Vicarious nucleophilic amination of five-membered 4,6-dinitrobenzoheterocycles

Article abstract of DOI:10.1007/s11172-020-2773-z

Reactions of isomeric 4,6-dinitro-1- and 4,6-dinitro-2-phenylindazoles, as well as 4,6-dinitro-2-phenylbenzo[b]furan, with various aminating agents were studied under the vicarious nucleophilic substitution conditions. It was found that depending on the a

Full text of DOI:10.1007/s11172-020-2773-z

Russian Chemical Bulletin, International Edition, Vol. 69, No. 2, pp. 390—393, February, 2020
390
Vicarious nucleophilic amination of five-membered 4,6-dinitrobenzoheterocycles
A. M. Starosotnikov,а M. A. Bastrakov,a V. V. Kachala,a I. V. Fedyanin,b and S. A. Sheveleva†
aN. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences,
47 Leninsky prosp., 119991 Moscow, Russian Federation.
E-mail: alexey41@list.ru
bA. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences,
28 ul. Vavilova, 119991 Moscow, Russian Federation
Reactions of isomeric 4,6-dinitro-1- and 4,6-dinitro-2-phenylindazoles, as well as 4,6-di-
nitro-2-phenylbenzo[b]furan, with various aminating agents were studied under the vicarious
nucleophilic substitution conditions. It was found that depending on the aminating system, the
starting compounds undergo either selective mono-amination at position 7 or double amination.
Key words: amination, benzoheterocycles, vicarious nucleophilic substitution of hydrogen,
aromatic nitro compounds, ortho-nitroamines.
Aromatic ortho-nitroamines and their derivatives,
ortho-diamines, are convenient precursors for a wide range
of benzannulated heterocycles (benzofuroxanes, benzo-
triazoles, benzimidazoles, etc.). One of the main appro-
aches to these derivative (besides nitration of arylamines)
is nucleophilic amination of nitroarenes. For example, it
was shown earlier1 that 2-aryl-4,6-dinitroindoles can be
aminated at position 7 under the conditions of vicarious
nucleophilic substitution of hydrogen (VNS) by treatment
with 1,1,1-trimethylhydrazinium iodide (TMHI) in the
presence of ButOK. This method was also used to aminate
mono- and dinitrobenzenes.2
erties of many benzofuran and especially indazole deriva-
tives. For example, an indazole fragment is contained in
numerous biologically active compounds, it is a part of
some alkaloids.10—13
The literature data3—9 on amination of aromatic and
heteroaromatic nitro compounds under the VNS condi-
tions are quite ample. The list of aminating agents in-
cluded, in particular, sulfenyl amides,3 4-amino-1,2,4-
triazole,4 1,1,1-trimethylhydrazinium iodide,2 O-methyl-
hydroxylamine,5 and some others. In most cases, the reac-
tions are carried out in the presence of an excess of a strong
base (for example, ButOK) in aprotic dipolar solvents
(DMSO, DMF) at a reduced temperature. In addition,
the use of hydroxylamine hydrochloride in the presence
of KOH in EtOH was described for the amination of nitro
compounds derived from benzene,6 naphthalene,7 benzo-
thiazole,8 and benzothiadiazole.9 In these cases, as a rule,
the reactions proceeded regioselectively with the introduc-
tion of one amino group into the aromatic ring.
It was found that the reaction does not take place when
4-amino-1,2,4-triazole is used as an aminating agent and
results in the recovery of the corresponding starting dinitro
compounds. The reaction with O-methylhydroxylamine
in the presence of ButOK gives only destruction products
of the starting compounds; varying the reaction conditions
(temperature, solvent, the use of copper(I) halides as
catalysts) did not lead to the desired result. Monoamino
derivatives 4 and 5 were obtained in good yields only when
[Me3NNH2]I (TMHI) was used as an aminating agent in
the presence of ButOK (Scheme 1).
