Mild and efficient addition of carbon nucleophiles to condensed pyridines: influence of structure and limits of applicability

Article abstract of DOI:10.1007/s10593-020-02628-1

[Figure not available: see fulltext.] A number of azolo- and azinopyridines with varying substituents and annulated heterocycles were synthesized and examined in dearomatization reactions with carbon nucleophiles. Depending on the structure, the resulting covalent σ-adducts were formed either under basefree conditions or in Et₃N-promoted process to give functionalized condensed dihydropyridines. Quantum-chemical calculations of the global electrophilicity index derived from FMO energies of azolopyridine series were performed to explain reactivity toward neutral and anionic C-nucleophiles. These values may be useful for qualitative prediction of particular reactivity pattern.

Full text of DOI:10.1007/s10593-020-02628-1

DOI 10.1007/s10593-020-02628-1
Chemistry of Heterocyclic Compounds 2020, 56(1), 92–100
Mild and efficient addition of carbon nucleophiles to condensed
pyridines: influence of structure and limits of applicability
Alexey M. Starosotnikov1*, Kirill V. Ilkov2, Maxim A. Bastrakov1,
Ivan V. Fedyanin3,4, Vladimir A. Kokorekin1
1 N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences,
47 Leninsky Ave., Moscow 119991, Russia; e-mail: alexey41@list.ru
2 National University of Oil and Gas ''Gubkin University'',
65 Leninsky Ave., Moscow 119991, Russia
3 A. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences,
28 Vavilova St., Moscow 119991, Russia
4 Plekhanov Russian University of Economics,
30 Stremyanny Per., Moscow 117997, Russia
Published in Khimiya Geterotsiklicheskikh Soedinenii,
2020, 56(1), 92–100
Submitted November 6, 2019
Accepted November 19, 2019
A number of azolo- and azinopyridines with varying substituents and annulated heterocycles were synthesized and examined in dearoma-
tization reactions with carbon nucleophiles. Depending on the structure, the resulting covalent -adducts were formed either under base-
free conditions or in Et3N-promoted process to give functionalized condensed dihydropyridines. Quantum-chemical calculations of the
global electrophilicity index derived from FMO energies of azolopyridine series were performed to explain reactivity toward neutral and
anionic C-nucleophiles. These values may be useful for qualitative prediction of particular reactivity pattern.
Keywords: carbon nucleophiles, condensed pyridines, nitrogen heterocycles, dearomatization, nucleophilic addition.
Electron-deficient aromatic and heteroaromatic com-
pounds have been extensively studied during past few
decades due to their interesting, sometimes exceptional
properties. Many monographs and reviews were dedicated
to the formation and reactivity of stable anionic σ-complexes
and covalent σ-adducts of electrophilic aromatics and
nucleophiles.1 It is well known that annulation of a strong
π-deficient heterocycle (furoxan, furazan, selenadiazole,
etc.) significantly increases π-deficiency of the aromatics.
Such compounds possess extremely high reactivity toward
nucleophiles, therefore, a special term ''superelectrophile''
was coined in order to distinguish them from other electro-
philic aromatics.2 For example, 4,6-dinitrobenzofuroxan (1)
(Fig. 1) was found to be more electrophilic than 4-nitro-
benzenediazonium cation in reactions with nucleophilic
indoles and pyrroles.3 It also reacts with various types of
neutral O-, S- and C-nucleophiles.4 Recently Remennikov
et al. reported another highly reactive neutral electrophile,
namely, 5-methoxyfuroxano[3,4-d]pyrimidine (2) which
formed stable adducts with enamines, silyl ethers, and other
related compounds.5
Previously, we have found that some aza analogs of
furoxan 1 possess similar reactivity and the covalent
neutral adducts with C- and N-nucleophiles can be isolated.
Indeed, 6-nitrofuroxanopyridine 3 readily reacts with
CH-acidic compounds,6 π-excessive arenes and azoles7
generally without added base to give stable 1,4-adducts 4–6
(Scheme 1). Analogous adducts were isolated upon treat-
ment of 6-nitropyridoselenadiazole 7 with the same
nucleophilic reagents under base-free conditions.7
Figure 1. Highly electrophilic 4,6-dinitrobenzofuroxan (1) and
5-methoxyfuroxano[3,4-d]pyrimidine (2).
0009-3122/20/56(1)-0092©2020 Springer Science+Business Media, LLC
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Chemistry of Heterocyclic Compounds 2020, 56(1), 92–100
Scheme 1
Scheme 2
This type of adducts is of particular interest from the
standpoint of design of novel pharmaceuticals since they
represent highly functionalized heteroaromatics combining
several pharmacophoric moieties in the same molecule (for
example, furoxan and 1,4-dihydropyridine). One could
expect some other condensed pyridines to be involved in
the mentioned process. Therefore, in this work, we tried to
figure out the influence of structural features of condensed
pyridines on the addition process. We considered variations
of heterocycle annulated to the pyridine ring and sub-
stituent in the pyridine cycle.
To check the influence of heterocycle annulated to
nitropyridine as well as of substituent in pyridine ring, a
number of azolo- and azinopyridines were selected for the
synthesis (Scheme 2). Substituted 2-amino-3-nitropyridines 8
and 9 were commercially available or synthesized analogously
to 5-unsubstituted derivatives (R = H).8 Reduction of the
nitro group in compounds 8a–c and treatment with CF3CO2H
resulted in the formation of imidazo[5,4-b]pyridines 10a–c
whereas nitrosation with the mixture of NaNO2 and AcOH
gave the corresponding triazole derivatives 11a,b.
Scheme 3
Oxidation of nitroamines 9b–d with PIDA led to
furoxanopyridines 12b–d and, finally, reduction of the
nitro group in compounds 9a–c,e followed by condensation
with glyoxal gave pyrido[2,3-b]pyrazines 13a–c,e. In addition,
isoxazolo[4,3-b]pyridine 14 was synthesized starting from
commercially available 2-chloro-3,5-dinitropyridine analo-
gously to the reported procedure (Scheme 3).9 Target com-
pounds 10a, 11a, 12b–d, and 13c were described before, while
others depicted in Scheme 2 were previously unknown.
