbon atom of the aromatic ring, and therefore the yield
of PQ is increased. These two chlorine atoms could also
cause steric hindrance around the carbonyl group and
slow down the reversible reaction leading to 12
(Scheme 2, dashed/dotted arrows, pink). As the
elimination of HF and the formation of 8 are irreversible,
more PQ is formed (Scheme 2, solid arrows, green). In
the case of 2,4-dichlorobenzaldehyde (1j), where the
steric hindrance around carbonyl group and the
probability of the attack of the amine group on the
carbon atom (Scheme 2) are comparable with that found
for the 2-chlorbenzaldehyde (1b), the reaction leads to an
expected BPP derivative (4j). The behavior of 2-chloro-
6-fluoro- and 2-fluoro-6-iodobenzaldehydes (1f and 1h)
The compound 14 was not isolated by the authors, but
another product, [5-(benzylideneamino)-1,3-dimethyl-
1H-pyrazol-4-yl](phenyl)methanol, 15a (R1,R2 = Me;
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Scheme 3. “Esteves-Souza’s” mechanism of the formation of PQ (3), BPP (4), 13, and 15 in the reaction of 2-fluorobenzaldehydes 1 and 1H-pyrazol-5-
amine 2. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
also confirms that conclusion: the most electronegative
fluorine atom is substituted, rather than chlorine or
iodine, respectively, and in both of those cases, the main
product is PQ (3f and 3h).
Irrespectively of the actual mechanism leading to the
formation of BPP and PQ in the condensation of 2-
halobenzaldehydes and 1H-pyrazol-5-amines, we are
additionally interested in the limitations of the
regioselective formation of the PQ molecules. In the next
part of the manuscript, we analyze mostly the limitations
and conditions of the reaction.
thesis, further experiments were conducted as described
next (Table 3).
In the following group of reactions, we used 2-
halobenzaldehydes with electron-withdrawing groups. As
the products of the reaction of 2a and 2-halo-5-
nitrobenzaldehydes (1l–n) are weakly soluble, the
separation and purification of the products were difficult.
Because of that, 2b was used in place of 2a in those
reactions. From Table 3, one can see that the presence of
the nitro group in 2-fluoro-5-nitrobenzaldehyde (1l)
increases the amount of PQ, when compared with the
reaction with 2-fluorobenzaldehyde (1a) (Table 1). In the
case of 2-chloro- and 2-bromo-5-nitrobenzaldehydes (1m
and 1n), more BPP is formed, than PQ, but the ratio is
changed in comparison with the reactions with these
The presented mechanisms suggest that the presence of
strong electron-withdrawing groups in the ortho or para
positions, in respect to the halogen atom, should also lead
favorably to the formation of PQ [21a]. To confirm that
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Vol 000
Table 3
Synthesis of 1,3-disubstituted-1H-pyrazolo[3,4-b]quinoline, PQ (3), and derivatives of 1,3,5,7-tetrasubstituted-4-(2′-halophenyl)-bis-pyrazolo[3,4-b,4′,3′-
e]pyridine, BPP (4) by the reaction of 1H-pyrazol-5-amines 2 with substituted benzaldehydes, 1.
Products
Entry
Amine
Aldehyde
PQ
Yields (%)
BPP
Yields (%)
1
2
3
4
5
6
2b (R1 = Ph, R2 = Me)
2b (R1 = Ph, R2 = Me)
2b (R1 = Ph, R2 = Me)
2a (R1, R3 = Ph)
1l (X = F, R6 = NO2, R8 = H)
1m (X = Cl, R6 = NO2, R8 = H)
1n (X = Br, R6 = NO2, R8 = H)
1o (X = F, R6 = H, R8 = CF3)
1p (X = Cl, R6 = H, R8 = CF3)
1q (X = Cl, R6 = CF3, R8 = H)
3l*
3m*
3n*
3o**
3p**
3q
56
6
7
52
6
2.5
4l
4m
4g
4h
4i
traces
30
27
traces
62
40
2a (R1, R3 = Ph)
2a (R1, R3 = Ph)
4j
*3l–n are the same compound, 6-nitro-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]quinoline.
**3o and 3p are the same compound, 8-(trifluoromethyl)-1,3-diphenyl-1H-pyrazolo[3,4-b]quinoline.
aldehydes without the nitro group. The presence of the
trifluoromethyl group does not significantly affect the
PQ/BPP ratio, when the halogen is chlorine; only in
the case of the reaction with 2-chloro-3-(trifluoromethyl)
benzaldehyde (1p), the yield of PQ (3p) is slightly
higher. When the halogen is fluorine, the trifluoromethyl
group located in the ortho position to it increases
the halogen’s reactivity (when compared with 2-
fluorobenzaldehyde 1a, Table 1). It is worth noting
that in this particular reaction, the yield (52%) is much
higher than in the Brack’s reaction [8] between
2-(trifluoromethyl)aniline and 5-chloro-1,3-diphenyl-1H-
pyrazol-4-carbaldehyde (<3%) [6g]. All the results
summarized in Table 3 are in agreement with the
proposed mechanisms.
The results of Abramov et al, [15] slightly different
to ours in the case of 2-chloro-5-nitrobenzaldehyde
(1m), could be explained by the use of acidic
conditions (CH3COOH) of the reaction and a lower
temperature. The amino group of the 1,3-disubstituted-
1H-pyrazol-5-amine, 2, could be protonated in those
conditions, leading the reaction mostly to a BPP
derivative.
nucleophilic
amine
(1,4-diazabicyclo[2.2.2]octane,
DABCO). The results are summarized in Table 4.
As can be seen in Table 4, small amounts of catalyst
(1 mol%) have relatively low influence on the yields of
both products, PQ and BPP: irrespectively of the
character of the additive, the yield is slightly increased.
When the concentration of the strong acid is increased,
Table 4
Products of the reactions between 1,3-diphenyl-1H-pyrazol-5-amine (2a)
and 2-fluorobenzaldehyde (1a) with different catalyst.
Products yields (%)
Entry
Catalyst*
p-TSA 1
p-TSA 10
p-TSA 100
p-TA 1
p-TA 10
p-TA 100
ZnCl2 1
ZnCl2 10
ZnCl2 100
DABCO 1
DABCO 10
DABCO 100
PQ
BPP
1
2
3
4
5
6
7
8
35
34
4
32
29
29
36
32
8
14
33
23
12
14
23
16
23
14
14
12
4
9
To understand the influence of the acids and bases on
the studied reactions, the condensation of 2-
fluorobenzaldehyde (1a) with 2a was repeated with the
addition of a relatively strong H-acid (p-toluenesulfonic
acid, p-TSA), weak H-acid (p-toluic acid, p-TA), Lewis
10
11
12
36
55
59
*Amount of catalyst in mol%.
PQ, 1,3-diphenyl-1H-pyrazolo[3,4-b]quinoline 3a; BPP, 1,3,5,7-tetraphenyl-
4-(2′-fluorophenyl)-bis-pyrazolo[3,4-b,4′,3′-e]pyridine 4a.
acid (zinc chloride, ZnCl2), and
a strong, non-
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2016
Facile and Regioselective Synthesis of Substituted 1H-Pyrazolo[3,4-b]quinolines
Table 5
the yield of PQ at first does not change, but in the case of
BPP, its yield increases. With the high concentration of
p-TSA (100mol%), the yield of both products is decreased,
but the amount of BBP is around six times higher than that
of PQ. Weak acid (p-TA) does not have significant
influence on the PQ yield, while the yield of BPP increases
with an increasing concentration of acid. Those
observations are in agreement with the proposed
mechanisms: while the concentration of H-acid is
increased, the amine 2 is deactivated by protonation of
the amine group; meanwhile, the aldehyde is activated by
the protonation of the oxygen atom of the formyl group:
the overall yield of the products is increased, because
more 9 on Scheme 2 (or 14 on Scheme 3) is formed.
High concentration of the strong acid deactivates 2 so
strongly, that the yield of both products is decreased. The
weak acid has less protonation ability than the strong
acid, so the deactivation of the amine is weaker. H-acid
also deactivates the amine group of 10, but the
protonation of only one of the amine groups of 12 (more
probable that the protonation of both groups) facilitates
the elimination of ammonia and the formation of BPP. It
was also observed that in acidic conditions, the yellow
by-product (presumably 13) was not formed: one
protonated amine substituent in 12 is a good leaving
group, leading the reaction at this stage mostly to BPP.