In the present work, we studied the reactions of iso-
meric 4,6-dinitro-1- and 4,6-dinitro-2-phenylindazoles
(1 and 2), as well as 4,6-dinitro-2-phenylbenzo[b]furan
(3), with various aminating agents. The choice of the
objects for research is substantiated by the valuable prop-
The direction of the nucleophilic attack was established
based on spectral data. Thus, a cross peak corresponding
to the interaction of spatially close protons of the amino
group and the ortho-protons of the N-phenyl substituent
1
is observed in the Н—1Н NOESY NMR spectrum of
compound 4, which unambiguously confirms the forma-
tion of the 7-amino derivative.
† Deceased.
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 2, pp. 0390—0393, February, 2020.
1066-5285/20/6902-0390 © 2020 Springer Science+Business Media LLC

Amination of 4,6-dinitrobenzoheterocycles
Russ. Chem. Bull., Int. Ed., Vol. 69, No. 2, February, 2020
391
Scheme 1
by X-ray diffraction. The data of 2D heteronuclear NMR
correlation spectroscopy (HSQC HMBC) allowed us to
assign all the hydrogen and carbon atoms of compound 7
and to conclude that both amino groups are in the benzene
ring. The 14N NMR spectrum of diamine 7 contains two
signals for nitro groups. Compounds 6 and 8 have an ex-
tremely low solubility in most common solvents, which
made it impossible to record even 1D 13C NMR spectra
for them. In the IR spectra, one can identify the absorption
bands of the amino groups involved in the formation of
associates (3160—3280 and 3350—3430 cm–1), as well
as for the nitro groups involved in hydrogen bonding
(1250—1280 and 1600—1620 cm–1). According to the
results of elemental analysis, compound 7 forms a mono-
hydrate and compound 8 forms a dihydrate (crystallization
water was detected in both cases), while compound 6 does
not contain any associated solvents.
The X-ray diffraction data for compounds 7 and 8
showed that bond lengths and bond angles in both mol-
ecules are typical of the corresponding fragments of
similar compounds. In both crystal structures, the mole-
cules are in almost planar conformations (Fig. 1). The
torsion angles between the mean planes of the heterocyclic
and the phenyl rings are 2.6 (for compound 7) and 3.1
Compound
1
3
X
NPh
O
Y
N
CPh
Product
Yield (%)
84
4
5
85
Reagents and conditions: [Me3NNH2]I, ButOK, DMSO, 20 C.
An unexpected result was obtained in the reaction of
dinitroindazoles 1 and 2, as well as dinitrobenzofuran 3,
with an excess of hydroxylamine hydrochloride and KOH
as a base in EtOH at 20—30 C. The TLC monitoring
showed that the complete conversion of the starting com-
pounds was observed already after 1 h and in each case
a single product was formed, namely, 5,7-diamino-4,6-
dinitro derivative 6, 7, or 8, respectively, which were
isolated in high yield (Scheme 2).
Scheme 2
а
O(5)
N(6)
H(7A) N(7)
H(7B)
С(9)
С(7)
С(7A)
N(1)
С(6)
С(10)
С(8)
O(4)
H(5B)
С(5)
С(13)
C(11)
N(2)
С(3)
N(5)
С(3A)
N(4)
С(4)
С(12)
Compound
X
NPh
N
Y
N
NPh
CPh
Product
Yield (%)
H(5A)
O(3)
1
2
3
6
7
8
87
98
91
O(2)
O
Reagents and conditions: NH2OH•HCl, KOH, EtOH, 20—30 C.
H(7A)
N(7)
b
O(5)
N(6)
H(7B)
O(1)
The structures of diamines 6—8 were established using
a combination of physicochemical methods (1D and 2D
polynuclear NMR spectroscopy, IR spectroscopy, mass
spectrometry, elemental analysis, and X-ray diffraction).