Thus, a representative set of condensed pyridines 10–14
was synthesized and examined in reactions with CH-acidic
compounds. Imidazo- and triazolopyridines 10a–c and
11a,b were found to be unreactive toward dimedone,
2,4-pentanedione, and N,N'-dimethylbarbituric acid even in the
presence of 1 equiv of Et3N: in all cases starting materials
were recovered. In the case of more electrophilic pyrido-
pyrazines 13, the substituent in pyridine ring played crucial
role. Covalent 1,4-adducts 15a–c were formed and isolated
only with nitro derivative 13a (Scheme 4). Dimedone and
cyclohexane-1,3-dione readily reacted with no base added
while acetylacetone required an equimolar amount of Et3N
added for reaction to proceed. Isoxazolopyridine 14 gave
the corresponding adduct 15d with dimedone in a base-free
reaction in 79% yield. The rate of the reaction was close to
that of superelectrophilic furoxanopyridine 3 thus indicating
high electrophilicity of isoxazolo[4,3-b]pyridine system.
Among furoxans 12b–d, only methoxycarbonyl derivative
12b underwent dearomative nucleophilic addition of carbon
nucleophiles. Dimedone, cyclohexane-1,3-dione, and
N,N'-dimethylbarbituric acid gave adducts 15e–g with no
added base (Scheme 4).
Scheme 4
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Chemistry of Heterocyclic Compounds 2020, 56(1), 92–100
All other derivatives 12 and 13 (Scheme 2) did not react
with CH acids applied neither in their acidic form nor as
triethylammonium salts. Unlike compounds 3 and 7, none
of the studied pyrazine and furoxan derivatives gave stable
adducts with π-excessive (het)arenes (phenols, anilines,
and indoles). The adduct formation was not observed or
(upon addition of a base) complex mixtures were generated.
All the above-mentioned fused pyridines had the same
structural features: all of them were azolo- or azino[b]-
pyridines. However, it was of interest to check the
influence of ring junction type on the reactivity of electro-
philes. In this context, we examined recently described
N-bridged 6,8-dinitrotriazolo[1,5-a]pyridines 1610 in
reactions with selected C-nucleophiles. It turned out that
dimedone readily reacts with triazolopyridine 16a, the
product precipitated shortly after mixing two reactants. At
the same time, addition of 1 equiv of Et3N was essential for
reactions of triazolopyridine 16b with dimedone and
triazolopyridine 16a with less acidic di- and trinitro-
toluenes (Scheme 5).
Figure 2. Molecular structure of compound 17c with atoms repre-
sented as thermal vibration ellipsoids of 50% probability.
Scheme 5
nent equal to 0.13. Due to the presence of multiple nitro
substituents, a number of intramolecular contacts are found
in compound 17с, the shortest of them are O(4)···O(5)
(2.864(3) Å with the major disordered component) and
O(10)···C(2) (2.856(2) Å). The hydrogen atom of the
triazole fragment participates in an intramolecular hydrogen
bond with the oxygen atom of the adjacent nitro group
(N(4)···O(1) 2.7210(15) Å, N(4)–H(4)···O(1) 107.0° with
N–H set to 1.015 Å). On the other hand, the molecules in
crystal are assembled into centrosymmetric H-bonded
homodimers via two intermolecular H bonds with the same
oxygen atoms of the neighboring molecules (N(4)···O(1)A
2.7634(16), N(4)–H(4)···O(1)A 161.9°) (Fig. 3). Such a
dimer is found in many structures of 2-nitroanilines and
related compounds,12 and its interesting feature is addi-
tional stabilization of the motif by the direct interaction
between the acceptor O atoms. In the case of molecule 17с,
due to relatively high strength of the intermolecular H bond
the refined O(1)···O(1A) distance of 2.682(2) Å is signifi-
cantly shorter than in the structure of 2,4,6-trinitroaniline.
All other intermolecular contacts in crystal are weak and
nondirectional.
NO2
N
NO2
N
H
N
N
N
NuH
R
R
MeCN, 20°C
For 17b–d
MeCN, Et3N, 20°C, 24 h
N
O2N
O2N
Nu
17a–d
16a R = H
b R = 4-MeOC6H4
NO2
H
NO2
H
N
N
OMe
N
N
N
N
O2N
O
O2N
O
O
O
Me
17a (91%)
Me
Me
17b (94%)
Me
NO2
NO2
H
N
H
N
N
N
N
O2N
N
NO2
O2N
O2N
17c (69%)
NO2
O2N
17d (84%)
NO2
Dearomatization products 17a–d were characterized by
spectral methods (NMR and HRMS) as well as X-ray study
for compound 17c (Fig. 2).
The crystal structure of molecule 17с was established by
single crystal X-ray diffraction. All bond lengths and
valence and torsion angles in compound 17с are within the
expected range as confirmed by Mogul geometry check;11
the only exception is C(3)–N(3) bond (1.3809(18) Å),
which is shorter than a typical C–N bond with nitro group
in aromatic compounds, but the length is typical for bond
adjacent to a conjugated diene system. One of the nitro
groups of the trinitrotoluene fragment is apparently
disordered with the refined occupancy of the minor compo-
Figure 3. Centrosymmetric dimer in crystal of molecule 17c.
Non-hydrogen atoms are represented as thermal vibration ellip-
soids with 50% probability, minor component of the disordered
nitro group O(5)–N(6)–O(6) is omitted for clarity.
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Chemistry of Heterocyclic Compounds 2020, 56(1), 92–100
As it was mentioned above, azolopyridines 10, 11 were
global electrophilicity index ω (Equation (1)) introduced by
Parr et al.17 characterizes the electrophilicity at the ground
state of a molecule, i.e., in its initial geometry. This index
is defined in terms of electronic potential μ and chemical
hardnessη and was proved to be very useful for prediction
of feasibility as well as mechanisms for a significant
number of polar organic reactions, including cyclo-
additions, nucleophilic addition, Friedel–Crafts reaction,
and other electrophile/nucleophile interactions (for a
review, see ref. 18).
unreactive toward CH-acidic compounds and their
triethylammonium salts, apparently, due to insufficient
π-deficiency of the annulated azole rings. At the same time,
nitropyridines are known to be 2π-partners in 1,3-dipolar
cycloaddition reactions with nucleophilic dipoles, such as
N-alkylazomethine ylides.13–15 We found that N-benzyl-
azomethine ylide which was generated in situ from aminal
18 formed adducts of double cycloaddition with com-
pounds 10a and 11a in moderate yields (Scheme 6). The
resulting products 19a,b consist of four different hetero-
cycles fused together and represent previously unknown
and hardly accessible heterocyclic system. It should be
noted that more electrophilic azolo- and azinopyridines
12–14 reported in this work and forming corresponding
adducts with carbon nucleophiles, in reactions with azo-
methine ylides generally gave complex unseparable
mixture of products.