Lewis acid with moderate concentration (10mol%)
increases the yield of BPP, while not significantly
changing the yield of PQ. A high concentration of ZnCl2
decreases the yields of both products, most probably
because of an inactivation of the amine group (as it was
observed in the case of p-TSA). An addition of amine
(DABCO) should not have any influence on the rate of
the reaction leading to BPP and 13 (dashed/dotted arrows,
pink on Scheme 2 and red on Scheme 3), as none of the
stages require a base to go forward. However, the
irreversible elimination of HF (solid arrows, green on
Schemes 2 and 3) would go faster, and therefore the yield
of PQ is increased. Protonated DABCO could also act as
a weak H-acid and assist in the elimination of 2 from 8.
As the addition of an amine proved to be the best
method to obtain PQ with the highest yield and
selectivity, other non-nucleophilic, high-boiling amines
were also examined: 1,9-diazabicyclo[5.4.0]undec-7-ene
(DBU), triethanolamine, quinoline, isoquinoline, and
2,4,6-trimethylpyridine, all 90 mol% to 1a and 2a. The
results are summarized in Table 5. A total of 90mol% of
amine was used instead of 100 mol% to prevent the
presence of free amines in the products.
Products of the reactions between 1,3-diphenyl-1H-pyrazol-5-amine (2a)
and 2-fluorobenzaldehyde (1a) in the presence of different amines.
Products yields (%)
Entry
Amine
PQ
BPP
1
2
3
4
5
DBU
6.5
31.5
60
traces
traces
10
triethanolamine
quinoline
isoquinoline
56
5
2,4,6-trimethylpyridine
55
traces
PQ, 1,3-diphenyl-1H-pyrazolo[3,4-b]quinoline, 3a; BPP, 1,3,5,7-tetraphenyl-
4-(2′-fluorophenyl)-bis-pyrazolo[3,4-b,4′,3′-e]pyridine, 4a.
comparing the toxicity of these three amines, DABCO and
2,4,6-trimethylpyridine seem to be the best choices: they
are non-toxic and not dangerous to the environment.
Quinoline is much cheaper, but it is classified as a
carcinogen and an environmental pollutant, toxic for
aquatic life. These factors are highly important, especially
when considering the use of such method in a large-scale
production.
The reactions of 2a with 2,6-dichlorobenzaldehyde (1g)
and 2b with 2-chloro-5-nitro-benzaldehyde (1m) were also
repeated, in the presence of 2,4,6-trimethylpyridine, to test
whether the change in conditions for these compounds will
change the PQ/BPP ratio to PQ’s advantage (Table 6).
The results confirmed the presented mechanisms – in
both cases, the amount of PQ increased, and the amount
of BBP decreased or remained unchanged. In the case of
2,6-dichlorobenzaldehyde (1g), the yields were even
inverted (when compared with the reaction with no
additives, Table 2).
We have also checked if the change in the ratio
between 2-fluorobenzaldehyde (1a) and 1,3-diphenyl-
1H-pyrazol-5-amine (2a) has any influence on the PQ/
BPP output proportion and PQ yield (the reaction was
performed in the presence of 2,4,6-trimethylpyridine,
compare with Table 5). In the case of 2a/1a = 2/1 ratio
(commonly used for the synthesis of BPP) [23], the
Table 6
Products of the reactions between 1H-pyrazol-5-amines 2 and selected
aldehydes 1 in the presence of 2,4,6-trimethylpyridine.
Products
Aldehyde and amine
PQ
Yields (%) BPP Yields (%)
From Tables 4 and 5, one can notice that the best yield
of PQ is achieved with DABCO and quinoline, but in
both cases, BPP is also formed. In the case of 2,4,6-
trimethylpyridine, the yield of PQ is 5 percentage points
lower, but PQ is practically the only product. When
1g + 2a
1m + 2b
3g
3m
43
15
4g
4m
11
35
PQ, 1H-pyrazolo[3,4-b]quinoline derivatives; BPP, bis-pyrazolo[3,4-b,4′,3′-e]
pyridine derivatives.
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P. Szlachcic, M. Kucharek, B. Jarosz, A. Danel, and K. Stadnicka
Vol 000
yield of PQ (3a) was 52%, and BPP (4a) was also
observed, with 2.5% yield. Changing the ratio
Finally, the last group of reactions was carried out in
order to check the reactivity of different 1H-pyrazol-5-
amines (2) with the 2-fluorobenzaldehyde (1a) in the best
conditions: 90mol% of 2,4,6-trimethylpyridine, temperature
170–180°C. The results are summarized in Table 7.
a
towards 2-fluorobenzaldehyde’s advantage (2:1 and even
5:1) lowered the yield of PQ to about 30–40%,
probably because of a more complicated purifying
procedure (excess of benzaldehyde was present in the
reaction mixture). BPP was no longer observed. These
results indicate that the yields are optimal when 1:1
ratio is used. Another important condition to be tested
is the temperature of the reaction. For all investigated
examples, the temperature of 170–180°C was used,
common in the BPP synthesis [23]. To check whether
such high temperature is required in the studied
reactions, we examined three most representative
examples: weakly reactive 2-fluorobenzaldeyde (1a),
reactive 2,6-difluorobenzaldehyde (1e), and highly
reactive pentafluorobenzaldehyde (1k) in the reaction
with 1,3-diphenyl-1H-pyrazol-5-amine (2a). The very
reactive 1k starts to form a product at 100°C; at 120°C,
the rate increases; and at 140°C, the reaction is finished
in 5–10min. 1e, less reactive than 1k, starts to form a
product at 120°C, and at 160°C, the reaction becomes
rapid enough to be finished in 10–15 min. For the not
activated 1a, the first traces of products are observed
above 130°C after 20 min, but below 160°C, the
reaction is too slow to be profitable. At 170–180°C, the
reaction is effectively finished after 45–60 min. Time of
the reaction should not be extended over 60–90min, as
significant amounts of temperature-degradation products
are formed (black tars adsorbed on the Al2O3 column)
and the overall yield is diminished.
From Table 7, one can observe that the change of the
substituent R1 of 1H-pyrazol-5-amine does not
significantly affect the PQ/BPP ratio. The situation is
different when phenyl in position 3 is changed to methyl
(3s and 4s, 3t and 4t): in these cases, more BPP is
formed. That cannot be explained by the mechanism
proposed in Scheme 1, also the “Hennig” mechanism
(Scheme 2, [23]) does not explain the change readily,
because the smaller methyl should not influence the
reaction at the stage of 10. Most probably, the difference
lies in the 12 formation stage, as the compound with two
methyl substituents in position 3 of 1H-pyrazol-5-amine
moiety should be more stable than that with phenyl
substituents. The third proposition (Scheme 3, [25]) could
also explain the changed preference in PQ/BPP ratio, as
the first intermediate, 14, could be attacked by another 2
molecule (dashed/dotted downward arrow, red), most
likely when the smaller methyl substituent in the position
3 of 1H-pyrazol-5-amine moiety is present. When the
phenyl in position 3 is changed to a bulky tert-butyl, PQ
is even more favored, than in the case of a phenyl
substituent, and BPP (4u) is not formed at all (compare
3u in Table 7 with 3a and 4a in the presence of 2,4,6-
trimethylpyridine, Table 5). Because of the steric
hindrance in the case of 3u, a higher temperature must be
used.
Table 7
Synthesis of 1,3-disubstituted-1H-pyrazolo[3,4-b]quinoline, PQ (3), and 1,3,5,7-tetrasubstituted-4-(2′-fluorophenyl)-bis-pyrazolo[3,4-b,4′,3′-e]pyridines,
BPP (4) by the reaction of 1H-pyrazol-5-amines, 2, with 2-fluorobenzaldehyde, 1a, in the presence of 2,4,6-trimethylpyridine.
Products
Entry
Amine
PQ
Yields (%)
BPP
Yields (%)
1
2
3
4*
2b (R1 = Ph, R2 = Me)
2c (R1 = Me, R2 = Ph)
2d (R1, R2 = Me)
3r
3s
3t
43
38
19
52
4r
4s
4t
18
5
22
0
2e (R1 = Ph, R2 = t-Bu)
3u
4u
*Because of lower reactivity of 2e, the reaction temperature was increased to 200°C.
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Facile and Regioselective Synthesis of Substituted 1H-Pyrazolo[3,4-b]quinolines
CONCLUSIONS Atlas CCD detector, using graphite-monochromated Mo
Kα radiation (50 kV, 0.8 mA).
In the present study, we proposed a regioselective
method for the synthesis of 1H-pyrazolo[3,4-b]quinoline
(PQ) derivatives, from 2-halogenbenzaldehydes and 1H-
pyrazol-5-amines. The method produced the best results
with 2-fluorobenzaldehydes in the presence of bases:
General procedure for the reaction of benzaldehydes with
1,3-diphenyl-1H-pyrazol-5-amine (2a).