С(9)
С(7)
С(7A)
С(6)
С(10)
O(4)
1
С(8)
The H NMR spectra of compounds 6—8 showed the
С(5)
H(5A)
С(2)
signals for phenyl substituents and heterocyclic frag-
ments, as well as for two amino groups (in the region of
δ 7.5—11.0). In the case of compound 6, the signals for
the NH2 protons appear at δ 7.5 and 9.5 as two broadened
singlets, while three signals (at δ 9.5, 9.8, and 10.9) with
relative intensities of 2 : 1 : 1 corresponding to two amino
groups show up in the spectrum of diamine 7, i.e., the
protons of one of the amino groups are nonequivalent.
This position of the signals is probably due to strong intra-
and intermolecular interactions, which was later confirmed
C(11)
С(13)
С(3)
N(5)
С(3A)
N(4)
С(4)
С(12)
H(5B)
O(3)
O(2)
Fig. 1. General view of molecule 7 (a) and one of the crystallo-
graphically independent molecules 8 (b) in the crystal according
to the X-ray diffraction data in the representation of atoms as
thermal ellipsoids (p = 50%).

Starosotnikov et al.
392
Russ. Chem. Bull., Int. Ed., Vol. 69, No. 2, February, 2020
Synthesis of compounds 4 and 5 (general procedure). Potassium
tert-butoxide (0.34 g, 3 mmol) was added to a solution of com-
pound 1 or 3 (1.5 mmol) and TMHI (0.6 g, 3 mmol) in DMSO
(20 mL). The reaction mixture was stirred for 2 h at room tem-
perature, poured into water (100 mL), and acidified with HCl to
pH 4. The precipitate was collected by filtration, in the case of
compound 4 it was washed with hot EtOH and dried in air. In
the case of compound 5, the product was purified by column
chromatography (SiO2—toluene).
and 3.4 (for two crystallographically independent mol-
ecules of 8). The hydrogen atoms of the amino groups are
involved into intramolecular hydrogen bonds with the
oxygen atoms of the nitro groups, as well as with the nitro-
gen (7) and oxygen atoms (8) of the heterocycle. The
presence of these intramolecular hydrogen bonds leads to
the absence of intermolecular hydrogen contacts, and the
structural fragments in the crystal packing of both com-
pounds show π-stacking and other weak non-specific
intermolecular interactions.
Note that this result of amination was unexpected,
since the introduction of two amino groups into the di-
nitrobenzene fragment using this aminating agent was not
previously described. Even in the case of highly electro-
philic substrates, such as 1,3,5-trinitrobenzene6 and
4,6-dinitrobenzofurazan,14 only monoamine derivatives
are usually formed. The only exception is 4,6-dinitrobenzo-
furoxan: its reaction with the NH2OH•HCl—KOH—
EtOH system under similar conditions leads to 5,7-di-
amino-4,6-dinitrobenzofuroxan.15 As for the isomeric
dinitroindazoles and, especially, dinitrobenzofuran stud-
ied in this work, they cannot be considered as highly
electrophilic compounds taking into account the π-ampho-
teric nature of the pyrazole ring.
7-Amino-4,6-dinitro-1-phenyl-1Н-indazole (4). The yield
1
was 84%. M.p. 213—215 C. H NMR, δ: 7.50 (s, 2 H, NH2.);
7.65—7.75 (m, 5 Н, Ph); 8.71 (s, 1 H, H(3)); 8.88 (s, 1 H, H(5)).
13C NMR, δ: 119.6, 119.7, 123.5, 126.6, 128.6, 129.8, 129.9,
130.1, 134.2, 138.1, 138.7. Found (%): C, 52.37; H, 3.18; N, 23.23.
C13H9N5O4. Calculated (%): C, 52.18; H, 3.03; N, 23.40.
7-Amino-4,6-dinitro-2-phenylbenzo[b]furan (5). The yield
1
was 45%. M.p. > 300 C. H NMR, δ: 7.56 (m, 3 Н, Ph); 7.85
(s, 1 Н, Н(3)); 8.21 (d, 2 Н, Ph, J = 7.1 Hz); 8.59 (br.s, 2 Н, NH2);
8.83 (s, 1 Н, Н(5)). Found (%): C, 56.63; H, 3.46; N, 13.80.