ωμ/2η

In turn, μ and η can be approximately defined as
functions of frontier molecular orbitals (FMO) energies:
μ ≈ 1/2(EHOMO + ELUMO) and η ≈ ELUMO – EHOMO. Values of
reactivity indices calculated for the series of condensed
pyridines are given in Table 1.
Based on the data provided in Table 1, a chart was built
arranging the studied and related compounds in order of
increasing of global electrophilicity values (Fig. 4). Except
for the few deviations, it can be concluded that compounds
with ω > 2.6 eV undergo 1,3-dipolar cycloaddition with
azomethine ylides, however, the reactions lead to stable cyclo-
adducts only in case of azolopyridines with ω 2.6–3.6 eV.
Compounds with ω from 3.4 eV and higher do react with
CH acids (with the exception of compound 11a with
ω 3.55 eV). Moreover, the higher ω value is, the wider
range of CH-acidic compounds can be involved in base-
free nucleophilic addition process. Finally, highly electro-
philic azolopyridines, such as pyridofuroxan 3 and its
benzenoid analog 1 with ω > 4.8 eV exhibit another type of
reactivity – Diels–Alder reactions with nucleophilic dienes
and dienophiles.16 Similar results were obtained earlier for
Scheme 6
All the above results together with the previously
obtained data on superelectrophiles 1–3, 7 allow to notice,
at least at qualitative level, that in a series of structurally
similar compounds, in particular, condensed pyridines, the
type of reactivity depends not only on structural features
(specific substituents, annulated rings) but also on some
electronic factors, presumably, electrophilicity of a mole-
cule. For example, highly electrophilic furoxan derivatives
1, 3 readily undergo Diels–Alder reactions with nucleo-
philic dienes and dienophiles,16 whereas much less electro-
philic imidazo- and triazolopyridines 10, 11 do not show
such reactivity. And vice versa, compounds 10, 11 gave
stable adducts with azomethine ylide (Scheme 6) while
superelectrophiles 1, 3 seem to be too reactive to give sole
and stable adduct. This was confirmed by our experiments:
when compounds 1, 3, and 7 were introduced in 1,3-dipolar
cycloadditions with nucleophilic dipoles, a complex
mixture was obtained along with considerable tarring. The
same is true for nucleophilic addition of CH acids: the
more electrophilic condensed pyridine is, the more it tends
to react without a base with a wider range of carbon
nucleophiles .
Table 1. Global electrophilicity parameters* for representative
condensed pyridines and related compounds
Compound
µ, eV
–5.93
–5.67
–5.77
–5.12
–5.61
–5.42
–5.42
–5.28
–4.77
–4.86
–5.05
–5.73
–5.73
–3.84
–3.74
η, eV
3.21
3.34
4.16
4.90
4.43
3.28
3.30
4.03
3.93
4.14
4.05
3.42
4.35
4.91
6.26
ω, eV
5.47
4.81
4.00
2.67
3.55
4.49
4.46
3.46
2.90
2.85
3.15
4.79
3.78
1.50
1.12
1
3
7
10a
11a
12b
12c
13a
13b
13c
13e
14
16a
Quinoline
Pyridine
To rationalize the reactivity of condensed pyridines in
nucleophilic reactions we performed calculations of
reactivity indices in the framework of DFT concept. The
* All quantities were evaluated at the B3LYP/6-31G** level of theory for
the ground-state optimized geometries, using the GAUSSIAN package of
programs.19
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Chemistry of Heterocyclic Compounds 2020, 56(1), 92–100
Figure 4. Relationship between global electrophilicity of π-deficient fused pyridines and some
related compounds and their reactivity in nucleophilic dearomatization processes.
[3+2] and [4+2] cycloaddition reactions of nitroarenes
pyridine core makes it possible to form covalent 1,4-adducts
even under base-free conditions. The less π-deficient
imidazo- and triazolopyridines were found to be unreactive
toward CH acids. However, another type of nucleophilic
reaction was possible, namely, 1,3-dipolar cycloaddition
with azomethine ylides. Calculation of the global electro-
philicity indices ω for most of the studied and related
compounds allowed to generalize the relationship between
structural features and particular type of reactivity of
condensed pyridines.
(benzo-annulated heterocycles):20 while less electrophilic
benzazoles (ω < 2.6 eV) did not undergo 1,3-dipolar
cycloaddition with azomethine ylides, their more electro-
philic derivatives with ω > 2.6 eV form adducts with
dipoles. The most electrophilic benzazoles such as com-
pound 1 with ω > 5 eV are able to undergo uncatalyzed
Diels–Alder reactions.16
As an extension of our previous work, a model series of
condensed pyridines were examined in reactions with
carbon nucleophiles. The study has revealed that changes
in substitution pattern of the pyridine ring or in the nature
of annulated heterocycle had a significant impact on the
formation of adducts with CH-acidic compounds. Thus,
annulation of π-deficient furoxan and pyrazine rings to
Experimental
1H NMR spectra were recorded on Bruker AM-300
spectrometer (300 MHz). 13C NMR spectra were recorded on
Bruker AM-300 (75 MHz), Bruker DRX-500 (126 MHz), and
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Chemistry of Heterocyclic Compounds 2020, 56(1), 92–100
Bruker Avance II 600 (151 MHz) spectrometers in DMSO-d6
13C NMR spectrum (151 MHz, DMSO-d6), δ, ppm: 148.7;
147.4; 142.6; 136.1; 126.9; 34.6. Found, m/z: 180.0519
[M+H]+. C6H6N5O2. Calculated, m/z: 180.0516.
or CDCl3, residual solvent peaks used as internal standard.
HRMS (ESI) spectra were recorded on a Bruker micrOTOF
II mass spectrometer. Melting points were measured on a
Stuart SMP 20 apparatus. All reactions were monitored by
TLC on ALUGRAM SIL G/UV254 plates, visualized with
UV light.