2a was prepared
from phenylhydrazine and benzoylacetonitrile by the
known procedure [27]. To the equimolecular mixture (1–
10mmol) of corresponding benz aldehyde (1) and 2a, a
few drops of ethanol were added to form a suspension.
The mixture was slowly heated on Wood’s alloy bath
until the temperature reached 170–180°C and then
maintained for 10–60min (monitored by TLC). After
that, the mixture was cooled to room temperature.
Brown glassy solid (or oil) was dissolved in chloroform
and flashed through aluminum oxide 90. In most cases,
Chromatotron was used for separation and purification
of products, using silica gel + gypsum plates (1- or 2-
mm thickness). Elution was started with petroleum
ether, followed by the mixture of that solvent with
toluene. The speed of solvent’s flow and the
composition of the solvent mixture were not constant;
those parameters were based on the still observation of
plate during the purification. If additional or different
separation and/or purification technique was used, it was
stated in each case.
1,3,5-trimethylpyridine,
1,4-diazabicyclo[2.2.2]octane
(DABCO), and quinoline. The highly reactive
pentafluoro- and 2-fluoro-5-nitrobenzaldehyde form
solely PQ, without the presence of any catalyst. The use
of 2-chlorobenzaldehydes gives satisfactory results only
for 2,6-dichloro- and 2-chloro-5-nitrobenzaldehyde. From
the possible 1H-pyrazol-5-amine derivatives, the best
results are obtained with phenyl and tert-butyl
substituents in position 3, while 3-methyl substituted
substrates give worse results, as significant amounts of
bis-pyrazolo[3,4-b,4′,3′-e]pyridine, BPP, are also formed.
As
a
wide variety of 2-fluorobenzaldehydes is
commercially available or easy to synthesize, this could
be the method of choice in those procedures when other
accessible methods result in a mixture of isomers that are
difficult to separate (condensation of 3-substituted
anilines with 5-chloro-1H-pyrazole-4-carbaldehydes) or
the yields are very low (condensation of 2-electron-
withdrawing group substituted anilines with 5-chloro-1H-
pyrazole-4-carbaldehydes). It could also be an excellent
choice, when the other possible regioselective methods
require multistep preparation procedures, and unstable or
expensive reagents.
Reaction of 2-fluorobenzaldehyde (1a) with 1,3-diphenyl-1
H-pyrazol-5-amine 2a.
Reaction was performed
according to the general procedure with 1mmol of 1a
and 2a (60 min):
1,3-Diphenyl-1H-pyrazolo[3,4-b]quinoline (3a).
Yellow
needles, 29% yield (94 mg); m.p. 163–164°C (Lit. 167°C
[28]); 1H-NMR (CDCl3): δ= 7.29–7.35 (m, 1H), 7.48–
7.63 (m, 6H), 7.80 (ddd, J =8.7, 6.7, 1.5 Hz, 1H), 8.03
(br d, J = 8.1 Hz, 1H), 8.16–8.22 (m, 3H), 8.61–8.64 (m,
2H), 8.94 (s, 1H); 13C-NMR (CDCl3) δ: 116.6, 120.7,
124.4, 124.8, 125.4, 127.5, 128.96, 129.03, 129.05,
129.08, 129.2, 130.8, 130.9, 132.6, 140.0, 144.6, 148.2,
150.9. Anal. Calcd for C22H15N3: C 82.22, H 4.70, N
13.08. Found: C 82.20, H 4.77, N 13.03.
EXPERIMENTAL
All the solvents used for purification were purchased
from Chempur (Polish supplier), and all were of
analytical grade. For Chromatotron purification, the
Harrison Research model 7924T was used [26]. Silica gel
with gypsum (for Chromatotron purification), silica gel
60, and aluminum oxide 90 (for column chromatography)
were purchased from Merck. Substituted benzaldehydes
were purchased from Alfa Aesar or Aldrich or prepared
as stated. 1H-Pyrazol-5-amines were prepared as stated.
CDCl3 with TMS was purchased from Aldrich. Melting
points were determined on a MEL-TEMP II apparatus,
1,3,5,7-Tetraphenyl-4-(2-fluorophenyl)-bis-pyrazolo[3,4-b,4′,3′-
e]pyridine (4a).
A light-yellow crystalline powder, 10%
yield (29mg); m.p. 263–264°C; 1H-NMR (CDCl3): δ =6.55
(ddd, J= 9.4, 8.4, 1.1 Hz, 1H), 6.64 (td, J= 7.5, 1.1 Hz, 1H),
6.83 (td, J=7.4, 1.8Hz, 1H), 7.03–7.10 (m, 5H), 7.15–7.18
(m, 6H), 7.32–7.38 (m, 2H), 7.55–7.62 (m, 4H), 8.52–8.56
(m, 4H); 13C-NMR (CDCl3): δ= 112.9, 114.9 (d,
1
and they are uncorrected. H-NMR and 13C-NMR were
JC–F = 21.4 Hz), 120.9, 121.7 (d, JC–F = 15.9 Hz), 123.2
recorded at 600 MHz and 150MHz, respectively, with a
Bruker Avance III 600 spectrometer using CDCl3 as a
solvent. Chemical shifts were given in ppm (δ) from
TMS as an internal standard. Elemental analyses were
conducted at Elementar Vario MICRO cube. Diffraction
data for structural analysis were collected at ambient
temperature for single crystal with an Agilent
Technologies SuperNova diffractometer, equipped with
(d, JC–F =3.2Hz), 125.7, 127.4, 127.8, 129.0, 129.1, 130.7
(d, JC–F =8.0Hz), 131.3 (d, JCÀF =1.9Hz), 132.3, 135.1,
139.6, 147.7, 150.5, 159.1 (d, JC–F =247.2Hz). Anal.
Calcd for C37H24FN5: C 79.70, H 4.34, N 12.56.
Found: C 80.02, H 4.41, N 12.44.
4-(1,3-Diphenyl-1H-pyrazolo[3,4-b]quinolin-4-yl)-1,3-diphenyl-
1H-pyrazol-5-amine (13a). The product was isolated from all
studied reactions between 1a and 2a and purified by
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

P. Szlachcic, M. Kucharek, B. Jarosz, A. Danel, and K. Stadnicka
Vol 000
crystallization from DMF/methanol; deep-yellow crystals,
315mg (estimated average yield 3%); m.p. 274°C; 1H-
NMR (CDCl3): δ=3.42 (s, 2H), 7.03–7.06 (m, 2H), 7.10–
7.13 (m, 1H), 7.22–7.23 (m, 2H), 7.26–7.29 (m, 3H), 7.32–
7.42 (m, 7H), 7.48–7.51 (m, 2H), 7.58–7.61 (m, 4H), 7.76
(ddd, J=8.7, 6.6, 1.5Hz, 1H), 8.07 (ddd, J=8.6, 1.5,
0.6 Hz, 1H), 8.24 (ddd, J =8.7, 1.2, 0.6 Hz, 1H), 8.62–8.63
(m, 1H); 13C-NMR (CDCl3): δ= 97.5, 115.6, 120.8, 124.2
(two overlapped signals), 124.5, 125.5, 126.8, 127.1, 127.5,
127.7, 127.8, 128.2, 128.3, 129.1, 129.2 (two overlapped
signals), 129.5, 130.8, 132.5, 132.6, 135.8, 138.1, 139.8,
143.8, 146.8, 148.9, 149.7, 150.6ppm. Anal. Calcd for
C37H26N6: C 80.12, H 4.73, N 15.15. Found: C 79.90, H
4.76, N 15.10.
1,3-Diphenyl-1H-pyrazolo[3,4-b]quinoline (3d, identical with
3a). Yellow crystals, 1.5% yield (5mg). H-NMR was
identical with corresponding spectra of 3a.
1
1,3,5,7-Tetraphenyl-4-(2-iodophenyl)-bis-pyrazolo[3,4-b,4′,3′-
e]pyridine (4d). The fraction obtained from column was
crystallized from toluene; a light-yellow crystalline powder,
1
37% yield (124 mg); m.p. 237–239°C; H-NMR (CDCl3):
δ =6.77 (ddd, J=8.0, 6.7, 2.3Hz, 1H), 6.90–6.94 (m, 2H),
7.02–7.05 (m, 4H), 7.15 (br t, J=7.5Hz, 2H), 7.17–7.20 (m,
4H), 7.15 (br t, J=7.4Hz, 2H), 7.42 (ddd, J=8.1, 1.0,
0.5Hz, 1H), 7.58–7.61 (m, 4H), 8.56–8.58 (m, 4H); 13C-
NMR (CDCl3): δ =99.2, 112.4, 120.8, 125.7, 127.1, 127.3,
127.8, 129.0, 129.4, 129.6, 130.7, 132.3, 138.5, 138.8,
139.6, 142.6, 147.8, 150.7. Anal. Calcd for C37H24IN5: C
66.77, H 3.63, N 10.52. Found: C 66.80, H 3.70, N 10.11.
