Features of quinoxaline reactions with C-nucleophiles: Examples of dimerization of heterocycle in course of hydrogen substitution

Article abstract of DOI:10.1134/S1070363215070105

Reaction of quinoxaline or its 6,7-difluoroderivative with C-nucleophiles in nitrogen atmosphere afforded along with the products of hydrogen substitution in the heterocyclic ring the corresponding bisquinoxalines. An ESR signal of the cation-radical of t

Full text of DOI:10.1134/S1070363215070105

ISSN 1070-3632, Russian Journal of General Chemistry, 2015, Vol. 85, No. 7, pp. 1635–1638. © Pleiades Publishing, Ltd., 2015.
Original Russian Text © Yu.А. Azev, О.S. Ermakova, V.А. Bakulev, I.S. Kovalev, А.N. Tsmokalyuk, А.N. Kozitsina, М.G. Pervova, V.I. Filyakova, 2015,
published in Zhurnal Obshchei Khimii, 2015, Vol. 85, No. 7, pp. 1111–1114.
Features of Quinoxaline Reactions with C-Nucleophiles:
Examples of Dimerization of Heterocycle
in Course of Hydrogen Substitution
Yu. А. Azeva, О. S. Ermakovaa, V. А. Bakuleva, I. S. Kovaleva,
А. N. Tsmokalyuka, А. N. Kozitsinaa, М. G. Pervovab, and V. I. Filyakovab
a Yeltsin Ural Federal University, ul. Mira 19, Yekaterinburg, 620002 Russia
e-mail: azural@yandex.ru
b Postovskii Institute of Organic Synthesis, Ural Branch, Russian Academy of Sciences, Yekaterinburg, Russia
Received February 17, 2015
Abstract—Reaction of quinoxaline or its 6,7-difluoroderivative with С-nucleophiles in nitrogen atmosphere
afforded along with the products of hydrogen substitution in the heterocyclic ring the corresponding bis-
quinoxalines. An ESR signal of the cation-radical of the diprotic salt of quinoxaline was detected in the DMSO
solution of quinoxaline and dimedone.
Keywords: quinoxalines, С-nucleophiles, hydrogen substitution, dimers of quinoxaline
DOI: 10.1134/S1070363215070105
N-Alkyl salt of quinoxaline is known to react with
1,3-diketones to form the 2,3-diadducts of
tetrahydroquinoxaline or the products of cycloaddition
to the С2–С3 bond [1, 2]. The unsubstituted quino-
xaline reacts in DMSO with 1,3-dimethylbarbituric
acid at room temperature to form the product of hyd-
rogen substitution [3]. N,N-Dimethylaniline when
fused with quinoxaline hydrochloride in the presence
of three-fold excess of sulfur gives 2-(N,N-dimethyl-
aminophenyl)quinoxaline and 3-(N,N-dimethylamino-
phenyl)quinoxalinethione-2 in 12 and 71% yield res-
pectively [4]. In the reaction of the same reagents in
DMF solution in an inert atmosphere at 140°С 2,2'-bis-
quinoxaline is formed. At the same time, quinoxaline
hydrochloride does not form any products when heated
with N,N-dimethylaniline in DMF in the air at 140°С
[4]. Recently, we reported that quinoxaline and its 6,7-
difluoroderivatives smoothly reacted with С-nucleo-
philes in DMSO solution in the presence of acid at
room temperature to form the products of mono-
substitution of hydrogen atoms in the pyrazine ring
[5, 6]. In the present work we have found that quino-
xalines Iа, Ib react with С-nucleophiles in nitrogen
atmosphere with the formation of not only the products
of substitution IIa, IIb–IVa, IVb, but also 2,2'-bis-
quinoxalines Va, Vb (Scheme 1). The largest amount
(7–11%) of dimers Va, Vb was observed in the
reaction of quinoxalines Ia, Ib with dimedone. At the
same time, when air was bubbling air through the
reaction mixture of quinoxaline Ib with dimedone, the
yield of dimer Vb did not exceed 2–3%.
The base peaks in the mass spectra of dimers Va,
Vb are the peaks of molecular ions. The fragmentation
of molecular ions of compounds Va, Vb occurs
similarly. In both cases peaks of low intensity of ions
[M – 28]+• are registered, whose formation, apparently,
results from two consecutive processes and which
correspond to fragments [M – Н – HCN]+•. The main
route of fragmentation is the formation of an intense
ion [M – C7H4N]+ in the case of dimer Va (Scheme 2)
or [M – С7H2F2N]+ in the case of Vb.
The ion formed by the fragmentation of compound
Va corresponds to cyanoquinoxaline cation (HRMS,
ESI: M = 157.0631, calculated for [C6H6N3 + Н]+ =
157.0634, Δm/m = 2 ppm). The mechanism of
formation of cyanoquinoxaline cation can be
rationalized by successive splitting of the С–С bond of
one of heterocyclic rings, the rearrangement with
migration of a hydrogen atom, and subsequent splitting
of the С–N bond.
1635