Methyl 3-methyl-3H-[1,2,3]triazolo[4,5-b]pyridine-
6-carboxylate (11b). Yield 2.23 g (91%), brown solid,
1
mp 157–158°C. H NMR spectrum (DMSO-d6), δ, ppm:
9.25 (1H, s, H Ar); 9.05 (1H, s, H Ar); 4.34 (3H, s, OCH3);
3.95 (3H, s, CH3). 13C NMR spectrum (126 MHz, DMSO-d6),
δ, ppm: 165.0; 151.1; 147.5; 135.6; 130.4; 122.2; 52.8; 33.2.
Found, m/z: 193.0717 [M+H]+. C8H9N4O2. Calculated, m/z:
193.0720.
All chemicals were of commercial grade and used
directly without purification. Compounds 8a–c and 9a–e
were purchased from commercial suppliers or synthesized
similarly to 2-amino-3-nitropyridine and 2-methylamino-
3-nitropyridine.8
Reduction of nitroamines 8a–c and 9a–e. Selective
reduction of the 3-NO2 group in dinitro compounds 8, 9 a
was implemented using (NH4)2S according to reported
procedure.21 For all other compounds, SnCl2 was used as
reducing agent similarly to the reported procedure.22
Spectral characteristics of the resulting 3-amino-2-(methyl-
amino)pyridines or 2,3-diaminopyridines coincided with
those published before.
Synthesis of compounds 12b–d (General method).
PhI(OAc)2 (1.93 g, 6 mmol) was added to a suspension of
compound 9b–d (4.6 mmol) in PhH (40 ml). The mixture
was refluxed for 2 h. The solvent was removed under
reduced pressure, and the residue was washed thoroughly
with hexane and dried on air.
Methyl [1,2,5]oxadiazolo[3,4-b]pyridine-6-carboxylate
1-oxide (12b). Yield 0.79 g (88%), yellow solid, mp 104–
106°C (mp 106.5–107.5°C25). 1H NMR spectrum (DMSO-d6),
δ, ppm: 9.21 (1H, br. s, H Ar); 8.69 (1H, br. s, H Ar); 3.94
(3H, s, OCH3). Found, m/z: 196.0348 [M+H]+. C7H6N3O4.
Calculated, m/z: 196.0353.
Synthesis of compounds 10a–c (General method).
Solution of the corresponding 3-amino-2-(methylamino)-
pyridine (4 mmol) in CF3CO2H (15 ml) was refluxed for
24 h, cooled to room temperature, and poured into H2O
(75 ml). The resulting mixture was neutralized with
saturated NaHCO3 solution, filtered, and dried on air.
3-Methyl-6-nitro-2-trifluoromethyl-3H-imidazo[4,5-b]-
pyridine (10a).23 Yield 0.69 g (70%), brown solid, mp 121–
6-Chloro-[1,2,5]oxadiazolo[3,4-b]pyridine
1-oxide
(12c).26 Yield 0.61 g (77%), brown solid, mp 128–129°C.
1H NMR spectrum (DMSO-d6), δ, ppm: 8.87 (1H, br. s,
H Ar); 8.55 (1H, br. s, H Ar).
6-Bromo-[1,2,5]oxadiazolo[3,4-b]pyridine 1-oxide (12d).
Yield 0.72 g (72%), brown solid, mp 206–207°C (mp 208–
1
122°C. H NMR spectrum (DMSO-d6), δ, ppm: 9.47 (1H,
1
s, H Ar); 9.22 (1H, s, H Ar); 4.06 (3H, s, CH3).
210°C27). H NMR spectrum (DMSO-d6), δ, ppm: 8.92
Methyl 3-methyl-2-trifluoromethyl-3H-imidazo[4,5-b]-
pyridine-6-carboxylate (10b). Yield 0.35 g (34%), white
solid, mp 118–119°C. 1H NMR spectrum (DMSO-d6),
δ, ppm: 9.13 (1H, s, H Ar); 8.77 (1H, s, H Ar); 4.01 (3H, s,
OCH3); 3.94 (3H, s, CH3). 13C NMR spectrum (126 MHz,
DMSO-d6), δ, ppm (J, Hz): 165.3; 150.1; 147.9; 143.0 (q,
(1H, br. s, H Ar); 8.70 (1H, br. s, H Ar).
Synthesis of compounds 13a–c,e (General method). A
solution of the corresponding 2,3-diaminopyridine (6.5 mmol)
and 40% aqueous glyoxal (0.9 ml, 7.8 mmol) in EtOH
(40 ml) was heated under reflux for 3 h (24 h for compound
13a), cooled to 0°C. The precipitate was filtered off,
washed with cold EtOH, and dried on air.
1
2JCF = 39.0); 131.9; 130.6; 122.2; 118.5 (q, JCF = 271.8);
52.6; 30.0. Found, m/z: 260.0639 [M+H]+. C10H9F3N3O2.
Calculated, m/z: 260.0641.
7-Nitropyrido[2,3-b]pyrazine (13a). Yield 0.68 g (60%),
brown solid, mp 195–196°C. 1H NMR spectrum (DMSO-d6),
δ, ppm: 9.86 (1H, s, H Ar); 9.37 (2H, s, H Ar); 9.30 (1H, s,
H Ar). 13C NMR spectrum (75 MHz, DMSO-d6), δ, ppm:
152.6; 151.3; 149.1; 147.7; 143.6; 135.9; 134.4. Found, m/z:
177.0408 [M+H]+. C7H4N4O2. Calculated, m/z: 177.0407.
Methyl pyrido[2,3-b]pyrazine-7-carboxylate (13b).
6-Chloro-3-methyl-2-trifluoromethyl-3H-imidazo[4,5-b]-
pyridine (10c). Yield 0.57 g (61%), gray solid, mp 126–
1
127°C. H NMR spectrum (DMSO-d6), δ, ppm: 8.65 (1H,
s, H Ar); 8.53 (1H, s, H Ar); 3.97 (3H, s, CH3). 13C NMR
spectrum (151 MHz, DMSO-d6), δ, ppm (J, Hz): 146.1;
145.6; 142.2 (q, 2JCF = 38.9); 133.0; 128.8; 126.5; 118.5 (q,
1JCF = 271.8); 29.8. Found, m/z: 236.0193 [M+H]+.
C8H6ClF3N3. Calculated, m/z: 236.0197.