Reaction of 2,6-difluorobenzaldehyde (1e) with 1,3-diphen-
Reaction of 2-chlorobenzaldehyde (1b) with 1,3-diphenyl-1H-
pyrazol-5-amine 2a.
Reaction was performed according
to the general procedure with 1mmol of 1b and 2a
(60min):
yl-1H-pyrazol-5-amine 2a.
according to the general procedure with 10mmol of 1e
and 2a (20 min):
5-Fluoro-1,3-diphenyl-1H-pyrazolo[3,4-b]quinoline (3e). The
product was isolated and purified by column chromatography
(silica gel, toluene/petroleum ether) followed by
crystallization from toluene; yellow fluorescent needles,
Reaction was performed
1,3-Diphenyl-1H-pyrazolo[3,4-b]quinoline (3b, identical with
1
3a). Yellow crystals, 2.5% yield (8 mg). H-NMR was
identical with corresponding spectra of 3a.
1,3,5,7-Tetraphenyl-4-(2-chlorophenyl)-bis-pyrazolo[3,4-b,4′,3′-
e]pyridine (4b).
A light-yellow powder, 52% yield
(147mg); m.p. 253–254°C (Lit. 251–253°C [18b]); 1H-
NMR (CDCl3): δ =6.78–6.83 (m, 1H), 6.89–6.95 (m, 2H),
7.00–7.06 (m, 5H), 7.13–7.18 (m, 6H), 7.33–7.38 (m, 2H),
7.57–7.62 (m, 4H); 13C-NMR (CDCl3): δ=112.7, 120.8,
125.7, 125.8, 127.4, 127.8, 128.8, 129.0, 129.1, 129.9,
131.2, 132.3, 133.1, 133.3, 138.3, 139.6, 147.8, 150.6.
Anal. Calcd for C37H24ClN5: C 77.41, H 4.21, N 12.20.
Found: C 77.30, H 4.25, N 12.15.
65% yield (2206mg); m.p. 210–211°C; H-NMR (CDCl3):
1
δ =7.14 (ddd, J=10.1, 7.6, 1.0Hz, 1H), 7.30–7.36 (m, 1H),
7.49–7.63 (m, 5H), 7.69 (ddd, J=8.8, 7.6, 6.2Hz, 1H), 7.97
(d, J=9.7 Hz, 1H), 8.14–8.17 (m, 2H), 8.56–8.59 (m, 2H),
9.17 (d, J=0.8Hz, 1H); 13C-NMR (CDCl3): δ=107.3
(d, JCÀF =19.4Hz), 116.1 (d, JCÀF =17.2Hz), 116.3 (d,
J
CÀF =1.8Hz), 120.8, 124.7 (d, JCÀF = 13.2 Hz), 124.7
(d, JCÀF = 3.7 Hz), 125.6, 127.5, 129.0, 129.1, 129.2, 130.2
(d, CÀF =9.5Hz), 132.2, 139.7, 144.9, 148.7 (d,
Reaction of 2-bromobenzaldehyde (1c) with 1,3-diphenyl-1H-
J
pyrazol-5-amine 2a.
Reaction was performed according
JCÀF = 2.8 Hz), 150.9, 159.0 (d, JCÀF =251.3Hz). Anal.
Calcd for C22H14FN3: C 77.86, H 4.16, N 12.38. Found: C
78.14, H 4.00, N 12.32.
to the general procedure with 1mmol of 1c and 2a
(60min):
1,3-Diphenyl-1H-pyrazolo[3,4-b]quinoline (3c, identical with
3a).
identical with corresponding spectra of 3a.
1,3,5,7-Tetraphenyl-4-(2-bromophenyl)-bis-pyrazolo[3,4-b,4′,3′-
1,3,5,7-Tetraphenyl-4-(2,6-difluorophenyl)-bis-pyrazolo[3,4-
b,4′,3′-e]pyridine (4e). The product was isolated from the
residues of 3e purification, separated from 3e and purified
by Chromatotron (silica gel, toluene/petroleum ether),
using a special technique that will be published at a later
date, a light-yellow solid, 2.5% yield (43 mg); m.p. 250–
Yellow crystals, 2% yield (6mg). 1H-NMR was
e]pyridine (4c).
A light-yellow powder, 45% yield
(140mg); m.p. 246–247°C (Lit. 242–243°C [18b]); 1H-
NMR (CDCl3): δ =6.83–6.97 (m, 3H), 7.01–7.06 (m, 4H),
7.12–7.19 (m, 7H), 7.32–7.38 (m, 2H), 7.56–7.62 (m, 4H),
8.54–8.57 (m, 4H); 13C-NMR (CDCl3): δ=112.6, 120.8,
123.4, 125.7, 126.3, 127.3, 127.8, 129.0, 129.2, 129.9,
131.3, 132.0, 132.3, 135.0, 139.6, 139.8, 147.8, 150.6.
Anal. Calcd for C37H24BrN5: C 71.85, H 3.91, N 11.32.
Found: C 71.49, H 3.93, N 11.20.
1
252°C; H-NMR (CDCl3): δ= 6.38–6.41 (m, 2H), 7.00–
7.05 (m, 1H), 7.08–7.10 (m, 4H), 7.17–7.20 (m, 2H),
7.23–7.25 (m, 4H), 7.34–7.36 (m, 2H), 7.54–7.60 (m,
4H), 8.53–8.54 (m, 4H); 13C-NMR (CDCl3): δ= 110.6
(dd, JCÀF = 21.1, 4.2 Hz), 111.6 (t, JCÀF = 20.3 Hz),
113.2, 120.9, 125.8, 127.5, 128.1, 128.9, 129.0, 131.2 (t,
J
J
CÀF = 10.0 Hz), 131.9, 139.5, 147.6, 150.5, 159.2 (dd,
Reaction of 2-iodobenzaldehyde (1d) with 1,3-diphenyl-1H-
pyrazol-5-amine 2a. Reaction was performed according
to the general procedure with 1 mmol of 1d and 2a
(60 min). The products were separated and purified by
column chromatography (silica gel, toluene/petroleum
ether):
CÀF = 249.4, 6.4 Hz). Anal. Calcd for C37H23F2N5: C
77.20, H 4.03, N 12.17. Found: C 76.80, H 4.22, N 11.82.
Reaction of 2-chloro-6-fluorobenzaldehyde (1f) with
1,3-diphenyl-1H-pyrazol-5-amine 2a.
Reaction was
performed according to the general procedure with
2.2 mmol of 1f and 2a (40 min):
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2016
Facile and Regioselective Synthesis of Substituted 1H-Pyrazolo[3,4-b]quinolines
5-Chloro-1,3-diphenyl-1H-pyrazolo[3,4-b]quinoline (3f). The
Chromatotron purification was followed by crystallization
from toluene; yellow, fluorescent needles, 57% yield
J=7.1, 1.1Hz, 1H), 8.16–8.19 (m, 3H), 8.58–8.60 (m,
2H), 8.54 (d, J=0.8Hz, 1H); 13C-NMR (CDCl3): δ =99.9,
117.7, 120.6, 125.6, 126.4, 127.6, 129.1, 129.20, 129.22,
130.1, 131.4, 132.3, 135.9, 136.0, 139.7, 144.8, 148.4,
151.1. Anal. Calcd for C22H14IN3: C 59.08, H 3.15, N
9.39. Found C 59.06, H 3.21, N 9.39.
1
(423 mg); m.p. 221–222°C; H-NMR (CDCl3): δ =7.33 (tt,
J= 7.4, 1.2 Hz, 1H), 7.51–7.54 (m, 1H), 7.57–7.63 (m,
5H), 7.67 (dd, J= 8.7, 7.3 Hz, 1H), 8.11 (dt, J=8.7, 1.0Hz,
1H), 8.16–8.18 (m, 2H), 8.57–8.60 (m, 2H), 9.33 (d,
J=0.9Hz, 1H); 13C-NMR (CDCl3): δ=117.0, 120.7,
122.9, 124.4, 125.6, 127.6, 128.2, 128.3, 129.1, 129.16,
129.22, 130.2, 132.3, 132.5, 139.7, 144.9, 148.7, 150.8.
Anal. Calcd for C22H14ClN3: C 74.26, H 3.97, N 11.81.
