A new regiospecific synthesis method of 1H-pyrazolo[3,4-b]quinoxalines – Potential materials for organic optoelectronic devices, and a revision of an old scheme

Article abstract of DOI:10.1016/j.tet.2017.06.061

A series of 6-substituted-1,3-diphenyl-1H-pyrazolo[3,4-b]quinoxalines were prepared using a new synthetic pathway: reductive cyclization of appropriate 5-(o-nitrophenyl)-pyrazoles with ferrous oxalate or triphenylphosphine. The main advantage of this procedure is that, contrary to the older protocols of pyrazolo[3,4-b]quinoxaline synthesis, this method allows for a substituent to be introduced to the carbocyclic ring without the formation of isomers. The pyrazole ring can also be modified to some extent. Furthermore, we propose a new mechanism for the oldest reported pyrazolo[3,4-b]quinoxaline synthesis, based on the condensation between o-phenylenediamine and 3,4-pyrazolin-5-diones.

Full text of DOI:10.1016/j.tet.2017.06.061

Accepted Manuscript
A new regiospecific synthesis method of 1H-pyrazolo[3,4-b]quinoxalines – Potential
materials for organic optoelectronic devices, and a revision of an oldest scheme
Andrzej Danel, Katarzyna Wojtasik, Paweł Szlachcic, Marlena Gryl, Katarzyna
Stadnicka
PII:
S0040-4020(17)30704-4
10.1016/j.tet.2017.06.061
TET 28826
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 21 February 2017
Revised Date: 13 June 2017
Accepted Date: 27 June 2017
Please cite this article as: Danel A, Wojtasik K, Szlachcic Paweł, Gryl M, Stadnicka K, A new
regiospecific synthesis method of 1H-pyrazolo[3,4-b]quinoxalines – Potential materials for organic
optoelectronic devices, and a revision of an oldest scheme, Tetrahedron (2017), doi: 10.1016/
j.tet.2017.06.061.
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ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
A new regiospecific synthesis method of 1H-pyrazolo[3,4-
b]quinoxalines – potential materials for organic optoelectronic
devices, and a revision of an oldest scheme
Andrzej Danela,*, Katarzyna Wojtasika, Paweł Szlachcica,*, Marlena Grylb, Katarzyna
Stadnickab
a Institute of Chemistry, Faculty of Food Technology, Agricultural University,
ul. Balicka 122, 31-149 Kraków, Poland
b Faculty of Chemistry, Jagiellonian University,
ul. Ingardena 3, 30-060 Kraków, Poland
Corresponding authors:
A. Danel (e-mail: rrdanela@cyf-kr.edu.pl)
Tel: +48-126624846
P. Szlachcic (e-mail: p.szlachcic@ur.krakow.pl)
Tel: +48-126624054
1

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Abstract
A series of 6-substituted-1,3-diphenyl-1H-pyrazolo[3,4-b]quinoxalines were prepared using a
new synthetic pathway: reductive cyclization of appropriate 5-(o-nitrophenyl)-pyrazoles with
ferrous oxalate or triphenylphosphine. The main advantage of this procedure is that, contrary
to the older protocols of pyrazolo[3,4-b]quinoxaline synthesis, this method allows for a
substituent to be introduced to the carbocyclic ring without the formation of isomers. The
pyrazole ring can also be modified to some extent. Furthermore, we propose a new
mechanism for the oldest reported pyrazolo[3,4-b]quinoxaline synthesis, based on the
condensation between o-phenylenediamine and 3,4-pyrazolin-5-diones.
Keywords:
1H-pyrazolo[3,4-b]quinoxaline,
palladium aminoarylation,
reductive cyclization,
ferrous oxalate,
Cadogan synthesis,
X-ray crystallography
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1. Introduction
In 1903 Sachs and Becherescu synthesized the first examples of the 1H-pyrazolo[3,4-
b]quinoxaline (PQX) system by heating o-phenylenediamine with 2,5-diphenylpyrazole-3,4-
dione.1 Since then, this particular class of compounds, sometimes called flavazoles, has
attracted the attention of many scientists. A significant amount of research has been carried
out in order to determine their biological properties. For example, it has been discovered that
1H-Pyrazolo[3,4-b]quinoxalines exhibit antibacterial activity.2 Additionally, these compounds
have been investigated as possible antifungal, antihypertensive, antiproliferative or anti-
inflammatory agents. 3 Regardless of their biological activity, the photophysical properties of
PQX make them quite attractive for practical applications. Many pyrazoloquinoxalines
exhibit strong fluorescence in solution, as well as in solid-state.4 Kucybała et al. synthesized a
series of pyrazoloquinoxaline dyes and tested them as novel photoinitiators for free radical
polymerization. 5 Numerous quinoxaline derivatives are applied in the field of organic
electronics, either as electron transporting materials ETM, or emissive materials EM. 6,7 1H-
Pyrazolo[3,4-b]quinolines substituted with N,N-dialkylamino groups have been applied as
green emitters in multilayer organic light emitting diodes OLED. 8 Quinoxaline-based
oligomers and polymers are used in the fabrication of organic photovoltaic devices.9 We have
previously synthesized fluorene/1,3-diphenyl-1H-pyrazolo[3,4-b]quinoxaline copolymers and
applied them in a bulk heterojunction solar cell.10 The most common synthetic procedures for
the production of pyrazolo[3,4-b]quinoxalines are depicted on Scheme 1.
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Scheme 1. Some of the synthetic approaches to the 1H-pyrazolo[3,4-b]quinoxaline system.
The procedure applied by Sachs and Becherescu belongs to the family of quinoxaline
derivatives syntheses, and is based on a condensation between 1,2-diaminobenzenes and two-
carbonyl-group-carrying molecules, mentioned in the recent reviews by Mamedov and
Zhukova.11 The method is limited only to unsubstituted 1,2-diaminobenzene (R3 = H) or to
symmetrical 4,5- and 3,6-disubstituted examples. Otherwise, 1,2-diaminobenzene and
12
pirazolin-3,4-dione condensation, results in a mixture of isomers.
Sometimes their
separation involves tedious chromatographic procedures, due to relatively close Rf values.
The majority of pyrazoloquinoxaline synthetic procedures described in the literature are based
on pyrazole ring formation. One of the most exploited synthetic pathways involves the
heating of o-phenylenediamine, an excess of phenylhydrazine, and a reducing sugar. As a
result, derivatives of 1-phenyl-1H-pyrazolo[3,4-b]quinoxaline modified in the 3 position of
the pyrazole ring are formed.13 Sardonick and Linker developed an easy synthetic procedure
for flavazole preparation starting from 2-acetylquinoxaline oxime and hydrazines. 14 The
pyrazol ring can also be formed by dehydrogenation, or dehydrohalogenation of appropriate
arylhydrazones prepared from 2-acylquinoxalines. 15,16 Modifications on the carbocyclic ring
of the flavazole system are less common. Credner prepared 7-N,N-diethylamine substituted
PQX by reacting N,N-diethyl-p-phenylenediamine and 4-methyl-N-(5-methyl-2-
phenylpyrazol-3-yl)benzenesulfonamide in the presence of potassium persulfate.4a Derivatives
of the same type were prepared by Wang et al., but in that case p-nitroso-N,N-dialkylamine
was used instead of p-phenylenediamine.8a We have developed a new synthetic method for
the synthesis of 6-substituted-1H-pyrazolo[3,4-b]quinoxalines, starting from substituted o-
nitroiodobenzene and commercially available 3-aminopyrazoles. Moreover, we have revised
the reaction mechanism of PQX formation based on the condensation of o-phenylenediamine
with pyrazolin-3,4-diones.
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2. Results and discussion
In previous studies, we used 1H-pyrazolo[3,4-b]quinolines as effective luminophores in
organic light emitting diodes, either as dopants in poly(9-N-vinylcarbazole),17 or as vacuum
evaporated films in multilayer devices.18 Afterwards we applied a structurally similar system
of 1H-pyrazolo[3,4-b]quinoxalines, PQX, because of its strong emission both in solution and
19
in solid-state.