1
Yield 0.90 g (74%), white solid, mp 180–181°C. H NMR
spectrum (DMSO-d6), δ, ppm (J, Hz): 9.56 (1H, d, J = 2.0,
H Ar); 9.26 (1H, s, H Ar); 9.19 (1H, s, H Ar); 8.96 (1H, d,
J = 2.0, H Ar); 3.99 (3H, s, OCH3). 13C NMR spectrum
(151 MHz, DMSO-d6), δ, ppm: 164.4; 153.0; 152.5; 150.5;
148.3; 140.0; 136.5; 126.8; 53.0. Found, m/z: 190.0616
[M+H]+. C9H8N3O2. Calculated, m/z: 190.0611.
Synthesis of compounds 11a,b (General method).
NaNO2 (1.92 g, 27.8 mmol) was added to a solution of the
corresponding 3-amino-2-(methylamino)pyridine (12.6 mmol)
in AcOH (40 ml) in portions at 20°C. The mixture was
stirred for 24 h at room temperature, poured into H2O
(200 ml), and extracted with AcOEt (3×50 ml). Combined
organic layers were dried over Na2SO4 and evaporated to
dryness.
7-Chloropyrido[2,3-b]pyrazine (13c). Yield 0.88 g (81%),
light-brown solid, mp 158–160°C (mp 159–160.5°C28).
1H NMR spectrum (DMSO-d6), δ, ppm (J, Hz): 9.20 (1H,
d, J = 2.4, H Ar); 9.17 (1H, s, H Ar); 9.11 (1H, s, H Ar);
8.78 (1H, d, J = 2.4, H Ar). 13C NMR spectrum (126 MHz,
DMSO-d6), δ, ppm: 153.2; 149.1; 148.8; 147.9; 137.6;
136.7; 131.5. Found, m/z: 166.0167 [M+H]+. C7H5ClN3.
Calculated, m/z: 166.0162.
3-Methyl-6-nitro-3H-[1,2,3]triazolo[4,5-b]pyridine (11a).
Yield 1.79 g (79%), brown solid, mp 144–146°C (151–
1
152°C24). H NMR spectrum (DMSO-d6), δ, ppm: 9.58
(1H, s, H Ar); 9.54 (1H, s, H Ar); 4.40 (3H, s, CH3).
97

Chemistry of Heterocyclic Compounds 2020, 56(1), 92–100
7-(Trifluoromethyl)pyrido[2,3-b]pyrazine (13e). Yield
2-(7-Nitro-5,8-dihydropyrido[2,3-b]pyrazin-8-yl)cyclo-
hexane-1,3-dione (15b), enolic form. Yield 0.232 g (81%),
light-yellow solid, mp 191–192°C (decomp.). 1H NMR
spectrum (DMSO-d6), δ, ppm (J, Hz): 10.94 (1H, s, OH);
10.63 (1H, d, J = 4.7, NH); 8.08 (1H, s, H Ar); 8.02 (1H, s,
H Ar); 7.98 (1H, d, J = 5.4, CH); 5.74 (1H, s, CH); 2.26
(4H, br. s, 2CH2); 1.72 (2H, br. s, CH2). 13C NMR spectrum
(151 MHz, DMSO-d6), δ, ppm: 151.2; 149.2; 146.5; 145.0;
141.4; 140.2; 138.0; 126.9; 119.0; 36.1; 30.4; 21.5. Found, m/z:
289.0931 [M+H]+. C13H13N4O4. Calculated, m/z: 289.0931.
3-(7-Nitro-5,8-dihydropyrido[2,3-b]pyrazin-8-yl)pentane-
2,4-dione (15c), mixture of enolic and dioxo forms in a
ratio of about 1:3. Yield 0.096 g (35%), brown solid,
0.77 g (60%), white solid, mp 149–150°C. 1H NMR spectrum
(DMSO-d6), δ, ppm (J, Hz): 9.50 (1H, d, J = 2.0, H Ar);
9.31 (1H, s, H Ar); 9.22 (1H, s, H Ar); 9.05 (1H, d, J = 2.0,
H Ar). 13C NMR spectrum (126 MHz, DMSO-d6), δ, ppm
(J, Hz): 152.1; 150.9; 149.5 (d, 3JCF = 3.7); 148.6; 137.2 (d,
2
3JCF = 3.7); 136.0; 126.2 (q, JCF = 33.0); 123.1 (q,
1JCF = 273.1). Found, m/z: 200.0431 [M+H]+. C8H4F3N3.
Calculated, m/z: 200.0430.
(6-Nitroisoxazolo[4,3-b]pyridin-3-yl)(phenyl)methanone
(14). A mixture of 2-chloro-3,5-dinitropyridine (1.02 g,
5 mmol), PdCl2(PPh3)2 (5 mol %), and Et3N (1.4 ml,
10 mmol) was suspended in anhydrous THF (10 ml) under
inert atmosphere. Phenylacetylene (0.62 ml, 5.5 mmol) was
then added followed by addition of CuI (2.5 mol %). The
reaction mixture was stirred under argon at 40°C for 3 h,
evaporated under reduced pressure, and the residue was
purified by column chromatography (CHCl3) to give 0.78 g
(58%) of (3,5-dinitropyridin-2-yl)phenylacetylene which
was used directly in the next step. The above compound
(0.27g, 1 mmol) was dissolved in anhydrous 1,2-dichloro-
ethane (20 ml), and iodine monochloride (3 mol %) was
added. The mixture was stirred under reflux for 4 h, cooled
to room temperature, washed with sat. aqueous Na2S2O3
and H2O, dried over Na2SO4, and concentrated under
reduced pressure. The obtained residue was purified by column
chromatography, eluent CHCl3. Yield 0.17 g (64%), beige
1
mp 182–183°C. H NMR spectrum (DMSO-d6), δ, ppm:
major tautomer: 8.40 (1H, s, NH); 7.93 (1H, s, H Ar); 7.90
(1H, s, H Ar); 7.44 (1H, s, CH); 5.94 (1H, s, CH); 4.82
(1H, s, CH); 2.28 (3H, s, CH3); 2.17 (3H, s, CH3); minor
tautomer: 9.02 (1H, s, NH); 8.31 (1H, s, H Ar); 7.55 (1H, s,
CH); 6.47 (1H, s, CH); 5.86 (1H, s, CH); 4.49 (1H, s , CH);
other signals overlap with a major tautomer signals.