Found C 74.08, H 4.04, N 11.59.
1,3,5,7-Tetraphenyl-4-(2-fluoro-6-iodophenyl)-bis-pyrazolo[3,4-
b,4′,3′-e]pyridine (4h).
A light-yellow powder, 9% yield
1
(30mg); m.p. 245–246°C; H-NMR (CDCl3): δ =6.62 (td,
J=8.6, 1.0Hz, 1H), 6.75 (td, J=8.2, 5.7Hz, 1H), 7.06–7.09
(m, 4H), 7.15–7.18 (m, 2H), 7.22 (d, J=7.9Hz, 1H), 7.24–
7.26 (m, 4H), 7.36 (tt, J=7.4, 1.2 Hz, 2H), 7.58–7.61 (m,
4H), 8.56–8.57 (m, 4H); 13C-NMR (CDCl3): δ =99.6,
112.6, 114.5 (d, JCÀF = 22.1 Hz), 120.8, 125.7, 127.2 (d,
1,3,5,7-Tetraphenyl-4-(2-chloro-6-fluorophenyl)-bis-pyrazolo[3,4-
b,4′,3′-e]pyridine (4f).
Light-yellow needles, 9% yield
(67 mg); m.p. 252°C; 1H-NMR (CDCl3): δ=6.53 (td, J=8.5,
1.0Hz, 1H), 6.76 (dt, J=8.2, 1.0 Hz, 1H), 6.80 (td, J=8.3,
6.0Hz, 1H), 7.06–7.09 (m, 4H), 7.16–7.18 (m, 2H), 7.22–
7.25 (m, 4H), 7.36 (tt, J=7.4, 1.1Hz, 2H), 7.58–7.61 (m,
4H), 8.54–8.56 (m, 4H); 13C-NMR (CDCl3): δ=113.0,
113.2 (d, JCÀF = 22.0 Hz), 120.8, 121.9 (d, JCÀF =19.4Hz),
124.6 (d, JCÀF = 3.1 Hz), 125.7, 127.4, 128.1, 128.9, 129.0,
J
CÀF = 18.1 Hz), 127.4, 128.0, 129.0, 129.2, 131.5 (d,
JCÀF = 8.6 Hz), 131.9, 134.2 (d, JCÀF =3.3Hz), 136.1,
139.6, 147.6, 150.6, 158.7 (d, JCÀF =250.5Hz). Anal. Calcd
for C37H23FIN5: C 65.02, H 3.39, N 10.25. Found: C
64.95, H 3.53, N 10.08.
Reaction of 2,4-difluorobenzaldehyde (1i) with 1,3-diphen-
yl-1H-pyrazol-5-amine (2a).
Reaction was performed
130.9 (d,
J
CÀF = 9.4 Hz), 131.3, 131.9, 134.2 (d,
according to the general procedure with 1 mmol of 1i and
2a (60 min):
J
CÀF = 4.1 Hz),
139.6, 147.7, 150.6, 159.5 (d,
JCÀF = 249.1 Hz). Anal. Calcd for C37H23ClFN5: C 75.06, H
7-Fluoro-1,3-diphenyl-1H-pyrazolo[3,4-b]quinoline (3i).
A
1
3.92, N 11.83. Found C 74.68, H 3.95, N 11.71.
yellow solid, 49% yield (165mg); m.p. 197–198°C; H-
NMR (CDCl3): δ =7.29 (ddd, J=9.1, 7.9, 2.5Hz, 1H),
7.32 (tt, J=7.4, 1.2Hz, 1H), 7.49–7.52 (m, 1H), 7.56–7.60
(m, 4H), 7.78 (dd, J=10.6, 1.3Hz, 1H), 7.98 (dd, J=9.1,
6.2Hz, 1H), 8.11–8.13 (m, 2H), 8.56–8.57 (m, 2H), 9.17
(d, J=0.6Hz, 2H); 13C-NMR (CDCl3): δ =112.0 (d,
Reaction of 2,6-dichlorobenzaldehyde (1g) with 1,3-diphe-
nyl-1H-pyrazol-5-amine (2a).
Reaction was performed
according to the general procedure with 2 mmol of 1g and
2a (60 min):
5-Chloro-1,3-diphenyl-1H-pyrazolo[3,4-b]quinoline
(3g,
identical with 3f). Yellow needles, 22% yield (155mg);
J=20.8Hz), 115.8 (d,
CÀF =2.3Hz), 120.7, 121.0, 125.6, 127.5, 129.0, 129.1,
129.2, 131.1, 131.3 (d, JCÀF = 10.6 Hz), 132.5, 139.8,
144.7, 149.2 (d, CÀF =13.6Hz), 151.3, 164.2 (d,
JCÀF =26.6Hz), 116.2 (d,
1
m.p. 220–221°C; H-NMR and 13C-NMR were identical
J
with corresponding spectra of 1f.
1,3,5,7-Tetraphenyl-4-(2,6-dichlorophenyl)-bis-pyrazolo[3,4-
b,4′,3′-e]pyridine (4g). A light-yellow powder, 38% yield
(230 mg); m.p. 252–255°C; 1H-NMR (CDCl3): δ= 6.88
(d, J =9.4 Hz, 1H), 6.88 (d, J = 6.4 Hz, 1H), 6.92 (dd,
J =6.4, 9.4Hz, 1H), 7.06–7.08 (m, 4H), 7.16 (tt, J = 7.5,
1.3Hz, 2H), 7.24–7.25 (m, 4H), 7.35 (tt, J= 7.4, 1.2 Hz,
2H), 7.58–7.61 (m, 4H), 8.55–8.57 (m, 4H); 13C-NMR
(CDCl3): δ= 112.5, 120.8, 125.7, 127.2, 127.3, 128.0,
128.9, 129.0, 130.3, 131.9, 132.1, 134.5, 135.0, 139.6,
147.7, 150.7ppm. Anal. Calcd for C37H23Cl2N5: C 73.03,
H 3.81, N 11.51. Found: C 73.20, H 3.72, N 11.31.
Reaction of 2-fluoro-6-iodobenzaldehyde (1h) with 1,3-dip-
J
J
CÀF =252.3Hz). Anal. Calcd for C22H14FN3: C 77.86, H
4.16, N 12.38. Found: C 77.90, H 4.25, N 12.30.
1,3,5,7-Tetraphenyl-4-(2,4-difluorophenyl)-bis-pyrazolo[3,4-
b,4′,3′-e]pyridine (4i).
Light-yellow crystals, 7% yield
1
(20.5 mg); m.p. 236–238°C; H-NMR (CDCl3): δ= 6.30
(td, J = 9.2, 2.4 Hz, 1H), 6.37 (td, J = 8.2, 2.3 Hz, 1H),
6.77 (td, J = 8.2, 6.4 Hz, 1H), 7.10–7.12 (m, 4H), 7.16–
7.18 (m, 4H), 7.21–7.24 (m, 2H), 7.35 (tt, J = 7.4, 1.2Hz,
2H), 7.57–7.60 (m, 4H), 8.52–8.53 (m, 4H) ppm; 13C-
NMR (CDCl3): δ= 103.3 (t, JCÀF = 25.5Hz), 110.5 (dd,
JCÀF = 21.6, 3.5 Hz), 113.0, 117.9 (dd, JCÀF = 16.2,
henyl-1H-pyrazol-5-amine 2a.
Reaction was performed
3.9 Hz), 120.8, 125.8, 127.5, 128.1, 129.0, 129.1, 132.0
(dd, JCÀF = 9.9, 4.0 Hz), 132.2, 133.8, 139.5, 147.5,
150.5, 159.2 (dd, JCÀF = 250.1, 12.4Hz), 163.5 (dd,
according to the general procedure with 1 mmol of 1h and
2a (30 min):
5-Iodo-1,3-diphenyl-1H-pyrazolo[3,4-b]quinoline (3h).
The
JCÀF = 251.6, 11.6Hz). Anal. Calcd for C37H23F2N5: C
77.20, H 4.03, N 12.17. Found: C 77.38, H 4.13, N 12.10.
Chromatotron purification was followed by crystallization
from toluene; deep-yellow needles, 68% yield (231mg);
m.p. 200–202°C; 1H-NMR (CDCl3): δ= 7.33 (tt, J=7.4,
1.2Hz, 1H), 7.45 (dd, J=8.6, 7.1Hz, 1H), 7.52–7.55 (m,
1H), 7.56–7.59 (m, 2H), 7.62–7.64 (m, 2H), 7.35 (dd,
Reaction of 2,4-dichlorobenzaldehyde (1j) with 1,3-diphe-
nyl-1H-pyrazol-5-amine (2a).