C14H9N3O5. Calculated (%): C, 56.19; H, 3.03; N, 14.04.
Synthesis of compounds 6—8 (general procedure). A solution
of KOH (2.9 g, 51.8 mmol) in MeOH (20 mL) was added drop-
wise to a suspension of compound 1, 2, or 3 (0.57 g, 2 mmol)
and NH2OH•HCl (1.18 g, 17.2 mmol) in EtOH (30 mL) at
20 C. The reaction mixture was stirred for 1—2 h (TLC), poured
into water (300 mL), and acidified with HCl to pH 5. The pre-
cipitate was collected by filtration and dried in air.
All the attempts to obtain monoamino derivatives at
a lower temperature (–15—10 C) led to the formation of
5,7-Diamino-4,6-dinitro-1-phenyl-1Н-indazole (6). The yield
was 87%. M.p. 318—320 C. IR, /cm–1: 1288 (NO2), 1600 (NO2),
3284 (NH2), 3432 (NH2). 1H NMR, δ: 7.55 (br.s, 2 H, NH2);
7.65 (m, 5 Н, Ph); 8.57 (s, 1 H, Н(3)); 9.5 (br.s, 2 H, NH2). MS,
m/z: 314 [M]+. Found (%): C, 50.09; H, 3.45; N, 26.51.
C13H10N6O4. Calculated (%): C, 49.69; H, 3.21; N, 26.74.
5,7-Diamino-4,6-dinitro-2-phenyl-2Н-indazole (7). The yield
1
a complex mixture, in which, according to the H NMR
spectral data, the starting dinitroindazoles 1 or 2, dinitro-
diamines 6 or 7, as well as two more compounds in each, pre-
sumably, isomeric 5- and 7-amino derivatives, were pre-
sent. This fact indicates that the rates of introduction of the
first and the second amino groups are very close, which results
in the impossibility to isolate monoamino derivatives.
In conclusion, we studied the reaction of isomeric
4,6-dinitro-1- and 4,6-dinitro-2-phenylindazoles, as well
as of 4,6-dinitro-2-phenylbenzo[b]furan, with various
aminating agents under the conditions of vicarious nucleo-
philic substitution. It was found that either selective
monoamination (at position 7) or double amination of the
starting 4,6-dinitrobicycles occurs depending on the choice
of the amination system.
1
was 98% (monohydrate). M.p. 276—278 C. H NMR, δ: 7.47
(t, 1 H, p-Ph, J = 7.6 Hz); 7.6 (t, 2 H, m-Ph, J = 7.8 Hz); 8.15
(d, 2 H, o-Ph, J = 7.8 Hz); 9.00 (s, 1 Н, Н(3)); 9.55 (br.s, 2 Н,
NH2); 9.80, 10.85 (both br.s, 2 Н, NH2). 13C NMR, δ: 110.3
(C(5)), 116.8 (C(7)), 117.0 (C(3a)), 119.9 (o-СPh), 123.4 (C(3)),
128.2 (p-СPh), 129.6 (m-СPh), 135.2 (C(4)), 138.9 (ipso-CPh),
147.8 (C(6)), 148.1 (C(7a)). 14N NMR, δ: –12.74, –19.27 (NO2).
IR, /cm–1: 1252 (NO2), 1284 (NO2), 1624 (NO2), 3176 (NH2),
3356 (NН2). MS, m/z: 314 [M]+. Found (%): C, 46.50; H, 3.49;
N, 25.10. C13H12N6O5. Calculated (%): C, 46.99; H, 3.64; N, 25.29.
5,7-Diamino-4,6-dinitro-2-phenylbenzo[b]furan (8). The
yield was 91% (dihydrate). M.p. 273—275 C. IR, /cm–1: 1280
(NO2), 1576 (NO2), 1624 (NO2), 3292 (NН2), 3444 (NН2).