13C NMR spectrum (151 MHz, DMSO-d6), δ, ppm: 194.2;
194.0; 169.1; 168.5; 152.1; 148.6; 138.9; 138.1; 136.5;
134.3; 129.4; 124.2; 118.6; 117.6; 111.9; 110.7; 89.0; 88.8;
55.2; 53.0; 30.5; 30.3; 16.3. Found, m/z: 277.0932 [M+H]+.
C12H13N4O4. Calculated, m/z: 277.0931.
5,5-Dimethyl-2-[6-nitro-3-(phenylcarbonyl)-4,7-dihydro-
isoxazolo[4,3-b]pyridin-7-yl]cyclohexane-1,3-dione (15d).
1
1
solid, mp 135–137°C. H NMR spectrum (CDCl3), δ, ppm
Yield 0.320 g (79%), yellow solid, mp 244–246°C. H NMR
(J, Hz): 9.55 (1H, d, J = 2.2, H Ar); 9.08 (1H, d, J = 2.2, H Ar);
8.23 (2H, d, J = 7.4, H Ph); 7.77 (1H, t, J = 7.4, H Ph); 7.63
(2H, t, J = 7.7, H Ph). 13C NMR spectrum (126 MHz,
CDCl3), δ, ppm: 181.1; 163.0; 150.4; 149.6; 144.7; 135.9;
135.7; 134.9; 131.2; 129.7; 122.7. Found, m/z: 270.0508
[M+H]+. C13H7N3O4. Calculated, m/z: 270.0509.
spectrum (DMSO-d6), δ, ppm (J, Hz): 11.18 (1H, br. s,
OH); 10.56 (1H, d, J = 6.1, NH); 8.13 (2H, d, J = 7.7,
H Ph); 8.01 (1H, d, J = 4.3, CH); 7.75 (1H, t, J = 7.3,
H Ph); 7.64 (2H, t, J = 7.5, H Ph); 5.75 (1H, br. s, CH);
2.27 (4H, br. s, 2CH2); 0.93 (6H, s, 2CH3). 13C NMR
spectrum (151 MHz, DMSO-d6), δ, ppm: 181.9; 173.1;
172.6; 158.6; 147.4; 138.6; 136.3; 135.3; 130.5; 130.2;
127.9; 50.9; 43.7; 32.9; 29.0; 28.5. Found, m/z: 410.1340
[M+H]+. C21H20N3O6. Calculated, m/z: 410.1347.
Synthesis of compounds 15a–g (General method).
Corresponding nucleophile (dimedone, cyclohexane-1,3-
dione, or N,N'-dimethylbarbituric acid) (1 mmol) was
added to a solution of compound 12b, 13a, or 14 (1 mmol)
in MeCN (10 ml). The reaction mixture was stirred at 20°C
for 1–2 h (monitored by TLC), the precipitated product was
filtered off, washed with MeCN, and dried on air. In case
of compound 15c, Et3N (0.14 ml, 1 mmol) was added to the
reaction mixture, the reaction mixture was stirred for 24 h,
poured into H2O (50 ml), acidified with concd HCl to pH 3,
Methyl 7-(4,4-dimethyl-2,6-dioxocyclohexyl)-4,7-di-
hydro[1,2,5]oxadiazolo[3,4-b]pyridine-6-carboxylate
1-oxide (15e). Yield 0.170 g (50%), brown solid, mp 125–
1
126°C (decomp.). H NMR spectrum (DMSO-d6), δ, ppm
(J, Hz): 10.45 and 10.38 (1H, both d, J = 5.5, NH of diketo
and enol forms); 7.32 (1H, d, J = 5.5, CH); 5.36 and 5.11
(1H, both s, CH); 3.52 (3H, s, OCH3), 2.20 (4H, br. s,
2CH2); 0.94 and 0.93 (6H, both s, 2CH3). 13C NMR spectrum
(126 MHz, DMSO-d6), δ, ppm: 165.6; 152.5; 136.2; 108.3;
59.8; 50.9; 31.6; 30.7; 27.6; 24.8; 20.8; 14.1. Found, m/z:
336.1188 [M+H]+. C15H18N3O6. Calculated, m/z: 336.1190.
Methyl 7-(2,6-dioxocyclohexyl)-4,7-dihydro[1,2,5]oxa-
diazolo[3,4-b]pyridine-6-carboxylate 1-oxide (15f). Yield
0.100 g (33%), brown solid, mp 144–146°C (decomp.).
1H NMR spectrum (DMSO-d6), δ, ppm (J, Hz): 11.07 (1H,
br. s, OH); 10.43 (1H, d, J = 5.2, NH); 7.30 (1H, d, J = 5.2,
CH); 5.12 (1H, s, CH); 3.52 (3H, s, OCH3); 2.28 (4H, br. s,
2CH2); 1.78–1.72 (2H, m, CH2). 13C NMR spectrum
(75 MHz, DMSO-d6), δ, ppm: 200.4; 166.0; 152.9; 137.6;
136.5; 131.1; 111.6; 108.6; 102.6; 60.2; 51.2; 25.6; 21.2;
20.9; 16.6; 14.5. Found, m/z: 308.0878 [M+H]+. C13H14N3O6.
Calculated, m/z: 308.0877.
1
filtered, and dried. H and 13C NMR spectra of compounds
15a–g in some cases contain double set of signals cor-
responding to the enol and dioxo forms of the product. Due
to the tautomerism of these two forms some signals
appeared as broad singlets.
5,5-Dimethyl-2-(7-nitro-5,8-dihydropyrido[2,3-b]pyrazin-
8-yl)cyclohexane-1,3-dione (15a). Yield 0.206 g (65%),
yellow solid, mp 185–186°C. 1H NMR spectrum (DMSO-d6),
δ, ppm (J, Hz): 10.83 (1H, br. s, OH); 10.62 (1H, d, J = 6.5,
NH); 8.09 (1H, s, H Ar); 8.03 (1H, s, H Ar); 8.00 (1H, d,
J = 6.5, CH); 5.74 (1H, s, CH); 2.21 (4H, br. s, 2CH2); 0.91
(6H, s, 2CH3). 13C NMR spectrum (75 MHz, DMSO-d6),
δ, ppm: 194.5; 170.9; 145.3; 143.9; 140.2; 138.9; 136.8;
125.8; 116.8; 102.4; 34.8; 31.7; 27.6. Found, m/z: 317.1240
[M+H]+. C15H17N4O4. Calculated, m/z: 317.1244.