Reaction was performed
according to the general procedure with 2 mmol of 1j and
2a (60 min):
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

P. Szlachcic, M. Kucharek, B. Jarosz, A. Danel, and K. Stadnicka
Vol 000
7-Chloro-1,3-diphenyl-1H-pyrazolo[3,4-b]quinoline (3j).
A
(Al2O3, toluene). All collected portions of 3l were
combined and crystallized from DMF.
yellow crystalline powder, 6% yield (40mg); m.p. 201–
202°C; 1H-NMR (CDCl3): δ=7.33 (tt, J= 7.4, 1.1 Hz,
1H), 7.44 (dd, J=8.8, 2.1Hz, 1H), 7.50–7.52 (m, 1H),
7.56–7.61 (m, 4H), 7.93 (d, J=8.8Hz, 1H), 8.12–8.13 (m,
2H), 8.20 (d, J=1.9Hz, 1H), 8.56–8.58 (m, 2H), 8.87 (s,
1H); 13C-NMR (CDCl3): δ=116.6, 120.7, 123.0, 125.6,
125.7, 127.5, 127.7, 129.0, 129.1, 129.2, 130.3, 130.9,
132.3, 136.9, 139.7, 144.7, 148.3, 151.1. Anal. Calcd for
C22H14ClN3: C 74.26, H 3.97, N 11.81. Found: C 73.89,
H 4.30, N 11.41.
1,3,5,7-Tetraphenyl-4-(2,4-dichlorophenyl)-bis-pyrazolo[3,4-
b,4′,3′-e]pyridine (4j). Light-yellow crystals, 49% yield
(300 mg); m.p. 215°C; 1H-NMR (CDCl3): δ= 6.77 (dd,
J =8.1, 1.9 Hz, 1H), 6.80 (d, J =8.1 Hz, 1H), 6.94 (d,
J =1.8 Hz, 1H), 7.08–7.11 (m, 4H), 7.15–7.17 (m, 4H),
7.21–7.24 (m, 2H), 7.35 (tt, J =7.4, 1.1 Hz, 2H), 7.57–
7.60 (m, 4H), 8.53–8.54 (m, 4H); 13C-NMR (CDCl3):
δ= 112.8, 120.9, 125.8, 126.1, 127.5, 128.1, 128.7,
129.1, 129.2, 131.7, 131.9, 132.2, 134.1, 135.4, 136.9,
139.6, 147.6, 150.6ppm. Anal. Calcd for C37H23Cl2N5:
C 73.03, H 3.81, N 11.51. Found: C 72.75, H 3.89, N
11.44.
6-Nitro-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]quinoline
(3l). Deep-yellow crystals, 56% yield (850mg); m.p. 259–
260°C (Lit. 260–263°C [10b]); 1H-NMR (CDCl3): δ=2.81
(s, 3H), 7.33 (tt, J=7.4, 1.2Hz, 1H), 7.56–7.59 (m, 2H),
8.25 (dt, J=9.4, 0.7Hz, 1H), 8.44–8.45 (m, 2H), 8.51 (dd,
J=9.4, 2.6Hz, 1H), 8.76 (br s, 1H), 9.00 (d, J=2.5Hz,
1H); 13C-NMR (CDCl3): δ=12.8, 119.8, 120.5, 122.1,
123.8, 125.8, 126.6, 129.2, 130.4, 132.3, 139.3, 143.6,
144.0, 150.0, 151.5. Anal. Calcd for C17H12N4O2: C
67.10, H 3.97, N 18.41. Found: C 66.80, H 3.98, N 18.11.
Reaction of 2-chloro-5-nitrobenzaldehyde (1m) with
3-methyl-1-phenyl-1H-pyrazol-5-amine (2a).
Reaction
was performed according to the general procedure with
4 mmol of 1m and 2b (60 min). 1m was prepared by
nitration of 2-chlorobenzaldehyde [30]. The mixture
obtained after flash chromatography was dissolved in
THF, mixed with Al2O3, and dried. Then, the products
(3m and 4m) adsorbed on Al2O3 were put on the long
column filled with Al2O3 and eluted with toluene.
6-Nitro-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]quinoline (3m,
identical with 3l). First collected fraction was identified
as 3m; a yellow crystalline powder, 6% yield (72mg); m.p.
Reaction of 2,3,4,5,6-pentafluorobenzaldehyde (1k) with
1
1,3-diphenyl-1H-pyrazol-5-amine (2a).
Reaction was
257–259°C. H-NMR and 13C-NMR were identical with
performed according to the general procedure with
0.5mmol of 1k and 2a (10 min):
corresponding spectra of 1l.
3,5-Dimethyl-1,7-diphenyl-4-(2-chloro-5-nitrophenyl)-bis-
5,6,7,8-Tetrafluoro-1,3-diphenyl-1H-pyrazolo[3,4-b]quinoline
(3k). The product was purified by crystallization from
toluene, yellow crystals with greenish fluorescence, 84%
yield (165mg); m.p. 210–210.5°C (Lit. 207–208°C [15]);
1H-NMR (CDCl3): δ=7.30 (br t, J=7.4, 1H), 7.52–7.61
(m, 5H), 8.06–8.07 (m, 2H), 8.51–8.53 (m, 2H), 9.04 (s,
1H). 13C-NMR (CDCl3): δ =112.2 (d, JCÀF =14.4Hz),
116.8 (br s), 120.2, 124.5–124.6 (m), 125.9, 127.4, 129.1,
129.2, 129.6, 131.5, ~134.3 (br d, JCÀF =10.9Hz), 136.1
pyrazolo[3,4-b,4′,3′-e]pyridine (2m).
The product was
eluted as a second fraction from 3m + 4m mixture
(described earlier), followed by crystallization from
toluene; yellow crystals, 30% yield (295 mg); m.p.
240–241°C; 1H-NMR (CDCl3): δ = 2.11 (s, 3H) 7.31
(br t, J = 7.4 Hz, 2H), 7.53–7.56 (m, 4H), 7.84 (d,
J = 8.8 Hz, 1H), 8.38–8.41 (m, 5H), 8.43 (dd, J = 8.8,
2.7 Hz, 1H); 13C-NMR (CDCl3): δ= 14.2, 112.8, 120.4,
125.4, 125.5 (two signals shifted by 0.04 ppm), 129.0,
130.8, 134.2, 135.2, 139.4, 140.3, 143.2, 146.2, 150.5.
Anal. Calcd for C27H19ClN6O2: C 65.52, H 3.87, N
16.98. Found: C 65.56, H 4.03, N 16.84.
(dt,
JCÀF = 252.2, ~15.5Hz), 139.2, ~141.7 (d×m,
JCÀF =~250Hz, 3×CF), 144.6, 150.2. Anal. Calcd for
C22H11F4N3: C 66.84, H 3.31, N 10.63. Found: C 66.95,
H 3.25, N 10.85.
Reaction of 2-fluoro-5-nitrobenzaldehyde (1l) with
3-methyl-1-phenyl-1H-pyrazol-5-amine (2b).
Reaction of 2-bromo-5-nitrobenzaldehyde (1n) with
3-methyl-1-phenyl-1H-pyrazol-5-amine (2b). Reaction was
performed according to the general procedure with
4 mmol of 1n and 2b (60 min). 1n was prepared by
nitration of 2-bromobenzaldehyde [29]. The products
were separated and purified by the method described for
3m and 4m (above):
Reaction
was performed according to the general procedure with
5 mmol of 1l and 2b (20 min). 1l was prepared by
nitration of 2-fluorobenzaldehyde using the method
described for 2-bromobenzaldehyde [29]; 3-methyl-1-
phenyl-1H-pyrazol-5-amine, 2b, was prepared from 3-
aminocrotononitrile and phenylhydrazine by the known
procedure [27]. Most of the product was isolated by
treating the solid obtained from the reaction mixture with
chloroform (3l is weakly soluble), and the solid was
filtered off. The remaining solution, still containing part
of 3l and impurities, was flashed through Al2O3, and then
the product was separated by column chromatography
6-Nitro-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]quinoline (3n,
identical with 3l). A yellow crystalline powder, 7% yield
1
(84 mg); m.p. 258–259°C. H-NMR and 13C-NMR were
identical with corresponding spectra of 1l.
3,5-Dimethyl-1,7-diphenyl-4-(2-bromo-5-nitrophenyl)-bis-
pyrazolo[3,4-b,4′,3′-e]pyridine (4n).