The 1,3-diphenyl-1H-pyrazolo[3,4-b]quinoxaline (5) luminophore was
prepared according to the procedure by Sachs and Becherescu, which involves heating
equimolar amounts of o-phenylenediamine (1) with 2,5-diphenylpyrazole-3,4-dione (3)
(Scheme 2; 5a R1,2 = Ph, R3 = H).1 The same procedure was applied for other methyl/phenyl
substituted pyrazoloquinoxalines 5b-d (Table 1).
Scheme 2. a) H2SO4, ethanol/reflux/2 hrs, b) glacial acetic acid/reflux/24 hrs.
Table 1. The reaction times and yields of unsubstituted 1H-pyrazolo[3,4-b]quinoxalines
Entry
Product
R1
R2
R3
H
H
H
H
Time
24 h
% Yield
70
1
2
3
4
Ph
Ph
5a
5b
5c
5d
Ph
Me
Ph
24 h
55
Me
Me
2-3 h
2-3 h
70
Me
70
Pyrazole-3,4-diones (3) were prepared in the reaction of appropriate 2,4-dihydro-3H-pyrazol-
3-ones with p-nitroso-N,N-dimethylaniline leading to imino compounds (2). These imino
compounds (2) have an interesting feature – in the crystalline state they form black crystals
(dark red in transmitted light) with a metallic, usually green, lustre. In our case this feature
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could be explained by analysing the crystal structure determined for (4Z)-4-[4-
(dimethylamino)phenyl]imino-5-methyl-2-phenyl-pyrazol-3-one (2b). Single crystals of 2b
were obtained from an acetone solution by slow evaporation at ambient temperature. The
measurement conditions and refinement parameters are summarized in Table S1
(Supplementary Data). The shape of the molecule is presented in Figure S1. The 2b molecule
is almost planar: dihedral angles between the rings do not exceed 10° (cf. Table S2). The
conformation is stabilized by intramolecular hydrogen-bond-like interactions of C-H…O and
C-H…N types (Table S3 and Figure S1). Additionally, the “single” bonds: N1-C11, N4-C41,
and C44-N50 are also significantly shortened (cf. Table S2), which is caused by strong
conjugation through the 1-phenyl pyrazol 4-phenyl N,N-dimethyl moieties. These
features are responsible for the dark-red colour of the chromophore in the solid-state
(observed as black by the naked eye), and red in solution: λꢀꢁꢂ(ꢃꢄꢃꢅ ) for 2b is 513 nm (green),
ꢆ
which is complementary to red. 20 The molecules of 2b form dimers in solid-state with π…π
and N…π interactions between the pyrazole rings (Table S3). The dimers form layers parallel
to (-101) (see Figure S2 in Supplementary Data). The conformation of the molecule of 2b and
the packing in the crystal structure are similar to those found previously for (4Z)-4-[4-
(diethylamino)phenyl]imino-5-methyl-2-phenyl-pyrazol-3-one. 21 These two characteristics
(i.e. the specific conformation of the molecules and their packing scheme) found for 2b might
be responsible for the metallic lustre of the crystals. The effect (metallic lustre of organic
crystals) was observed previously, and it was explained to be caused by the specific relative
position of molecules in the crystalline state, which form layers consisting of relatively long
molecules with conjugated π-systems.22
Subsequent hydrolysis of 2 with dilute H2SO4 produced 3 (Scheme 2). Sachs and Becherescu
noticed that a red precipitate was formed in the first stage of the reaction between 1 and 3.1 It
was transformed into pyrazoloquinoxaline 5 after prolonged heating in glacial acetic acid at
reflux. At that time the structure of the red precipitate was not fully determined. Ohle and
Melkonian after studying Becherescu’s results, concluded that the intermediate product was
2,5-diphenyl-4-phenyliminopyrazol-3-one 4a (Scheme 3). 23 Kappe et al. also reached the
same conclusion.24 On the other hand, Metwally and co-workers suggested a formation of
spiro-compound (4b), resulting from the condensation of two of o-phenylenediamine amino
groups with a carbonyl group at C4 of the pyrazole ring.25 The proposed structure was based
on elemental analyses and 1H NMR (DMSO, 90 MHz) spectra.
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Scheme 3. Structures of intermediate products 4a/4b in PQX synthesis proposed in the literature
To clarify the uncertainties concerning the exact structure of 4, we isolated the red crystalline
intermediate mentioned earlier.1,25 After studying the 13C NMR spectra of the supposed spiro
system 4b (R1,2 = Ph, R3 = H) we discovered the presence of 17 signals instead of 14. The
13
presence of the phenyl ring perpendicular to the pyrazole should reduce the amount of C
NMR signals (in 4a the phenyl ring has six different carbon atoms, in 4b there are only three
as an effect of the symmetry plane perpendicular to the ring). The same situation occurred
when analyzing the intermediate products in the case of 3-methyl-1-phenyl-1H-pyrazolo[3,4-
1
b]quinoxaline synthesis. An analysis of the H NMR spectra again suggested quite different
1
structure of the isolated compounds. In the downfield region of the H NMR spectra, two
peaks of one-proton singlets at 12.60-12.20 ppm and at 9.80-9.60 ppm, respectively, were
observed. This fact excludes both of the previously proposed intermediate structures 4a and
4b. It seems that at the beginning of the reaction one amino group of o-phenylenediamine (1)
reacts first with the keto group at C4 of 3, forming a labile intermediate compound 4a, which
immediately reacts further (Scheme 4). Subsequently an attack on the second carbonyl group
in the 4a molecule, by the second amino group in that molecule (red arrows), leads to an
opening of the pyrazole ring, and the formation of phenylhydrazone 6 (Scheme 4; path a, red
arrows). From the crystal structure analysis performed for 6a (see below), it can be concluded,
that after the formation of 6, it rearranges itself to the more stable, but less reactive 6’
conformer (green arrows, hydrogen bond in 6’ marked by green dashed line).
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Scheme 4. The proposed mechanism of intermediate 6 and 1H-pyrazolo[3,4-b]quinoxaline 5 formation.
The heating of phenylhydrazones 6a,b in boiling glacial acetic acid resulted in the formation
of pyrazolo[3,4-b]quinoxaline 5a,b (Scheme 4, path b, blue arrows). The R1 substituent plays
a crucial role in the formation of 5. If a phenyl group acts as R1 substituent, it is able to
delocalize a pair of electrons – therefore 6 is more stable (in the form of 6’) and the reaction
time is much longer (up to 24 h), than in the case of alkyl R1 substituents. An alkyl substituent
allows for a shorter reaction time, with the reaction being complete within 2-3 h.
The structure of 6 was conclusively confirmed by the crystal structure analysis performed for
3-[(Z)-phenyl(2-phenylhydrazinylidene)methyl]quinoxalin-2(1H)-one (6a). Single crystals of
6a were obtained from the DMF solution by slow evaporation at ambient temperature. The
measurement conditions and refinement parameters are summarized in Table S1
(Supplementary Data). The shape of the 6a molecule is presented at Figure 1a, with the
intramolecular N-H…N hydrogen bond marked by a dashed line. Figure 1b shows the
intermolecular N-H…O hydrogen bonds between two molecules of 6a in the crystalline state.
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a)
b)
Figure 1. a) The shape of molecule for 6a with the atom numbering scheme. Displacement ellipsoids are drawn
at the 50% probability level. The intramolecular N-H…N hydrogen bond is marked by dashed line. b) Two
molecules of 6a with intermolecular N-H…O hydrogen bonds marked by dashed lines.
The energy of these hydrogen bonds was calculated with DFT methodology using the
Gaussian09 suite of programs.26 Counterpoise corrected interaction energy was calculated for
the dimer of 6a at the experimental geometry fitted to neutron X-H distances using M052X/6-
311+G(2df,2p) functional/basis set. 27,28 The basis set superposition error (BSSE) corrected
energy is equal to -20.94 kcal/mole. For comparison: interaction energy calculated using the
same approach for uracil dimer is: -8.47 kcal/mol. 29 QTAIM charge density analysis
performed for the dimer of 6a, evaluated the intra- and intermolecular hydrogen bond
energies. 30 It has previously been proven that hydrogen bond energy can be correlated to the
pressure employed on the electrons around the critical point: E(HB) = ½ V(rcp).31 Taking this
relation into account, the selected interactions (Table S4 and Figure S3, see Supplementary
Data) can be classified as intermediate between closed and shared shell. These energy barriers,
stabilizing such conformation of 6a (Figure 1, and 6’ on Scheme 4), are responsible for the
relatively low reactivity of 6a and 6b. The reaction of these compounds, leading to 1H-
pyrazolo[3,4-b]quinoxalines 5a and 5b, respectively, needs 24 h of heating under reflux in
acetic acid solution, until the reaction is finished. The geometrical parameters of 6a are
summarized in Table S5, whereas the data for hydrogen bonds can be found in Table S6 (for
1
both tables see Supplementary Data). Additionally, the comparison of H NMR data of the
compound 6a obtained by us, with the product obtained by Mamedov et al. (they prepared 6a
from phenylhydrazine and 3-benzoyl-1H-quinoxalin-2-one)32 confirms the proposed structure.