98

Chemistry of Heterocyclic Compounds 2020, 56(1), 92–100
Methyl 7-(1,3-dimethyl-2,4,6-trioxohexahydropyrimidin-
Synthesis of compounds 19a,b (General method). 0.1 M
solution of CF3CO2H in CH2Cl2 (1 ml) was added to an ice-
cold solution of compound 10a or 11a (1 mmol) and amine
1829 (1.04 ml, 4 mmol) in CH2Cl2 (10 ml). The mixture was
stirred for 24 h at 20°C, washed with saturated NaHCO3
solution, and the solvent was removed under reduced pressure.
The residue was purified by column chromatography,
eluent CHCl3.
5-yl)-4,7-dihydro[1,2,5]oxadiazolo[3,4-b]pyridine-6-carb-
oxylate 1-oxide (15g). Yield 0.126 g (36%), white solid,
1
mp 189–190°C (decomp.). H NMR spectrum (DMSO-d6),
δ, ppm (J, Hz): 10.87 (1H, d, J = 5.3, NH); 7.51 (1H, s,
CH); 4.79 (1H, s, CH); 3.55 (3H, s, OCH3); 3.14 (3H, s, CH3);
3.06 (3H, s, CH3). 13C NMR spectrum (75 MHz, DMSO-d6),
δ, ppm: 165.8; 164.1; 159.6; 150.0; 149.5; 136.0; 135.9;
128.9; 97.6; 54.1; 53.4; 51.7; 29.2; 28.8; 28.1. Found, m/z:
352.0883 [M+H]+. C13H14N5O7. Calculated, m/z: 352.0888.
Synthesis of compounds 17a–d (General method).
Triazolo[1,5-a]pyridine 16a,b10 (1 mmol) and nucleophile
(1.1 mmol) were dissolved in MeCN (10 ml). Compound
17a precipitated in few minutes and was filtered off,
washed with MeCN, and dried on air. In case of adducts
17b–d, Et3N (0.14 ml, 1 mmol) was added and the mixture
was stirred for 24 h, poured into H2O (50 ml), and acidified
with concd HCl to pH 2. The precipitated products were
filtered off, washed with H2O, and dried.
6,9-Dibenzyl-3-methyl-7b-nitro-2-(trifluoromethyl)-
3,5,6,7,7a,7b,8,9,10,10a-decahydrodiimidazo[1,5-a:4',5'-e]-
pyrrolo[3,4-c]pyridine (19a). Yield 0.162 g (32%), light-
1
yellow solid, mp 141–142°С. H NMR spectrum (CDCl3),
δ, ppm (J, Hz): 7.30–7.26 (10H, m, H Ph); 4.04 (1H, br. s,
CH); 3.98 (1H, d, J = 5.7, CH); 3.84–3.78 (3H, m, CH,
CH2); 3.63–3.57 (5H, m, CH, NCH3); 3.39 (2H, dd,
J = 15.3, J = 10.1, CH2); 3.13 (1H, t, J = 9.4, CH); 3.03
(2H, dd, J = 9.0, J = 6.5, CH2); 2.91 (1H, d, J = 10.4, CH);
2.81 (2H, dd, J = 8.6, J = 5.9, CH2). 13C NMR spectrum
(126 MHz, CDCl3), δ, ppm (J, Hz): 137.6; 135.6; 130.1 (q,
2JCF = 39.3); 128.7; 128.5; 128.3; 127.5; 122.9; 119.2 (q,
1JCF = 268.6); 91.2; 71.7; 64.6; 60.0; 59.2; 58.6; 57.7; 52.8;
41.3; 30.7. Found, m/z: 513.2219 [M+H]+. C26H28F3N6O2.
Calculated, m/z: 513.2220.
2-(6,8-Dinitro-1,5-dihydro[1,2,4]triazolo[1,5-a]pyridin-
5-yl)-5,5-dimethylcyclohexane-1,3-dione (17a). Yield
0.33 g (91%), yellow solid, mp 226–227°C (decomp.).
1H NMR spectrum (DMSO-d6), δ, ppm: 8.76 (1H, s, H Ar);
8.41 (1H, s, H Ar); 6.92 (1H, s, CH); 2.21 (4H, br. s,
2CH2); 0.91 (6H, s, 2CH3). 13C NMR spectrum (151 MHz,
DMSO-d6), δ, ppm: 143.0; 141.5; 141.3; 127.3; 127.2;
106.9; 52.7; 49.2; 31.7; 27.7; 27.5. Found, m/z: 350.1086
[M+H]+. C14H16N5O6. Calculated, m/z: 350.1095.
6,9-Dibenzyl-3-methyl-7b-nitro-3,5,6,7,7a,7b,8,9,10,10a-
decahydroimidazo[1,5-a]pyrrolo[3,4-c][1,2,3]triazolo-
[4,5-e]pyridine (19b). Yield 0.29 g (65%), brown solid,
mp 137–139°С. 1H NMR spectrum (CDCl3), δ, ppm
(J, Hz): 7.43–7.20 (10H, m, H Ph); 4.06–3.96 (5H, m, CH,
CH2); 3.88 (3H, s, NCH3); 3.83–3.59 (4H, m, CH2); 3.49
(1H, d, J = 10.6, CH); 3.25 (2H, t, J = 9.0, CH2); 3.08–2.98
(1H, m, CH); 2.90–2.81 (2H, m, CH2). 13C NMR spectrum
(75 MHz, CDCl3), δ, ppm: 138.0; 137.5; 137.4; 130.4;
128.6; 128.3; 127.6; 127.5; 90.1; 70.9; 64.2; 59.5; 59.2;
58.5; 57.7; 52.8; 40.1; 33.9. Found, m/z: 446.2298 [M+H]+.
C24H28N7O2. Calculated, m/z: 446.2299.
X-ray diffraction data of compound 17c were collected
on a Bruker APEX DUO diffractometer (λ(MoKα) 0.71073
Å, 2θ < 61.10°). Red crystals, obtained by the slow evapo-
ration of the solution of compound 17c in Me2CO, of
C13H8N8O10 at 120(2) K are monoclinic, space group P21/c;
a 13.4033(6), b 10.3227(5), c 12.1255(5) Å; β 103.4020
(10)°; V 1631.98(13) Å3; Z 4 (Z' 1); dcalc 1.776 g·cm–3.