1H NMR, δ: 7.50 (m, 3 H, Ph); 7.80 (s, 1 H, Н(3)); 8.20 (m, 2 H,
Ph); 9.10 (s, 2 H NH2); 9.95 (s, 2 H, NH2). Found (%): C, 48.31;
H, 3.98; N, 16.20. C14H14N4O7. Calculated (%): C, 48.00;
H, 4.03; N, 15.99.
Experimental
Melting points were measured on a Stuart SMP20 instrument.
1Н and 13С NMR spectra were recorded on Bruker AC-200
(1Н 200 МHz, 13С 50 МHz) and Bruker AM-300 (1Н, 300 МHz;
13С, 75 МHz) spectrometers. All the experiments were carried
out according to standard Bruker procedures. Chemical shifts
X-ray diffraction studies of compound 7 were carried out on
a Bruker SMART 1000 CCD diffractometer (λ(Mo-Kα) =
= 0.71072 Å, ω-scan technique, 2θ < 60). Red crystals
C13H10N6O4 at 296 K: a monoclinic crystal system, space group
P21/n, a = 7.2170(5), b = 23.8805(15), c = 8.1508(5) Å,
are given relative to Me4Si (1Н and 13С) and CH3NO2 14N).
(
NMR spectra were recorded in DMSO-d6. IR spectra were re-
corded on a Bruker Alpha spectrometer, samples were prepared
in KBr pellets. The reaction progress and the purity of compounds
were monitored by TLC on Silica gel 60 F254 plates (Merk).
Compounds 1,16 2,17 3,18 and TMHI2 were synthesized accord-
ing to the described procedures.
β = 111.4891(13), V = 1307.11(15) Å3, Z = 4 (Z´ = 1), dcalc
=
= 1.597 g cm–3. Unit cell parameters and intensities of 3794
independent reflections (Rint = 0.0303) out of 11217 collected
were used to determine and refine the structure. The structure
was solved by the direct method and refined by the full-matrix

Amination of 4,6-dinitrobenzoheterocycles
Russ. Chem. Bull., Int. Ed., Vol. 69, No. 2, February, 2020
393
least-squares method in the anisotropic approximation. Hydrogen
atoms bonded to nitrogen atoms were localized and refined
isotropically. The positions of the remaining hydrogen atoms
were calculated geometrically and refined using the riding
model. The final R factors: R1 = 0.0456 (for 2309 reflections with
I > 2σ(I)), wR2 = 0.1226, and GOOF = 1.027.
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X-ray diffraction studies of compound 8 were carried out on
a Bruker Apex II diffractometer (λ(Mo-Kα) = 0.71072 Å, ω-scan
technique, 2θ < 60). Dark red crystals C14H10N4O5 (and solvent)
at 120 K, orthorhombic, space group P212121, a = 6.9828(9),
b = 17.551(2), c = 24.942(3) Å, V = 3056.7(7) Å3, Z = 8 (Z´ = 2).
Intensities of 8908 independent reflections (Rint = 0.1703) out
of 35572 collected were used to determine and refine the structure.
The structure was solved by the direct method and refined by the
full-matrix least-squares method in the anisotropic approxima-
tion. Hydrogen atoms of amino groups were found from difference
Fourier synthesis; the positions of the remaining hydrogen atoms
were calculated. The positions of all hydrogen atoms were refined
using the riding model. The contribution to diffraction from the
disordered solvent was implicitly modeled using the SQUEEZE
procedure implemented in the PLATON software package.19
The final R factors: R1 = 0.0767 (for 4226 reflections with
I >2σ(I)), wR2 = 0.1891, and GOOF = 1.074.
All the calculations were performed using the SHELXT
software package;20 the SHELXL software package21 was used
for refinement. The full structural data were deposited with the
Cambridge Crystallographic Data Center, CCDC 1914801 (8)
and 1914802 (7).
References
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Shevelev, Russ. Chem. Bull., 2008, 57, 1539.
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1996, 61, 2934.
Received September 3, 2019;
accepted October 1, 2019