Vinot et al. also observed an intermediate product of similar structure, while conducting the
9

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reaction between o-phenylenediamine and 4-(2-phenylhydrazinylidene)-2H-chromene-
2,3(4H)-dione.33
As mentioned earlier, the condensation of substituted o-phenylenediamines with 2,5-
disubstituted pyrazolin-3,4-diones leads to isomer formation (Scheme 3; for R3≠H). In order
to avoid isomer formation in the synthesis of 1H-pyrazolo[3,4-b]quinoxalines, we applied a
different synthetic pathway, depicted in Scheme 5 and 6.
Scheme 5. a) K2CO3/DMF or KOH/H2O/Pd2dba3/(o-biphenyl)P(t-Bu)2; b) FeC2O4 2H2O
/sulfolane/250 °C/10 min.
In the search for new OLED luminophores we synthesized 6-N,N-dimethyl-3-methyl-1-
phenyl-1H-pyrazolo[3,4-b]quinoxaline, in order to investigate its photophysical properties.4c
The derivative 9 (R3=NMe2) was cyclised according to a modified procedure for phenazine
synthesis used by Vivian et al.34 They used ferrous oxalate/lead shot mixture as a reducing
agent in the synthesis of phenazines from 2-nitrodipenylamines. The exact mechanism of this
reaction is not yet fully established. It seems that in the first stage ferrous oxalate decomposes
and the resulting products are involved in the deoxygenation of the nitro group. The resulting
nitrene attacks a neighbouring aromatic ring and phenazines are formed. Pyrazolo[3,4-
b]quinoxaline 5 (R1 = Ph, R2 = Me, R3 = NMe2) was prepared via the cyclization of 9 using
ferrous oxalate in boiling sulfolane. However due to the harsh reaction conditions, the
resulting product underwent partial decomposition and the final yield of 5 was relatively low
( 27%).
4-Nitro-5-arylaminoderivative (9) can be prepared either by heating 7 with aniline 8 in the
presence of anhydrous potassium carbonate in DMF, or by a palladium aminoarylation
protocol developed by Surry and Buchwald.35 The reductive cyclization of 9 is limited to only
two types of pyrazoloquinoxalines 5: R1 = Ph / R2 = Me and R1,2 = Me. It is linked to the
synthesis of a starting reagent 5-chloro-4-nitropyrazole (7). This compound can be prepared
either by nitration of appropriate 5-chloropyrazoles with fuming HNO3 in acetic anhydride
(for R1 = Ph, R2 = Me), or with a mixture of fuming H2SO4 and HNO3 (R1,2 = Me).36
Unfortunately, attempts to prepare 7 with R1,2 = Ph or R1 = Me, R2 = Ph failed. In both cases,
10

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we obtained a mixture of polynitrated compounds. Thus, the pathway according to scheme 5
is limited as far as the modification of pyrazole ring is concerned. This inconvenience can be
avoided by applying a slightly different synthetic procedure using aminopyrazoles as starting
materials (Scheme 6).
Scheme 6. a) BINAP, Pd2dba3 b) FeC2O4 2H2O/sulfolane or Ph3P/o-chlorobenzene.
Certain aminopyrazoles 11 can be purchased from commercial chemical suppliers, or
37
prepared in a reaction of aryl/alkyl hydrazines with aroyl/acetylacetonitriles.
Nitroderivatives 10 were prepared by nitration of p-substituted acetanilides, followed by
removal of the protecting group, and subsequent Sandmayer iodination.38 The coupling of 10
and 11 was accomplished via a palladium catalyzed reaction in the presence of rac-BINAP.34
The structure of compound 12 in the solid state was determined for 12a and 12b by crystal
structure analysis. Single crystals were obtained by slow cooling of hot, saturated toluene
solutions. The details of measurement conditions, together with refinement parameters can be
found in Table S1 (see Supplementary Data). Additionally, the most important geometrical
parameters for the analyzed structures are listed in Supplementary Data in Table S7 and Table
S8 contains the geometry of intramolecular N-H…O hydrogen bonds and the most important
weak interactions. Figure S4 shows the shape of the molecules 12a and 12b. The geometry of
both molecules is comparable with that found earlier for a similar compound, methyl 4-[(1-
acetyl-3-tert-butyl-1H-pyrazol-5-yl)amino]-3-nitrobenzoate,
with
corresponding
intramolecular hydrogen bonds also observed for this structure.39
Compound 12 was heated with ferrous oxalate dihydrate in boiling sulfolane, yielding
pyrazolo[3,4-b]quinoxaline 5. The yields varied between 27-70% (Table 2). An alternative
strategy for this reaction is the application of triethylphosphite/triphenylphosphine as a
reducing agent. This method was employed in the synthesis of phenazines, indoles, and
40
carbazoles, starting from the appropriate nitro compounds.
When we applied
triphenylphosphine in the synthesis of unsubstituted pyrazoloquinoxalines from 12 (R3=H),
the yields varied between 7-50% for the final products (Table 2).
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Table 2. The reaction conditions for cyclization of 12
Entry Product
R1
Ph
Ph
Me
Me
Ph
Ph
Me
Me
Ph
Ph
Ph
Ph
Ph
R2
Ph
Me
Ph
Me
Ph
Me
Ph
Me
Ph
Ph
Ph
Ph
Ph
R3
H
Reagent Solvent
Time
% Yield
68
50
44
51
52
16
8
1
2
FeC2O4 sulfolane 20 min
FeC2O4 sulfolane 20 min
FeC2O4 sulfolane 20 min
FeC2O4 sulfolane 20 min
5a
5b
5c
5d
5a
5b
5c
5d
5e
5f
H
3
H
4
H
5
H
Ph3P
Ph3P
Ph3P
Ph3P
DCBa
DMAcb
DCBa
24 h
46 h
43 h
48 h
6
H
7
H
8
H
DMAcb
7
9
Cl
Br
F
FeC2O4 sulfolane 20 min
FeC2O4 sulfolane 20 min
FeC2O4 sulfolane 20 min
FeC2O4 sulfolane 20 min
FeC2O4 sulfolane 20 min
61
24
15
43
38
10
11
12
13
5g
5h
5i
Me
MeO
a 1,2-Dichlorobenzene
b N,N-Dimethylacetamide
The reaction conditions were unoptimized. 6-N,N-Diphenylamine-1,3-diphenyl-1H-
pyrazolo[3,4-b]quinoxaline (5j) (R1,2 = Ph, R3 = N,N-Ph) was prepared by the palladium-
catalysed aminoarylation of 5e (R1,2 = Ph, R3 = Cl) with diphenylamine. All of the
pyrazolo[3,4-b]quinoxalines 5a-j will be tested as potential luminophores for use in OLEDs.
12

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3. Conclusions
We have developed a new regiospecific method for the synthesis of pyrazoloquinoxalines
from aminopyrazoles and substituted o-iodonitrobenzene derivatives. This method is suitable
for the modification of both the carbocyclic ring and the pyrazole. It is anticipated that the
application of appropriate o-iodonitro derivatives will also allow for a regiospecific synthesis
of 8-, 7- and 5-substituted pyrazoloquinoxaline derivatives. Furthermore, we have determined
the specific mechanism of the oldest reported 1H-pyrazolo[3,4-b]quinoxaline synthesis.
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4. Experimental
4.1.
Materials and methods
All reagents and solvents were purchased from commercial sources (Aldrich and POCh –
Polish chemical company) and were used without further purification. Aluminium oxide 90
active neutral 70-230 mesh purchased from Merck, was used for column chromatography.