Intensities of 5003 independent reflections (Rint 0.0303) out
of 29504 collected were used in structure solution and
refinement. The structure was solved by the dual-space
method with SHELXT program30 and refined by the full-
matrix least-squares technique against F2 in the anisotropic
approximation with SHELXL program.31 The hydrogen atom
connected to the nitrogen atom was found from the difference
Fourier synthesis and refined isotropically. Other hydrogen
atoms were placed in calculated positions and refined in the
riding model with Uiso(H) equal to 1.2Ueq(C) of the
connected carbon atoms. The refinement converged to
R10.0430 (calculated for 4027 observed reflections with
2-[2-(4-Methoxyphenyl)-6,8-dinitro-1,5-dihydro[1,2,4]-
triazolo[1,5-a]pyridin-5-yl]-5,5-dimethylcyclohexane-
1,3-dione (17b). Yield 0.44 g (94%), yellow solid, mp 205–
1
207°C. H NMR spectrum (DMSO-d6), δ, ppm (J, Hz):
8.45 (1H, s, H Ar); 7.98 (2H, d, J = 8.7, H Ar); 7.09 (2H, d,
J = 8.7, H Ar); 6.94 (1H, s, CH); 3.83 (3H, s, OCH3); 2.23
(4H, br. s, 2CH2); 0.92 (6H, s, 2CH3). 13C NMR spectrum
(126 MHz, DMSO-d6), δ, ppm: 161.8; 151.5; 144.5; 129.3;
127.4; 127.0; 116.5; 114.4; 107.1; 55.5; 52.8; 46.4; 31.9;
28.0; 27.5. Found, m/z: 456.1501 [M+H]+. C21H22N5O7.
Calculated, m/z: 456.1514.
6,8-Dinitro-5-(2,4,6-trinitrobenzyl)-1,5-dihydro[1,2,4]-
triazolo[1,5-a]pyridine (17c). Yield 0.31 g (69%), brown
solid, mp 162–163°C (decomp.). 1H NMR spectrum
(DMSO-d6), δ, ppm (J, Hz): 9.07 (2H, s, H Ar); 8.66 (1H,
s, H Ar); 8.47 (1H, s, H Ar); 6.34 (1H, dd, J = 7.9, J = 6.0,
CH); 3.76 (1H, dd, J = 14.3, J = 6.0, CH2); 3.55 (1H, dd,
J = 14.3, J = 8.2, CH2). 13C NMR spectrum (151 MHz,
DMSO-d6), δ, ppm: 150.9; 146.7; 143.0; 142.6; 130.2;
128.3; 124.6; 123.0; 107.2; 58.0; 32.2. Found, m/z:
437.0435 [M+H]+. C13H9N8O10. Calculated, m/z: 437.0436.
5-(2,4-Dinitrobenzyl)-6,8-dinitro-1,5-dihydro[1,2,4]-
triazolo[1,5-a]pyridine (17d). Yield 0.33 g (84%), orange
solid, mp 210–211°C (decomp.). 1H NMR spectrum
(DMSO-d6), δ, ppm (J, Hz): 8.78 (1H, s, H Ar); 8.69 (1H,
s, H Ar); 8.44–8.39 (2H, m, H Ar); 7.56 (1H, d, J = 8.3,
H Ar); 6.35 (1H, br. s, CH); 3.75–3.58 (2H, m, CH2).
13C NMR spectrum (126 MHz, DMSO-d6), δ, ppm: 149.4;
146.7; 142.8; 142.5; 137.3; 134.8; 128.4; 127.2; 124.4;
120.0; 107.0; 58.8; 36.3. Found, m/z: 392.0580 [M+H]+.
C13H10N7O8. Calculated, m/z: 392.0585.
I
>
2σ(I)), wR2 0.1141 and GOF 1.013. Full
crystallographic data is deposited at the Cambridge
Crystallographic Data Center (deposit CCDC 1943950).
Global electrophilicity parameters calculations.
Geometry optimization of isolated molecules was carried
99

Chemistry of Heterocyclic Compounds 2020, 56(1), 92–100
14. Bastrakov, M. A.; Kucherova, A. Yu.; Fedorenko, A. K.;
out at the B3LYP/6-31G** level of theory. The GAUSSIAN
program was used for calculation.19
Starosotnikov, A. M.; Fedyanin, I. V.; Dalinger, I. L.;
Shevelev, S. A. ARKIVOC 2017, (iii), 181.
1
15. Bastrakov, M. A.; Fedorenko, A. K.; Starosotnikov, A. M.;
Kachala, V. V.; Shevelev, S. A. Chem. Heterocycl. Compd.
2019, 55, 72. [Khim. Geterotsikl. Soedin. 2019, 55, 72.]
16. (a) Vichard, D.; Halle, J.-C.; Huguet, B.; Pouet, M.-J.;
Terrier, F.; Riou, D. Chem. Commun. 1998, 791.
(b) Sepulcri, P.; Halle, J. C.; Goumont, R.; Riou, D.;
Terrier, F. J. Org. Chem. 1999, 64, 9254. (c) Halle, J.-C.;
Vichard, D.; Pouet, M.-J.; Terrier, F. J. Org. Chem. 1997, 62,
7178. (d) Terrier, F.; Sebban, M.; Goumont, R.; Halle, J. C.;
Moutiers, G.; Cangelosi, I.; Buncel, E. J. Org. Chem. 2000,
65, 7391.
17. Parr, R. G.; Szenpaly, L. V.; Liu, S. J. Am. Chem. Soc. 1999,
122, 1922.
18. Perez, P.; Domingo, L. R.; Aizman, A.; Contreras, R. In
Theoretical Aspects of Chemical Reactivity; Toro-Labbe, A.,
Ed.; Elsevier Science, 2007, Chapter 9, p. 139.
Supplementary information file containing H, 13C NMR
spectra and HRMS analyses of the synthesized compounds is
available at the journal website at http://link.springer.com/
journal/10593.
This work was supported by the Russian Science
Foundation (grant 19-73-20259). X-ray diffraction studies
were performed with financial support from the Ministry of
Science and Higher Education of the Russian Federation
using the equipment of the Center for molecular composition
studies of the A. N. Nesmeyanov Institute of Organoelement
Compounds of the Russian Academy of Sciences.
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