1636
AZEV et al.
Scheme 1.
R
N
N
R
Nu
R
R
N
N
IIa, IIb, IIIa, IVa
HNu
HCl
N
N
Ia, Ib
R
N
N
R
R
R
Va, Vb
O
O
H3C
N
(II),
(III),
(IV).
R = H (a), F (b); Nu =
CH3
CH3
N
O
O
O
Scheme 2.
+
N
N
N
_C7H4N
_HCN
N
+
N+
N
H
N
N
H
N
m/z = 156
m/z = 129
_CN
m/z = 258
N+ CH
N
_HCN
_HCN
+
.
.
.
+ N
H
m/z = 130
m/z = 103
m/z = 76
When studying transformations of quinoxaline Iа
with dimedone in the DMSO solution in the presence
of acid at room temperature in the probe of the ESR
spectrometer, after 15–20 min an ESR signal appeared
(see figure), whose intensity increased during 3–5 h.
hyperfine structure corresponds to interaction of the
unshared electron with two equivalent nitrogen nuclei
(αNNH = 0.68 Gs) and two protons coupled with them
(αHNH = 0.62 Gs), as well as with the groups of the in
pair equivalent protons (αH2,3 = 0.39 Gs, αH5,8 = 0.14 Gs,
αH6,7 = 0.08 Gs).
The investigation of the hyperfine structure of the
ESR spectrum obtained by the reaction of compound
Iа with dimedone in DMSO is indicative of the
presence of radical cation of the diprotic salt of
quinoxaline in the reaction mixture. Indeed, the
Note that hyperfine structure of the radical we have
detected is fully consistent with that of the earlier
described for the radical cation of the diprotic salt of
quinoxaline [4].
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 85 No. 7 2015

FEATURES OF QUINOXALINE REACTIONS WITH C-NUCLEOPHILES
It can be assumed that the formation of the products
1637
I
of monosubstitution IIa, IIb, IIIa, IVa when carrying
out the reaction in nitrogen atmosphere is due to the
addition of nucleophiles to the С2 atom of quinoxaline
and the oxidation of the formed intermediates I1, I2 by
the starting quinoxalines I or their protic salts. In turn,
intermediates I1, I2, when oxidized, can form radical
cations in the process of one-electron reduction of the
starting protic salts of quinoxaline. The reaction of
cation-radical with the starting quinoxalines is a
typical reaction of hetarylation to form the final dimers
Va, Vb (Scheme 3).
To the best of our knowledge, the described
examples of the reaction of hydrogen substitution,
when the role of the oxidant of the formed σ-adducts
was played by the starting quinoxalines or their protic
salts, which, in turn, were converted into the dimers of
quinoxalines, were observed for the first time. At the
same time, the examples of reduction of pyridines,
quinoxalines with active metals to radical anions and
the use of the latter in the syntheses of bisheterocyclic
derivatives in the reactions of hetarylation of
nucleophilic aromatic compounds have been described
earlier [7–9].
Magnetic field, Gs
ESR spectrum (first derivative) of the radical cation of
quinoxaline.
Daltonics mass spectrometer. EI mass spectra were ob-
tained on a Varian MAT 311A spectrometer at 200°С
(70 eV) with direct admission of the sample into the
ion source. ESR spectrum was obtained on an
ELEXSYS E500 instrument in the CW mode in the
range of 9.5 GHz.
Reaction of quinoxalines Iа, Ib with dimedone.
1.0 mmol of quinoxaline Iа or Ib was stirred with
1.0 mmol of dimedone in 1 mL of DMSO in the
presence of 0.1 mL of conc. HСl at 20–25°С in
nitrogen atmosphere during of 48–50 h. The formed pre-
cipitate was filtered, washed with chloroform (3 × 3 mL),
EXPERIMENTAL
1Н NMR spectra were registered on a Bruker DRX-
400 spectrometer (400 MHz). Mass spectrum (HRMS-
ESI) was recorded on a micrOTOF-Q II Bruker
Scheme 3.
Cl_
Cl_
H
H
N
R
R
N
R
R
_H
+
HNu
HCl
Ia, Ib
H
+
N
N
Nu
Nu
H
HCl
H
H
I1a, I1b
I2a, I2b
Cl_
_HCl
_H
H
R
R
N
+
IIa, IIb, IIIa, IVa
Ia, Ib
Va, Vb
N
H
R = H (a), F (b).
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 85 No. 7 2015

1638
AZEV et al.
and crystallized from DMF to obtain the corresponding
dimer Va or Vb. The chloroform solutions from
washing the solid products of the reaction were
evaporated in a vacuum to obtain the products of
substitution IIa, IIb.
ACKNOWLEDGMENTS
This work was financially supported by the
Ministry of Education and Science of the Russian
Fderation: State contract, project part no. 4.1626.2014/K.
2,2'-bisquinoxaline (Vа). Yield 7.5%. mp 273–
274°С (mp 272–274°С [7]). 1Н NMR spectrum
(СDCl3), δ, ppm: 7.80–7.92 m (4Н, НAr); 8.20–8.25 m
(2Н, НAr); 8.22–8.32 m (2Н, НAr); 10.15 s (2Н, НAr).
Mass spectrum (EI), m/z (Irel, %): 258 (98), 257(4), 230
(8), 156 (100), 130 (35), 103 (45), 76 (45).
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The reaction of quinoxaline Iа with indandione was
carried out similarly to the reaction of Ia with
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ylidene)-1Н-1,2-dihydroquinoxaline IIIа (25%) were
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(2.8%) and 2-(1-phenyl-3-methyl-5-oxypyrazol-4-yl-
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obtained, mp 158–160°С (mp 158–160°С [5]).
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