The purity of final compounds was monitored using silica gel GF254 precoated thin layer
13
chromatography (TLC) plates (Merck). The compounds were characterized by 1H NMR, C
1
NMR, and elemental analyses. H NMR and 13C NMR spectra were recorded on Bruker
Avance III 600. Chemical shifts (δ) were reported in ppm, using TMS as internal standard.
Melting points were determined on a Mel-Temp II Apparatus (capillary), and they were left
uncorrected. Elemental analyses were conducted at Elementar Vario MICRO cube. IR spectra
were recorded on a Thermo Nicolet iS5 infrared spectrometer with ATR. Diffraction datasets
were collected for single crystals either with an Agilent Technologies SuperNova™
41
diffractometer, (low-temperature Cryo-Jet device, Atlas CCD detector), using Mo Kα
radiation or Cu Kα radiation; or with the Nonius KappaCCD diffractometer using graphite
42
monochromated Mo Kα radiation (data collection: COLLECT, cell refinement: HKL
SCALEPACK, 43 data reduction: HKL DENZO and SCALEPACK).42 The programs used for
44
the crystal structure analyses: SIR92 for solving the structures with direct methods,
45
SHELXL2013 for the refinement of the structures,
ORTEP3 for the preparation of
46
molecular graphics,
were working under WinGX environment. 47 The supplementary
materials were stored at CCDC.48
4.2. General procedure for synthesis of 4-[4-(dimethylamino)phenyl]imino-2,5-disubstituted
pyrazol-3-ones (2)
Compounds were prepared using modified literature procedure1. A 30% solution (3.0 mL) of
Na2CO3 was added in portions to a stirred hot (75 °C) solution of 4-nitroso-N,N-
dimethylaniline (3.0 g, 0.02 mol) in ethanol (20 mL). After 5 min, a solution of appropriate
pyrazolone (0.02 mol) in ethanol (50 mL) was added dropwise. The reaction mixture was kept
at 85 °C for 3 h. After the reaction was complete it was refrigerated overnight at 4 °C and the
resulting precipitate was filtered off and recrystallized from toluene.
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4.2.1. (4Z)-4-[4-(dimethylamino)phenyl]imino-2,5-diphenyl-pyrazol-3-one (2a)
Black prisms with green metallic lustre, 5.2 g, 70%, mp. 216-217 °C (toluene) (lit. 218.5 °C1);
1H NMR (600 MHz, CDCl3, ppm): δ = 8.29-8.26 (m, 4H), 8.09-8.07 (m, 2H), 7.48-7.43 (m,
13
5H), 7.22 (t, J = 7.3 Hz, 1H), 6.74-6.71 (m, 2H), 3.15 (s, 6H, N(CH3)2); C NMR (75 MHz,
CDCl3, ppm ) δ = 153.7, 153.4, 148.7, 141.6, 138.7, 136.6, 133.2, 131.1, 129.4, 128.8, 128.4,
128.2, 125.1, 119.1, 111.1, 40.3; IR (ATR): ν = 3059, 1679, 1600, 1492, 1372, 1299, 1147,
1109, 932, 821, 761, 691, 669, 504 cm-1. Anal. Calcd for C23H20N4O: C, 74.98; H, 5.47; N,
15.21. Found: C, 74.81; H, 5.50; N, 15.13.
4.2.2. (4Z)-4-[4-(dimethylamino)phenyl]imino-5-methyl-2-phenyl-pyrazol-3-one (2b)
Black prisms with green metallic lustre, 2.4 g, 42%, mp. 190-191 °C (toluene) (187 °C49); 1H
NMR (600 MHz, CDCl3, ppm): δ = 8.29-8.27 (m, 2H), 7.97-7.95 (m, 2H), 7.42-7.39 (m, 2H),
7.17 (t, J = 7.4 Hz, 1H), 6.72-6.69 (m, 2H), 3.13 (s, 6H, N(CH3)2), 2.30 (s, 3H); 13C NMR (75
MHz, CDCl3, ppm): δ = 153.8, 153.2, 152.0, 142.8, 138.6, 136.4, 133.2, 128.7, 124.8, 118.8,
111.1, 40.3, 12.5; IR (ATR): ν = 3250, 2914, 1666, 1476, 1435, 1369, 1299, 1255, 1169,
1100, 992, 818, 751, 688, 656, 517, 457 cm-1. Anal. Calcd for C18H18N4O: C, 70.57; H, 5.92;
N, 18.29. Found: C, 70.44; H, 5.93; N, 18.12.
4.2.3. (4Z)-4-[4-(dimethylamino)phenyl]imino-2-methyl-5-phenyl-pyrazol-3-one (2c)
1
Black small needles with green metallic lustre, 1.5 g, mp. 135-136 °C (toluene). H NMR
(600 MHz, CDCl3, ppm): δ = 8.30-8.28 (m, 2H), 8.14-8.12 (m, 2H), 7.44-7.38 (m, 3H), 6.72-
6.69 (m, 2H), 3.49 (s, 3H), 3.14 (s, 6H).13C NMR (75 MHz, CDCl3, ppm): δ = 154.9, 153.2,
147.5, 141.8, 136.7, 133.0, 131.2, 129.1, 128.2, 128.1, 111.1, 40.3, 32.2; IR (ATR): ν = 3053,
1654, 1616, 1499, 1473, 1372, 1337, 1166, 1033, 973, 821, 755, 647, 527, 495, 463 cm-1.
Anal. Calcd for C18H18N4O: C, 70.57; H, 5.92; N, 18.29. Found: C, 70.45; H, 5.61; N, 18.01.
4.2.4. (4Z)-4-[4-(dimethylamino)phenyl]imino-2,5-dimethyl-pyrazol-3-one (2d)
Black small prisms with metallic lustre, 2.1 g, 50%, mp. 174-176 °C (toluene) (lit. 172 °C50).
1H NMR (600 MHz, CDCl3, ppm): δ = 8.28-8.26 (m, 2H), 6.69-6.67 (m, 2H), 3.36 (s, 3H),
15

ACCEPTED MANUSCRIPT
13
3.12 (s, 6H), 2.18 (s, 3H); C NMR (75 MHz, CDCl3, ppm): δ = 155.1, 153.0, 150.2, 143.2,
136.4, 132.9, 111.1, 40.2, 31.8, 12.3; IR (ATR): ν = 2908, 2819, 1644, 1609, 1527, 1486,
1432, 1356, 1318, 1248, 1226, 1160, 1046, 1017, 941, 824, 770, 644, 603, 571, 517, 463 cm-1.
Anal. Calcd for C13H16N4O: C, 63.91; H, 6.60; N, 22.93. Found: C, 63.96; H, 6.38; N, 22.39.
4.3. General procedure for 2,5-disubstituted pyrazolin-3,4-dione (3)
The diones 3a, 3b and 3d were prepared according to literature procedures. 1,51,52
4.3.1. 2-methyl-5-phenyl-pyrazole-3,4-dione (3c)
Compound 2c (1.53 g, 5 mmol) was dissolved in ethanol (20 mL), and 10 mL of 10% H2SO4
was added. The reaction mixture was heated at 85 °C for 3 h. After cooling, the contents were
poured into water (100 mL) and extracted with ethyl acetate (3 × 25 mL). The organic phase
was dried over anhydrous MgSO4 and evaporated. The residue was recrystallized from
toluene/petrol ether.
Brown powder, 836 mg, 87%, mp. 102-104 °C; 1H NMR (600 MHz, CDCl3, ppm): δ = 8.05-
13
8.03 (m, 2H), 7.48-7.44 (m, 3H), 3.49 (s, 3H); C NMR (75 MHz, CDCl3, ppm): δ = 185.0,
157.1, 150.6, 139.8, 131.3, 129.1, 126.8, 32.8. IR (ATR): ν = 3240, 2923, 1685, 1087, 1036,
859, 751, 685, 647, 590 cm-1. Anal. Calcd for C10H8N2O2: C, 63.82; H, 4.28; N, 14.89.
Found: C, 63.76; H, 4.19; N, 14.56.