Yellow crystals, 27%
yield (291mg); m.p. 251–252°C; 1H-NMR (CDCl3):
δ =2.10 (s, 6H), 7.31 (tt, J= 7.4, 1.1 Hz, 1H), 7.53–7.56
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2016
Facile and Regioselective Synthesis of Substituted 1H-Pyrazolo[3,4-b]quinolines
(m, 4H), 8.03 (d, J=8.8Hz, 1H), 8.33 (dd, J=8.8, 2.7Hz,
1H), 8.38 (d, J= 2.7 Hz, 1H), 8.39–8.41 (m, 4H); 13C-
NMR (CDCl3): δ=14.3, 112.6, 120.3, 125.1, 125.3,
125.4, 129.0, 130.4, 134.0, 136.0, 137.4, 139.4, 143.2,
146.8, 150.5. Anal. Calcd for C27H19BrN6O2: C 60.12, H
3.55, N 15.58. Found: C 60.18, H 3.63, N 15.55.
129.2, 129.4, 130.1, 132.1, 132.2, 139.5, 144.8, 148.8,
151.5. Anal. Calcd for C23H14F3N3: C 70.95, H 3.62, N
10.79. Found: C 70.79, H 3.68, N 10.72.
1,3,5,7-Tetraphenyl-4-[2-chloro-5-(trifluoromethyl)phenyl]-bis-
pyrazolo[3,4-b,4′,3′-e]pyridine (4q). A light-yellow powder,
1
40% yield (130mg); m.p. 260–261°C; H-NMR (CDCl3):
Reaction of 2-fluoro-3-(trifluoromethyl)benzaldehyde (1o)
with 1,3-diphenyl-1H-pyrazol-5-amine (2a). Reaction was
performed according to the general procedure with
5 mmol of 1o and 2a (15 min):
δ =7.03–7.06 (m, 5H), 7.12–7.17 (m, 6H), 7.18 (br d,
J=1.9Hz, 1H), 7.25 (dd, J=8.4, 1.9Hz, 1H, partially
overlapped with CHCl3 signal), 7.36 (tt, J=7.4, 1.2Hz,
2H), 7.58–7.61 (m, 4H), 8.53–8.54 (m, 4H); 13C-NMR
(CDCl3): δ= 112.5, 120.3, 123.0 (q, JCÀF =272.5Hz),
125.8, 126.4 (q, JCÀF =3.6Hz), 127.5, 128.1, 128.2 (q,
8-(Trifluoromethyl)-1,3-diphenyl-1H-pyrazolo[3,4-b]quinoline
(3o). Yellow fluorescent crystals, 52% yield (1030mg);
m.p. 183–184°C (Lit. 179–181°C [7g]); 1H-NMR
(CDCl3): δ =7.31 (tt, J=7.3, 1.1Hz, 1H), 7.49–7.52 (m,
2H), 7.56–7.60 (m, 4H), 8.12–8.17 (m, 4H), 8.74–8.75 (m,
2H), 8.92 (br s, 1H); 13C-NMR (CDCl3): δ =116.9, 119.9,
122.7, 124.2 (q, JCÀF =273.3Hz, CF3), 124.7, 125.4,
127.2 (q, JCÀF =29.5Hz), 127.5, 129.0, 129.1, 129.3,
129.6 (q, JCÀF =5.4Hz), 131.3, 132.2, 133.7, 139.8,
144.0, 144.4, 150.0. Anal. Calcd for C23H14F3N: C 70.95,
H 3.62, N 10.79. Found: C 70.59, H 3.64, N 10.73.
Reaction of 2-chloro-3-(trifluoromethyl)benzaldehyde (1p)
with 1,3-diphenyl-1H-pyrazol-5-amine (2a). Reaction was
performed according to the general procedure with
1 mmol of 1p and 2b (60 min).
JCÀF = 3.8Hz), 128.6 (q, JCÀF = 33.4 Hz), 129.0, 129.1,
129.4, 131.8, 133.6, 136.1, 136.9 (br d, JCÀF =1.3Hz),
139.4, 147.4, 150.5. Anal. Calcd for C38H23ClF3N5: C
71.08, H 3.61, N 10.91, O 5.17. Found: C 70.93, H 3.67,
N 10.81.
General procedure for the reaction of 2-fluorobenzaldehy-
de (1a) with 1H-pyrazol-5-amines (2b–e).
1-Methyl-3-
phenyl-1H-pyrazol-5-amine (2c) was prepared from
methylhydrazine and benzoylacetonitrile by the
known procedure [27]. 1,3-Dimethyl-1H-pyrazol-5-amine
(2d) was prepared from 3-aminocrotononitrile and
methylhydrazine by the known procedure [27]. 3-tert-
Butyl-1-phenyl-1H-pyrazol-5-amine (2e) was prepared
from phenylhydrazine and 4,4-dimethyl-3-oxopen-
tanenitrile, applying the known procedure [27]. The
equimolecular mixture (1 mmol) of 1a, corresponding
1H-pyrazol-5-amine (2) and 2,4,6-trimethylpyridine
(90mol%), was prepared. The mixture was slowly heated
on Wood’s alloy bath until it reached 180°C and then
maintained for 45–70min (monitored by TLC). After
that, the mixture was cooled to room temperature. Brown
oil was dissolved in chloroform and flashed through
the aluminum oxide 90. Crude product was purified by
the methods described in General Procedure for the
Reaction of Benzaldehydes with 1,3-diphenyl-1H-
pyrazol-5-amine (2a) section.
8-(Trifluoromethyl)-1,3-diphenyl-1H-pyrazolo[3,4-b]quinoline
(3p, identical with 3o).
Yellow fluorescent crystals, 6%
1
yield (22mg); m.p. 182–183°C. H-NMR and 13C-NMR
were identical with corresponding spectra of 3o.
1,3,5,7-Tetraphenyl-4-[2-chloro-3-(trifluoromethyl)phenyl]-bis-
pyrazolo[3,4-b,4′,3′-e]pyridine (4p). A light-yellow powder,
1
62% yield (200mg); m.p. 234–236°C; H-NMR (CDCl3):
δ=6.91 (t, J= 7.7 Hz, 1H), 7.02–7.06 (m, 5H), 7.13–7.17
(m, 6H), 7.36 (tt, J=7.4, 1.1Hz, 2H), 7.40 (dd, J=7.9,
1.6Hz, 1H), 7.58–7.60 (m, 4H), 8.53–8.55 (m, 4H); 13C-
NMR
(CDCl3):
δ=112.6,
120.8,
122.3
(q,
JCÀF =273.6Hz), 125.7, 125.8, 127.4 (q, JCÀF =5.4Hz),
127.5, 128.1, 128.7 (q, JCÀF =31.4 Hz), 129.0, 129.1, 131.4
(broad signal), 131.9, 134.1, 135.6, 136.7, 139.5, 147.5,
150.5. Anal. Calcd for C38H23ClF3N5: C 71.08, H 3.61, N
10.91. Found C 71.01, H 3.81, N 10.77.
Reaction of 2-fluorobenzaldehyde (1a) with 3-methyl-1-
phenyl-1H-pyrazol-5-amine (2b). Reaction was performed
according to the general procedure with 1mmol of 1a
and 2b (60min). For Chromatotron separation and
purification, toluene/petroleum ether mixture was used as
a solvent (elution of 3r) followed by pure toluene
(elution of 4r).
Reaction of 2-chloro-5-(trifluoromethyl)benzaldehyde (1q)
with 1,3-diphenyl-1H-pyrazol-5-amine (2a). Reaction was
performed according to the general procedure with
1 mmol of 1q and 2b (60 min):
6-(Trifluoromethyl)-1,3-diphenyl-1H-pyrazolo[3,4-b]quinoline
(3q). A deep-yellow powder, 3% yield (11mg); m.p. 176–
177°C; 1H-NMR (CDCl3): δ=7.35 (tt, J=7.4, 1.1Hz, 1H),
7.51–7.54 (m, 1H), 7.57–7.62 (m, 4H), 7.92 (dd, J=9.0,
2.1Hz, 1H), 8.13–8.14 (m, 2H), 8.27 (d, J=9.0Hz, 1H),
8.35 (br s, 1H), 8.56–8.57 (m, 2H), 9.00 (s, 1H); 13C-
NMR (CDCl3): δ =117.3, 120.8, 123.2, 124.1 (q,
3-Methyl-1-phenyl-1H-pyrazolo[3,4-b]quinoline (3r).