4.4. Synthesis of 1,3-disubstituted-1H-pyrazolo[3,4-b]quinoxalines (5) from 1,2-
phenylenediamine - general procedure
A mixture of 1,2-diphenylamine 1 (0.34 g, 2 mmol) and corresponding pyrazolin-3,4-dione 3
(2 mmol) in 5 mL glacial acetic acid was stirred and heated at reflux for 24 h in the case of 5a
and 5b, or 2-3 h for 5c and 5d. The reaction was cooled and the resulting precipitate was
collected by filtration and washed with ethanol, and recrystallized from the solvent indicated
in each case.
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4.4.1. 1,3-Diphenyl-1H-pyrazolo[3,4-b]quinoxaline (5a)
1
Light orange needles, 456 mg, 70%, mp. 238-239 °C (toluene) (lit. 231 °C1); H NMR (600
MHz, CDCl3, ppm): δ = 8.77 (dd, J = 8.3, 1.2 Hz, 2H), 8.57 (dd, J = 8.6, 1 Hz, 2H), 8.35 (dd,
J = 8.5, 0.9 Hz, 1H), 8.22 (dd, J = 8.6, 0.8 Hz, 1H), 7.86 (dtd, J = 7.5, 1.4, 1.5 Hz, 1H), 7.77
(dtd, J = 7.5, 1.3, 1.6 Hz, 1H), 7.62-7.58 (m, 4H), 7.50 (t, J = 7.4 Hz, 1H), 7.35 (t, J = 7.4 Hz,
1H); 13C NMR (150 MHz, CDCl3, ppm): δ = 143.4, 143.0, 141.4, 141.3, 139.5, 137.0, 131.2,
131.1, 130.6, 129.4, 129.2, 129.1, 128.8, 128.2, 127.4, 125.8, 120.1; IR (ATR): ν = 3056,
1590, 1562, 1459, 1416, 1353, 1252, 1195, 1125, 983, 751, 688, 669, 641, 599, 492, 422 cm-1.
4.4.2. 3-Methyl-1-phenyl-1H-pyrazolo[3,4-b]quinoxaline (5b)
Deep yellow needles, 286 mg, 55%, mp. 135-136 °C (toluene) (lit. 133.5-134 °C25); 1H NMR
(600 MHz, CDCl3, ppm): δ = 8.45 (dd, J = 8.7, 1.1Hz, 2H), 8.28 (dd, J = 8.9, 1.3 Hz, 1H),
8.20 (dd, J = 8.6, 0.8 Hz, 1H), 7.84 (dtd, J = 7.5, 1.4, 1.5 Hz, 1H), 7.75 (dtd, J = 7.5, 1.4, 1.7
Hz, 1H), 7.58-7.55 (m, 2H), 7.31 (t, J = 7.4 Hz, 1H), 2.89 (s, 3H); 13C NMR (150 MHz,
CDCl3, ppm): δ = 144.4, 142.6, 141.6, 140.8, 139.4, 137.8, 130.9, 130.2, 129.20, 129.1, 128.0,
125.4, 119.6, 11.8; IR (ATR): ν = 3063, 1597, 1562, 1499, 1429, 1356, 1233, 1192, 1112,
1074, 745, 685, 672, 656, 599, 504, 419 cm-1.
4.4.3. 1-Methyl-3-phenyl-1H-pyrazolo[3,4-b]quinoxaline (5c)
1
Light orange crystalline powder, 187 mg, 70%, mp. 165°C (toluene); H NMR (600 MHz,
CDCl3, ppm): δ = 8.64 (dd, J = 8.3, 1.2 Hz, 2H), 8.33 (dd, J = 8.6, 0.9 Hz, 1H), 8.14 (dd, J =
8.6, 0.8 Hz, 1H), 7.82 (dtd, J = 7.8, 1.4, 1.5 Hz, 1H), 7.73 (dtd, J = 7.8, 1.3, 1.7 Hz, 1H), 7.56
(t, J = 7.5 Hz, 2H), 7.45 (t, J = 7.4 Hz, 1H); 4.29 (s, 3H); 13C NMR (150 MHz, CDCl3, ppm):
δ = 143.3, 141.9, 141.4, 141.3, 135.7, 131.6, 130.9, 130.7, 128.9, 128.8, 128.5, 127.5, 126.9,
34.2; IR (ATR): ν = 3053, 1575, 1486, 1464, 1198, 1122, 1084, 929, 881, 755, 742, 691, 675,
656, 631, 599, 504, 422 cm-1.
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4.4.4. 1,3-Dimethyl-1H-pyrazolo[3,4-b]quinoxaline (5d)
Yellow flat needles, 277 mg, 70%, mp. 140-141 °C (toluene/petrol ether 60-90) (lit. 137-138
16
1
°C ); H NMR (600 MHz, CDCl3, ppm): δ = 8.27 (dd, J = 8.6, 0.9 Hz, 1H), 8.14 (dd, J =
8.6, 0.8 Hz, 1H); 7.81 (dtd, J = 7.5, 1.4, 1.6 Hz, 1H), 7.71 (dtd, J = 7.5, 1.3, 1.7 Hz, 1H), 4.19
(s, 3H), 2.81 (s, 3H); 13C NMR (150 MHz, CDCl3, ppm): δ = 143.1, 142.2, 141.8, 140.7,
136.4, 130.7, 130.3, 128.5, 127.3, 33.8, 11.7; IR (ATR): ν = 2977, 1581, 1518, 1486, 1400,
1378, 1347, 1309, 1179, 1122, 960, 764, 653, 628, 599, 425 cm-1.
4.5. Synthesis of 3-acyl-1H-quinoxalin-2-one hydrazones (6) - general procedure
A mixture of 1,2-diaminobenzene 1 (108 mg, 1 mmol) and corresponding pyrazolin-3,4-dione
3 (1 mmol) in 5 mL glacial acetic acid was heated at reflux for 30 min. After cooling, the
resulting precipitate was filtered off.
4.5.1. 3-Benzoyl-1H-quinoxalin-2-one phenylhydrazone (6a)
Red needles, 260 mg, 76%, mp. 255-256 °C (Lit. 240-241 °C1); 1H NMR (600 MHz, CDCl3,
ppm): δ = 12.61 (br. s, 1H), 9.86 (s, 1H), 7.84 (dd, J = 8.0, 1.2 Hz, 1H), 7.62 (t, J = 7.75 Hz,
1H), 7.51-7.50 (m, 2H), 7.41 (dd, J = 8.2, 1.0 Hz, 1H), 7.36-7.31 (m, 3H), 7.23-7.20 (m, 3H),
13
7.17-7.15 (m, 2H), 6.77 (t, J = 7.2 Hz, 1H); C NMR (150MHz, CDCl3, ppm): δ = 155.9,
154.3, 145.7, 138.0, 137.7, 133.4, 133.0, 131.6, 129.6, 129.5, 128.9, 128.1, 125.7, 123.7,
119.9, 116.1, 113.1; IR (ATR): ν = 3173, 2967, 2884, 2817, 1663, 1592, 1513, 1489, 1427,
1248, 1224, 1130, 1092, 777, 756, 738, 688, 571, 535 cm-1.
4.5.2. 3-Acetyl-1H-quinoxalin-2-one phenylhydrazone (6b)
Red crystalline powder, 123 mg, 44%, mp. 234-235 °C. (Lit. 223 °C25); 1H NMR (600 MHz,
CDCl3, ppm): δ = 12.21 (br.s, 1H), 9.65 (s, 1H), 7.72 (d, J = 7.9 Hz, 1H), 7.46 (t, J = 7.4 Hz,
13
1H), 7.32-7.20 (m, 6H), 6.80 (t, J = 7.2 Hz, 1H), 2.28 (s, 3H); C NMR (150 MHz, CDCl3,
ppm): δ = 154.1, 153.9, 145.8, 139.9, 132.5, 132.1, 130.3, 129.3, 128.8, 123.5, 120.4, 115.3,
114.0, 13.7; IR (ATR): ν = 3173, 2976, 2881, 2831, 1666, 1592, 1510, 1218, 1165, 1130,
1080, 1065, 909, 741, 686, 585, 541 cm-1.
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4.6. Synthesis of 5-(4-R-2-nitrophenyl)-amino-1,3-disubstituted pyrazoles (12) (R = H, Cl, Br,
F, CH3, OCH3) – general procedure
The appropriate 4-substituted-1-iodo-2-nitrobenzene 10 (1 mmol), appropriate 1,3-
disubstituted-5-aminopyrazole 11 (1.3 mmol), and anhydrous potassium carbonate (248 mg,
1.8 mmol) were heated in the presence of rac-BINAP (23 mg, 0.036 mmol, 3.7 mol%),
Pd2dba3 (23 mg, 0.024 mmol, 2.5 mol%), and 18-crown-6 (10 mg, 0.038 mmol) in toluene (8
mL, purged with argon) at 100 °C. The reaction was carried out under argon for 24 h. After
cooling the reaction mixture was filtered and purified using column chromatography on
aluminium oxide with toluene, or a toluene-ethyl acetate mixture (10:1) as an eluent. The
product was recrystallized from toluene.
4.6.1. (2,5-diphenyl-2H-pyrazol-3-yl)-(2-nitrophenyl)-amine (12a)
Red long plates, 345 mg, 97%, mp. 130-131 °C; 1H NMR (600 MHz, CDCl3, ppm): δ = 9.42
(s, 1H), 8.2 (dd, J = 8.5, 1.5 Hz, 1H), 7.9 (d, J = 7.1 Hz, 2H), 7.59 (dd, J = 8.6, 1.2 Hz, 2H),
7.47-7.34 (m, 5H), 7.37-7.34 (m, 2H), 7.22 (dd, J = 8.5, 1.0 Hz, 1H), 6.87 (dtd, J = 7.8, 1.2,
13
1.3 Hz, 1H), 6.7 (s 1H); C NMR (150 MHz, CDCl3, ppm): δ = 151.7, 141.6, 138.1, 138.0,
136.2, 132.8, 129.4, 128.7, 128.4, 128.3, 128.1, 126.53, 125.56, 124.0, 119.0, 116.3, 98.8; IR
(ATR): ν = 3246, 3056, 1609, 1587, 1555, 1506, 1494, 1341, 1270, 1238, 1140, 1071, 954,
777, 737, 691, 616, 515, 470 cm-1. Anal. Calcd for C21H16N4O2: C, 70.77; H, 4.53; N, 15.72.
Found: C, 71.28; H, 4.61; N, 15.25.
4.6.2. (5-methyl-2-phenyl-2H-pyrazol-3-yl)-(2-nitrophenyl)-amine (12b)
1
Orange plates, 250 mg, 85%, mp. 108 °C; H NMR (600 MHz, CDCl3, ppm): 9.36 (s, 1H);
8.18 (dd, J = 8.5, 1.5 Hz, 1H), 7.49 (dd, J = 8.7, 1.2 Hz, 2H), 7.45-7.39 (m, 3H), 7.31 (t, J =
7.4 Hz, 1H), 7.16 (dd, J = 8.6, 1.0 Hz, 1H), 6.85 (dtd, J = 7.8, 1.2, 1.3 Hz, 1H), 6.18 (s, 1H),
2.38 (s, 3H); 13C NMR (150 MHz, CDCl3, ppm): δ = 149.5, 141.7, 138.1, 137.2, 136.1, 133.5,
129.3, 127.7, 126.5, 123.8, 118.7, 116.2, 101.2, 14.2; IR (ATR): ν = 3323, 3072, 1606, 1578,
1559, 1498, 1435, 1337, 1270, 1138, 1022, 767, 739, 698, 686, 636, 485 cm-1. Anal. Calcd for
C16H14N4O2: C, 65.30; H, 4.79; N, 19.04. Found: C, 65.32; H, 4.81; N, 18.81.
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4.6.3. (2-methyl-5-phenyl-2H-pyrazol-3-yl)-(2-nitrophenyl)-amine (12c)
1
Orange prisms, 265 mg, 90%, mp. 114 °C; H NMR (600 MHz, CDCl3, ppm): δ = 9.15 (s,
1H), 8.25 (dd, J = 8.8, 1.5 Hz, 1H), 7.79 (dd, J = 8.4, 1.3 Hz, 2H), 7.47-7.40 (m, 3H), 7.34-
7.31 (m, 1H), 6.91-6.88 (m, 2H), 6.51 (s, 1H), 3.80 (s, 3H); 13C NMR (150 MHz, CDCl3,
ppm): δ = 150.6, 142.6, 137.8, 136.4, 133.4, 133.1, 128.7, 127.9, 126.6, 125.3, 118.8, 115.9,
98.9, 35.3; IR (ATR): ν = 3320, 3063, 1616, 1575, 1551, 1492, 1333, 1259, 1142, 1039, 953,
759, 741, 683, 665, 538, 518, 500 cm-1. Anal. Calcd for C16H14N4O2: C, 65.30; H, 4.79; N,
19.04. Found: C, 65.29; H, 4.81; N, 19.02.
4.6.4. (2,5-dimethyl-2H-pyrazol-3-yl)-(2-nitrophenyl)-amine (12d)
1
Yellow flat needels, 208 mg, 90% yield, mp. 126-127 °C; H NMR (600 MHz,CDCl3, ppm):
δ = 9.08 (s, 1H), 8.23 (d, J = 8.5 Hz, 1H), 7.44 (t, J = 7.9 Hz, 1H), 6.87 (t, J = 7.7 Hz, 1H),
6.83 (d, J = 8.5 Hz, 1H), 5.97 (s, 1H), 3.67 (s, 3H), 2.29 (s, 3H); 13C NMR (150 MHz, CDCl3,
ppm): δ = 148.0, 142.7, 137.0, 136.3, 133.3, 126.5, 118.5, 115.9, 101.1, 34.8, 14.1; IR (ATR):
ν = 3332, 3098, 1610, 1551, 1507, 1489, 1336, 1262, 1212, 1139, 783, 749, 677, 668, 647,
541, 503 cm-1. Anal. Calcd for C11H12N4O2: C, 56.89; H, 5.21; N, 24.12. Found: C, 56.75; H,
5.22; N, 24.05.
4.6.5. (2,5-diphenyl-2H-pyrazo-3-yl)-(4-chloro-2-nitrophenyl)-amine (12e)
Dark red crystalline powder, 289 mg, 74%, mp. 98-99 °C; 1H NMR (600 MHz, CDCl3, ppm):
δ = 9.34 (s, 1H), 8.19 (d, J = 2.5 Hz, 1H), 7.89 (d, J = 7.1 Hz, 2H), 7.56 (d, J = 7.4 Hz, 2H),
13
7.46-7.43 (m, 4H), 7.39-7.35 (m, 3H), 7.15 (d, J = 9.1 Hz, 1H), 6.69 (s, 1H); C NMR (150
MHz, CDCl3, ppm):
δ = 151.8, 140.3, 138.0, 137.5, 136.3, 132.6, 129.5, 128.7, 128.4, 128.2,
125.8, 125.6, 123.9, 123.8, 117.6, 99.22, 99.21; IR (ATR): ν = 3322, 3058, 1598, 1563, 1495,
1334, 1257, 1124, 1065, 950, 897, 754, 736, 674, 644, 485 cm-1. Anal. Calcd for
C21H15ClN4O2: C, 64.54; H, 3.87; N, 14.34. Found: C, 64.25; H, 3.52; N, 14.05.
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4.6.6. (2,5-diphenyl-2H-pyrazo-3-yl)-(4-bromo-2-nitrophenyl)-amine (12f)
Dark red oil, quantitative yield; 1H NMR (600 MHz, CDCl3, ppm): δ = 9.35 (s, 1H), 8.34 (d, J
= 2.3 Hz, 1H), 7.87 (d, J = 7.2 Hz, 2H), 7.56 (d, J = 7.6 Hz, 2H), 7.46-7.43 (m, 4H), 7.39-7.35
(m, 3H), 7.09 (d, J = 9.1 Hz, 1H), 6.69 (s, 1H); 13C NMR (150 MHz, CDCl3, ppm): δ =
151.78, 140.7, 138.0 137.4, 136.5, 132.6, 129.5, 128.7, 128.4, 128.2, 125.59, 125.57, 124.1,
123.9, 117.9, 99.27, 99.26; IR (ATR): ν = 3329, 2917, 2846, 1739, 1607, 1495, 1454, 1330,
1251, 1145, 1071, 1012, 945, 756, 683, 485 cm-1. Anal. Calcd for C21H15BrN4O2: C, 57.95; H,
3.47; N, 12.87. Found: C, 57.75; H, 3.22; N, 12.75.
4.6.7. (2,5-diphenyl-2H-pyrazo-3-yl)-(4-fluoro-2-nitrophenyl)-amine (12g)
Dark red crystalline powder, 299 mg, 80%, mp. 89 °C; 1H NMR (600 MHz, CDCl3, ppm): δ =
9.27 (s, 1H), 7.92-7.88 (m, 3H), 7.57 (d, J = 7.7 Hz, 2H), 7.46-7.43 (m, 4H), 7.37-7.35 (m,
2H), 7.24-7.18 (m, 2H), 6.68 (s, 1H); 13C NMR (150 MHz, CDCl3, ppm): δ = 154.4 (d, JC-F
=
242.8 Hz), 151.8, 138.4, 138.1, 138.0, 132.9 (d, JC-F = 8.2 Hz), 132.7, 129.5, 128.7, 128.4,
128.2, 125.6, 124.6 (d, JC-F = 23.5 Hz), 124.0, 117.8 (d, JC-F = 7.2 Hz), 112.1 (d, JC-F = 26.7
Hz), 98.8; IR (ATR): ν = 3319, 3063, 1578, 1556, 1511, 1495, 1410, 1274, 1230, 1125, 1059,
941, 751, 675, 533, 489 cm-1. Anal. Calcd for C21H15FN4O2: C, 67.37; H, 4.04; N, 14.97.
Found: C, 67.75; H, 4.22; N, 14.85.
4.6.8. (2,5-diphenyl-2H-pyrazo-3-yl)-(4-methyl-2-nitrophenyl)-amine (12h)
1
Yellow crystalline powder, 277 mg, 75%, mp. 109-110 °C; H NMR (600 MHz, CDCl3,
ppm): δ = 9.31 (s, 1H), 8.00 (s, 1H), 7.89 (d, J = 7.6 Hz, 2H), 7.59 (d, J = 7.8 Hz, 2H), 7.46-
7.42 (m, 4H), 7.37-7.34 (m, 2H), 7.28 (d, J = 8.3 Hz, 1H), 7.15 (d, J = 8.6 Hz, 1H), 6.67 (s,
13
1H), 2.31 (s, 3H); C NMR (150 MHz, CDCl3, ppm): δ = 151.6, 139.4, 138.5, 138.2, 137.5,
132.8, 129.4, 128.9, 128.7, 128.3, 128.0, 125.9, 125.6, 124.0, 116.3, 98.43, 98.41, 20.1; IR
(ATR): ν = 3360, 3060, 1628, 1565, 1518, 1496, 1337, 1268, 1217, 1150, 799, 767, 685, 644,
476, 435 cm-1. Anal. Calcd for C22H18N4O2: C, 71.34; H, 4.90; N, 15.13. Found: C, 71.55; H,
4.72; N, 15.05.
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4.6.9. (2,5-diphenyl-2H-pyrazo-3-yl)-(4-methoxy-2-nitrophenyl)-amine (12i)
Dark red crystalline powder, 247 mg, 64%, mp. 79-80 °C; 1H NMR (600 MHz, CDCl3, ppm):
δ = 9.27 (s, 1H), 7.89 (d, J = 7.1 Hz, 2H), 7.64 (d, J = 3.0 Hz, 1H), 7.60-7.59 (m, 2H), 7.46-
7.42 (m, 4H), 7.37-7.34 (m, 2H), 7.11 (d, J = 9.3 Hz, 1H), 7.13 (dd, J = 9.3, 3.0 Hz, 1H), 6.65
(s, 1H), 3.82 (s, 3H); 13C NMR (150 MHz, CDCl3, ppm): δ = 152.1, 151.6, 138.7, 138.2,
136.2, 133.3, 132.8; 129.4, 128.7, 128.3, 128.0m 126.1, 125.6, 124.0, 117.9, 107.4, 98.0,
55.9; IR (ATR): ν = 3281, 3056, 1584, 1553, 1515, 1451, 1315, 1280, 1214, 1125, 1059,
1030, 761, 694, 666, 653, 542, 451 cm-1. Anal. Calcd for C22H18N4O3: C, 68.38; H, 4.70; N,
14.50. Found: C, 68.00; H, 4.52; N, 14.35.
4.7. Reductive cyclization of 12 with ferrous oxalate – general procedure: method A
Equimolar amounts of (2,5-disubstituted-2H-pyrazol-3-ylo)-(4-substituted-2-nitrophenyl)-
amine 12a-i (1 mmol), and iron(II) oxalate dihydrate (179 mg, 1 mmol) in sulfolane (5 mL)
were heated at 250 °C for 20 min. After cooling, the reaction mixture was added to a saturated
sodium chloride solution (20 mL) and stirred for 30 min. The precipitate was filtered off and
dried. After drying, the compounds were purified by column chromatography on aluminium
oxide 90 with chloroform as an eluent. The product was crystallized from toluene.
4.8. Reductive cyclization of 12 with triphenylphosphine – general procedure: method B
(2,5-disubstituted-2H-pyrazo-3-yl)-(2-nitrophenyl)-amine
12a-d
(0.5
mmol)
and
triphenylphosphine (459 mg, 1.75 mmol) in dimethylacetamide or 1,2-dichlorobenzene (4
mL) were heated at reflux for 24 – 48 h. After cooling the reaction mixture was purified by
column chromatography on aluminium oxide with toluene as an eluent.
4.7.1. and 4.8.1. 1,3-Diphenyl-1H-pyrazolo[3,4-b]quinoxaline (5a)
Light orange needles, method A: 218 mg, 68%, method B: 83.7 mg, 52%; 1H/13C NMR, m.p.
and Rf (toluene/SiO2) corresponds to the data recorded for 5a in section 4.4.1.
22

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4.7.2. and 4.8.2. 3-Methyl-1-phenyl-1H-pyrazolo[3,4-b]quinoxaline (5b)
Deep yellow needles, method A: 130 mg, 50%, method B: 20.8 mg, 16%; 1H/13C NMR, m.p.
and Rf (toluene/SiO2) corresponds to the data recorded for 5b in section 4.4.2.
4.7.3. and 4.8.3. 1-Methyl-3-phenyl-1H-pyrazolo[3,4-b]quinoxaline (5c)
1
Light orange crystalline powder, method A: 114 mg, 44%, method B: 9.7 mg, 7.5%; H/13C
NMR, m.p. and Rf (toluene/SiO2) corresponds to the data recorded for 5c in section 4.4.3.
4.7.4. and 4.8.4. 1,3-Dimethyl-1H-pyrazolo[3,4-b]quinoxaline (5d)
Yellow flat needles, method A: 101 mg, 51%, method B: 6.9 mg, 7%; 1H/13C NMR, m.p. and
Rf (toluene/SiO2) corresponds to the data recorded for 5d in section 4.4.4.
4.7.5. 6-chloro-1,3-diphenyl-1H-pyrazolo[3,4-b]quinoxaline (5e)
1
Orange crystalline mass, method A: 217 mg, 61%, mp. 220 °C; H NMR (600 MHz, CDCl3,
ppm): δ = 8.70 (d J = 7.7 Hz, 2H), 8.50 (d, J = 7.7 Hz, 2H), 8.31 (d, J = 2.2 Hz, 1H), 8.11 (d,
J = 9.1 Hz, 1H), 7.75 (dd, J = 9.1, 2.3 Hz, 1H), 7.59-7.55 (m, 4H), 7.48 (t, J = 7.4 Hz, 1H),
13
7.34 (t, J = 7.4 Hz, 1H); C NMR (150 MHz, CDCl3, ppm): δ = 143.2, 142.8, 141.2, 139.6,
139.2, 137.4, 133.9, 132.2, 130.9, 130.2, 129.5, 129.2, 129.1, 128.8, 127.3, 125.9, 120.0; IR
(ATR): ν = 3063, 1594, 1496, 1486, 1420, 1391, 1340, 1252, 1163, 1125, 1062, 831, 748, 739,
685, 666, 647, 495, 419 cm-1. Anal. Calcd for C21H13ClN4: C, 70.69; H, 3.67; N, 15.70.
Found: C, 70.96; H, 3.72; N, 15.35.
4.7.6. 6-bromo-1,3-diphenyl-1H-pyrazolo[3,4-b]quinoxaline (5f)
1
Orange crystalline powder, method A: 94 mg, 24%, mp. 206-207 °C; H NMR (600 MHz,
CDCl3, ppm): δ = 8.70 (d, J = 7.7 Hz, 2H), 8.51 (d, J = 2.2 Hz, 1H), 8.50 (d, J = 8.1 Hz, 2H),
8.05 (d, J = 9.1 Hz, 1H), 7.88 (dd, J = 9.1, 2.2 Hz, 1H), 7.59-7.56 (m, 4H), 7.49 (t, J = 7.4 Hz,
13
1H), 7.34 (t, J = 7.4 Hz, 1H); C NMR (150 MHz, CDCl3, ppm): δ = 143.3, 142.8, 141.6,
139.9, 139.2, 137.3, 134.6, 132.5, 130.9, 130.2, 129.6, 129.2, 128.8, 127.3, 125.9, 122.0,
23

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120.0; IR (ATR): ν = 3063, 1594, 1496, 1480, 1420, 1340, 1252, 1166, 1119, 989, 929, 821,
748, 745, 688, 669, 644, 489, 422 cm-1. Anal. Calcd for C21H13BrN4: C, 62.86; H, 3.27; N,
13.96. Found: C, 62.99; H, 3.43; N, 13.68.
4.7.7. 6-fluoro-1,3-diphenyl-1H-pyrazolo[3,4-b]quinoxaline (5g)
Orange needles, method A: 51 mg, 15%, mp. 235 °C; 1H NMR (600 MHz, CDCl3, ppm): δ =
8.72 (d, J = 7.2 Hz, 2H), 8.52 (d, J = 7.7 Hz, 2H), 8.20 (dd, J = 9.3, 5.7 Hz, 1H), 7.94 (dd, J =
9.3, 2.7 Hz, 1H), 7.67-7.63 (m, 1H), 7.60-7.57 (m, 4H), 7.49 (t, J = 7.4 Hz, 1H), 7.34 (t, J =
7,4 Hz, 1H); 13C NMR (150 MHz, CDCl3, ppm): δ = 161.6 (d, JC-F = 251.4 Hz), 142.9, 142.8
(d, JC-F = 2.2 Hz), 141.6 (d, JC-F = 13.2 Hz), 139.3, 138.4, 137.3, 131.0, 130.9 (d, JC-F = 9.8
Hz), 129.5, 129.2, 128.8, 127.3, 125.9, 122.3 (d, JC-F = 27.3 Hz), 120.0, 113.1 (d, JC-F = 21.5
Hz); IR (ATR): ν = 3066, 1625, 1590, 1496, 1404, 1340, 1201, 1122, 1103, 979, 824, 748,
729, 682, 669, 653, 647, 606, 536, 489, 428 cm-1. Anal. Calcd for C21H13FN4: C, 74.11; H,
3.85; N, 16.46. Found: C, 74.49; H, 3.99; N, 16.06.
4.7.8. 6-methyl-1,3-diphenyl-1H-pyrazolo[3,4-b]quinoxaline (5h)
1
Yellow crystalline mass, method A: 144 mg, 43%, mp. 229-230 °C; H NMR (600 MHz,
CDCl3, ppm): δ = 8.75 (d, J = 7.1 Hz, 2H), 8.55 (dd, J = 8.6, 1.0 Hz, 2H), 8.06 (d, J = 8.9 Hz,
2H), 7.65 (dd, J = 8.7, 1.8 Hz, 1H), 7.60-7.57 (m, 4H), 7.48 (t, J = 7.4 Hz, 1H), 7.33 (t, J =
7,4 Hz, 1H), 2.61 (s, 3H); 13C NMR (150 MHz, CDCl3, ppm): δ = 143.1, 142.9, 141.5, 139.7,
139.5, 138.6, 136.7, 133.8, 131.3, 129.3, 129.2, 129.0, 128.7, 128.5, 127.3, 125.6, 120.0, 21.7;
IR (ATR): ν = 3060, 1597, 1489, 1407, 1344, 1255, 1188, 1128, 983, 818, 751, 694, 666, 641,
495, 419 cm-1. Anal. Calcd. for C22H16N4: C, 78.55; H, 4.79; N, 16.66. Found: C, 78.71; H,
4.89; N, 16.25.
4.7.9. 6-methoxy-1,3-diphenyl-1H-pyrazolo[3,4-b]quinoxaline (5i)
Yellow crystalline powder, method A: 133 mg, 38%, mp. 203-204 °C; 1H NMR (CDCl3, 600
MHz, ppm): δ = 8.73 (dd, J = 8.3, 1.2 Hz, 2H), 8.53 (dd, J = 8.6, 1.0 Hz, 2H), 8.04 (d, J = 9.3
Hz, 1H), 7.59-7.57 (m, 4H), 7.52 (d, J = 2.7 Hz, 1H), 7.50-7.46 (m, 2H), 7.33 (t, J = 7.4 Hz,
24

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13
1H), 4.00 (s, 3H); C NMR (150 MHz, CDCl3, ppm): δ = 159.6, 142.9, 142.6, 142.5, 139.6,
137.6, 136.3, 131.5, 129.8, 129.2, 129.1, 128.7, 127.3, 125.8, 125.6, 120.0, 106.5, 55.8; IR
(ATR): ν = 3060, 1625, 1600, 1492, 1404, 1356, 1217, 1119, 1024, 983, 827, 767, 748, 736,
694, 688, 669, 653, 609, 530, 495, 425 cm-1. Anal. Calcd. for C22H16N4O: C, 74.98; H, 4.58;
N, 15.90. Found: C, 74.81; H, 4.92; N, 15.66.
4.9. 6-N,N-diphenylamino-1,3-diphenyl-1H-pyrazolo[3,4-b]quinoxaline (5j)
6-chloro-1,3-diphenyl-1H-pyrazolo[3,4-b]quinoxaline 5e (114 mg, 0.32 mmol),
diphenylamine (65 mg, 0.38 mmol), sodium tert-butoxide (44 mg, 0.45 mmol), Pd2dba3 (2.92
mg, 0.0032 mmol, 1mol%), (o-biphenyl)P(t-Bu)2 (1.9 mg, 0.0064 mmol, 2 mol%), and
toluene (2 mL) were added to a Schlenk flask, and the mixture was then purged with argon.
The reaction was carried out under argon at 80 °C for 20 h. After cooling, the reaction
mixture was filtered and purified using column chromatography on aluminium oxide with
toluene or mixture toluene: ether (3:1) as an eluent. The product was crystallized from toluene.
Red crystalline powder, 81 mg, 52%, mp. 209-210 °C; 1H NMR (600 MHz, CDCl3, ppm): δ =
8.68 (d, J = 7.1 Hz, 2H), 8.54 (d, J = 7.7 Hz, 2H), 8.01 (d, J = 9.3 Hz, 1H); 7.73 (d, J = 2.5
Hz, 1H), 7.67 (dd, J = 9.3, 2.5 Hz, 1H), 7.59-7.57 (m, 2H), 7.55-7.53 (m, 2H), 7.44 (t, J = 7.4
Hz, 1H), 7.37-7.31 (m, 5H), 7.24 (d, J = 7.5 Hz, 4H), 7.17 (t, J = 7.4 Hz, 2H); 13C NMR (150
MHz, CDCl3, ppm): δ = 147.9, 146.9, 143.0, 142.8, 142.6, 139.6, 138.3, 136.7, 131.4, 129.7,
129.20, 129.18, 129.11, 129.06, 128.7, 127.3, 125.58; 125.55; 124.4, 120.0, 117.8; IR (ATR):
ν = 3060, 1600, 1483, 1404, 1255, 1122, 989, 821, 745, 736, 685, 672, 656, 647, 492, 416 cm-
1. Anal. Calcd. for C33H23N5: C, 80.96; H, 4.74; N, 14.31. Found: C, 80.85; H, 4.85; N, 13.99.
Acknowledgments
This research was supported in part by PL-Grid Infrastructure. The authors would like to
thank the European Regional Development Fund within the Polish Innovation Economy
Operational Program for purchasing part of the equipment used in the research (contract no.
POIG.02.01.00-12-023/08). The synthetic part of this project was financed by Ministry of
Science and Higher Education of the Republic of Poland.
25

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Appendix A. Supplementary data
Supplementary data related this article can be found at
26

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