A
yellow crystalline powder, 38% yield (98 mg); m.p. 97–
1
98°C (Lit. 88–90°C [12]); H-NMR (CDCl3): δ =2.74 (s,
3H), 7.26 (tt, J = 7.4, 1.2 Hz, 1H), 7.46 (ddd, J= 8.0, 6.6,
1.2 Hz, 1H), 7.53–7.56 (m, 2H), 7.75 (ddd, J =8.3, 6.7,
1.5 Hz, 1H), 7.95 (br d, J= 8.2 Hz, 1H), 8.15 (d,
J = 8.6 Hz, 1H), 8.49–8.51 (m, 3H); 13C-NMR (CDCl3)
δ =12.8, 118.3, 120.0, 124.0, 124.1, 124.8, 128.8, 129.0
(two slightly shifted signals), 129.6, 130.6, 140.0, 143.3,
JCÀF =272.0Hz), 125.8, 126.2 (q, JCÀF =2.8Hz), 126.3 (q,
JCÀF =32.6Hz), 127.4 (q, JCÀF =4.6Hz), 127.5, 129.1,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

P. Szlachcic, M. Kucharek, B. Jarosz, A. Danel, and K. Stadnicka
Vol 000
148.3, 150.4. Anal. Calcd for C17H13N3: C 78.74, H 5.05,
N 16.21. Found: C 78.57, H 4.99, N 16.37.
13C-NMR (CDCl3) δ: 116.8, 123.3, 123.7, 128.1, 129.3,
129.7, 130.5, 141.0, 148.4, 151.1. Anal. Calcd for
C12H11N3: C 73.07, H 5.62, N 21.31. Found: C 73.15, H
5.55, N 21.22.
3,5-Dimethyl-1,7-diphenyl-4-(2-fluorophenyl)-bis-pyrazolo[3,4-
b,4′,3′-e]pyridine (4r). A yellowish crystalline powder, 18%
yield (38.5mg); m.p. 253–255°C (Lit. 265–266°C [20]); 1H-
NMR (CDCl3): δ= 2.17 (s, 6H), 7.28–7.34 (m, 3H), 7.36 (td,
J=7.5, 1.0Hz, 1H), 7.44 (td, J=7.3, 1.8Hz, 1), 7.53–7.56
(m, 4H), 7.58–7.61 (m, 1H), 8.40–8.42 (m, 4H); 13C-NMR
(CDCl3): δ= 14.2, 113.7, 115.9 (d, JCÀF =21.2Hz), 120.3,
121.9 (d, JCÀF =16.9Hz), 124.0 (d, JCÀF = 3.7 Hz), 125.2,
128.9, 131.2 (d, JCÀF =2.3Hz), 131.4 (d, JCÀF =7.8Hz),
134.3, 139.6, 144.1, 150.5, 159.5 (d, JCÀF =247.1Hz).
Anal. Calcd for C27H20FN5: C 74.81, H 4.65, N 16.16.
Found: C 74.51, H 4.61, N 15.94.
Reaction of 2-fluorobenzaldehyde (1a) with 1-methyl-3-
phenyl-1H-pyrazol-5-amine (2c). Reaction was performed
according to the general procedure with 1 mmol of 1a
and 2c (60 min). For Chromatotron separation and
purification, toluene was used as a solvent (elution of 3s)
followed by toluene/ethyl acetate mixture (elution of 4s).
1,3,5,7-Tetramethyl-4-(2-fluorophenyl)-bis-pyrazolo[3,4-b,4′,3′-
e]pyridine (4t). A white powder, 22% yield (31mg); m.p.
1
165–166°C; H-NMR (CDCl3): δ=2.08 (s, 6H), 4.08 (s,
6H), 7.26–7.29 (m, 1H), 7.32 (td, J=7.4, 0.8Hz, 1H), 7.36
(td, J=7.3, 1.8Hz, 1H), 7.53–7.56 (m, 1H); 13C-NMR
(CDCl3): δ=14.0, 33.4, 111.7, 115.7 (d, JCÀF =21.3Hz),
122.5 (d, JCÀF =16.9Hz), 123.8 (d, JCÀF =3.6Hz), 131.1
(d, JCÀF =7.8Hz), 131.2 (d, JCÀF = 2.6 Hz), 133.8, 141.8,
151.9, 159.5 (d,
C17H16FN5: C 66.01, H 5.21, N 22.64. Found: C 65.70, H
5.25, N 22.53.
JCÀF =246.9Hz). Anal. Calcd for
Reaction of 2-fluorobenzaldehyde (1a) with 3-tert-butyl-1-
phenyl-1H-pyrazol-5-amine (2e). Reaction was performed
according to the general procedure with 3mmol of 1a
and 2e (70min). The Chromatotron purification was
followed by crystallization from methanol.
1-Methyl-3-phenyl-1H-pyrazolo[3,4-b]quinoline (3s).
A
3-tert-Butyl-1-phenyl-1H-pyrazolo[3,4-b]quinoline (3u).
Light-yellow needles, 52% yield (466 mg); m.p. 114°C;
1H-NMR (CDCl3): δ =1.66 (s, 9H), 7.25–7.27 (m, 1H),
7.76 (ddd, J =8.4, 6.6, 1.5 Hz, 1H), 7.53–7.56 (m, 2H),
7.76 (ddd, J =8.7, 6.6, 1.6 Hz, 1H), 7.98 (dd, J= 8.3,
1.3 Hz, 1H), 8.16 (d, J= 8.6 Hz, 1H), 8.55–8.57 (m, 2H),
8.75 (s, 1H); 13C-NMR (CDCl3) δ= 29.8, 34.7, 116.3,
120.2, 123.8, 124.0, 124.7, 128.7, 129.0, 129.1, 130.5,
131.3, 140.2, 147.8, 151.0, 153.9. Anal. Calcd for
C20H19N3: C 79.71, H 6.35, N 13.94. Found C 79.36, H
6.07, N 14.01.
yellow, cotton-wool-like solid, 43% yield (110mg); m.p.
1
146–147°C (Lit. 149°C [28]); H-NMR (CDCl3): δ= 4.29
(s, 3H), 7.43–7.46 (m, 2H), 7.54–7.57 (m, 2H), 7.76
(ddd, J = 8.7, 6.6, 1.5 Hz, 1H), 7.98 (br d, J = 8.2 Hz, 1H),
8.05–8.07 (m, 2H), 8.12 (br d, J =8.7 Hz, 1H), 8.85 (s,
1H); 13C-NMR (CDCl3) δ: 34.1, 115.0, 123.7, 124.5,
127.1, 128.3, 128.6, 129.1, 129.4, 130.7, 131.0, 133.1,
142.8, 148.3, 151.4. Anal. Calcd for C17H13N3: C 78.74,
H 5.05, N 16.21. Found: C 79.02, H 5.02, N 15.86.
1,7-Dimethyl-3,5-diphenyl-4-(2-fluorophenyl)-bis-pyrazolo[3,4-
b,4′,3′-e]pyridine (4s). A white powder, 5% yield (10mg);
1
m.p. 228–229°C; H-NMR (CDCl3): δ=4.26 (s, 6H), 6.53
(ddd, J=9.6, 8.3, 1.0Hz, 1H), 6.61 (td, J=7.5, 1.1Hz,
1H), 6.77 (td, J= 7.3, 1.8 Hz, 1H), 7.00–7.02 (m, 4H),
7.03–7.05 (m, 1H), 7.06–7.08 (m, 4H), 7.10–7.13 (m, 2H);
13C-NMR (CDCl3): δ=33.9, 110.9, 114.8 (d,
Acknowledgments. The part of the research was carried out
with the equipment purchased, thanks to the financial support
of the European Regional Development Fund in the
framework of the Polish Innovation Economy Operational
Program (contract no. POIG.02.01.00-12-023/08). Chemicals
for the purpose of the research were financed by the Ministry
of Science and Higher Education of the Republic of Poland
(DS 3133/IChiF/15).
J
J
J
CÀF =21.8Hz), 122.3 (d, JCÀF =16.0Hz), 123.1 (d,
CÀF =3.3 Hz), 127.3, 127.4, 128.9, 130.4 (d,
CÀF =8.2 Hz), 131.3 (d, JCÀF =2.1Hz), 132.8, 134.4,
145.8, 151.8, 159.2 (d, JCÀF =247.4Hz). Anal. Calcd for
C27H20FN5: C 74.81, H 4.65, N 16.16. Found: C 74.50, H
4.60, N 16.20.
REFERENCES AND NOTES
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pyrazol-5-amine (2d). Reaction was performed according
to the general procedure with 1mmol of 1a and 2
(45min). For Chromatotron separation and purification,
toluene was used as a solvent (elution of 3t) followed
by toluene/ethyl acetate mixture (elution of 4t):
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DOI 10.1002/jhet

Month 2016
Facile and Regioselective Synthesis of Substituted 1H-Pyrazolo[3,4-b]quinolines
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet