S N H Amidation of nitroquinolines: synthesis of amides on the basis of nitro- and nitrosoquinolines

Article abstract of DOI:10.1007/s10593-019-02508-3

[Figure not available: see fulltext.] Direct S_N ^H amidation of 5-, 6-, 7-, and 8-nitroquinolines in anhydrous DMSO was used to obtain the respective aroylamino derivatives of nitro- and nitrosoquinolines.

Full text of DOI:10.1007/s10593-019-02508-3

DOI 10.1007/s10593-019-02508-3
Chemistry of Heterocyclic Compounds 2019, 55(7), 623–631
H
SN Amidation of nitroquinolines: synthesis of amides
on the basis of nitro- and nitrosoquinolines
Gulminat А. Amangasieva1, Elena K. Avakyan1, Oleg P. Demidov1,
Anastasia A. Borovleva1, Diana Yu. Pobedinskaya1, Ivan V. Borovlev1*
1 North-Caucasus Federal University,
1a Pushkina St., Stavropol 355009, Russia; е-mail: ivborovlev@rambler.ru
Submitted March 22, 2019
Accepted April 2, 2019
Translated from Khimiya Geterotsiklicheskikh Soedinenii,
2019, 55(7), 623–631
Direct SNH amidation of 5-, 6-, 7-, and 8-nitroquinolines in anhydrous DMSO was used to obtain the respective aroylamino derivatives of
nitro- and nitrosoquinolines.
Keywords: nitroquinolines, N-(nitroquinolinyl)benzamides, N-(nitrosoquinolinyl)benzamides, SNH amidation, disproportionation.
The quinoline system is widely regarded as a privileged
structure in the sense that many compounds containing
quinoline ring as the key structural motif have shown a
broad spectrum of biological and pharmaceutical activity
and comprise a large category of natural alkaloids.1 There
is still a considerable interest in searching for new synthetic
routes that would provide access to derivatives of this
heterocyclic system.2 The current possibilities of organic
synthesis include direct C–H-functionalization of aromatic
compounds, such as formation of C–N bonds,3 which can
be performed in accordance with the principles of green
chemistry, while achieving good atom economy.4
Direct C–H-functionalization of aromatic compounds
can be currently performed by catalyzed or noncatalyzed
reactions. Significant progress has been achieved with the
first of these two options, where C–H bonds are activated
in the presence of transition metal complexes as catalysts.
This allows to selectively introduce amine and amide
substituents in the molecules of electron-donating hetero-
cycles.5 However, this approach is problematic for the
synthesis of active pharmaceutical ingredients6a and
organic dyes for solar cells,6b since the presence of
transition elements even in trace amounts is unacceptable
for these applications.
substitution.7 Both routes start from a nucleophilic addition
step with the formation of a σH-adduct, followed by its
aromatization either by the elimination of simple HX
molecules, when a good leaving group X is bonded to the
nucleophilic center, or by the action of external oxidant.
The mechanism of dehydroaromatization in the presence of
oxidant is affected both by the structure of the σН-complex,
as well as the type of oxidant used, as well as the reaction
conditions.7a,8 The most likely sequence of mechanistic
steps leading to the aromatization includes a transfer of one
electron, a proton, and another electron (the EPE mechanism)
to the oxidant.8a In any case, the hydrogen atom is lost in
the form of a proton, not a hydride ion.
The procedure for oxidative nucleophilic substitution of
hydrogen does not require preliminary introduction of
auxiliary or nucleofugic groups into the molecule of the
substrate or reactant and does not require the use of costly
catalysts or ligands. The oxidation of σH-adducts can be
achieved by using organic or inorganic compounds, air
oxygen,9,10 while stable intermediates can be oxidized
electrochemically on anode.11 In the absence of an external
oxidant, the NO2 group12 or C=N bond of substrate13 also
H
can act as acceptors of hydride ion. The SN methodology
is already used on industrial scale14 and in many cases offer
an attractive alternative to cross-coupling reactions in the
presence of transition metals.15
Noncatalyzed C–H-functionalization can include, in
particular, nucleophilic substitution of hydrogen (SNH) in
the case of π-electron-poor substrates, such as π-electron-
poor hetarenes and nitroarenes. Such reactions proceed
mostly along two different routes: as vicarious or oxidative
The goal of this work was to study the possibilities for
direct nucleophilic substitution of hydrogen with N-amide
functionality in the molecules of nitroquinolines containing
0009-3122/19/55(7)-0623©2019 Springer Science+Business Media, LLC
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Chemistry of Heterocyclic Compounds 2019, 55(7), 623–631
Scheme 1
a nitro group in the benzene ring of the molecule. It is
known that such compounds readily participate both in
oxidative amination16 and arylamination reactions,17 as well
H
as in vicarious SN amination,18 while the regioselectivity
of the process is determined solely by the presence of a
nitro group.
H
In contrast to SN amination processes, amidation
reactions by direct substitution of hydrogen are still quite
H
rare. Oxidative SN amidation was first accomplished with
nitrobenzene in 1993,19a even though an intramolecular
variant of a similar reaction had been reported earlier.19b In
a later study, the reaction of benzamide with 1,3-dinitro-
benzene under anaerobic conditions gave a low yield of
N-(2,4-dinitrophenyl)benzamide.12 Subsequent efforts at
our laboratory led to successful oxidative SNH amidation of
1,3,7-triazapyrene,20 acridine,21 and 3-nitropyridine.22 The
reactions in all cases were performed in anhydrous DMSO
by treating the starting materials with separately prepared
anions of the respective carboxamides at room temperature,
using air oxygen20 or K3Fe(CN)621,22 in the role of oxidant.
When studying the reaction of 5-nitroquinoline (1) with
benzamide, we found that the optimal stoichiometry was
2 equiv of benzamide anion for 1 equiv of the starting
material. The anions were generated separately by adding
NaH to a solution of the respective benzamide in
anhydrous DMSO at room temperature. After the addition
of 5-nitroquinoline (1), the reaction reached completion in
2 h and gave a mixture of two products, which were
separated by chromatography on silica gel. The products
were identified as N-(5-nitroquinolin-8-yl)benzamide (2a)
and N-(5-nitrosoquinolin-6-yl)benzamide (3a), with the
overall yield of 66% (Scheme 1, Table 1, entry 1). The
reaction proceeded in the presence of air oxygen, but the
yield of nitro product 2a was only slightly lower when the
reaction was performed under argon atmosphere (entry 2).
Interestingly, the use of an external single-electron oxidant
(K3Fe(CN)6) also was not very effective (entry 3). The
obtained data indicate that, similarly to the case of 3-nitro-
pyridine,23 5-nitroquinoline exhibited dual reactivity, acting
not only as a substrate, but also as the primary oxidant of
σH-adducts during the formation of nitroamides 2. Such
dual reactivity clearly reduced the yields of the target
products and resulted in the presence of resinification
products. We should also note that increasing the reaction
temperature to 65–70°C accelerated the process (0.5 h), but
improvement in the yield of nitroamide 2a to 22% was
accompanied by sharp decrease in the yield of nitrosoamide
3a (entry 4).
Table 1. Optimization of reaction conditions and product
yields in SNH amidation of 5-nitroquinoline (1)*
Reaction
time, h
Product
(yield**, %)
Entry
Ar
1
2
3
4
5
6
7
Ph
2
2
2a (12)
3a (54)
3a (57)
3a (57)
3a (31)
3b (71)
3c (52)
4 (46%)
Ph***
2a (8)
2a (14)
2a (22)
2b (13)
2c (19)
2d (7%)
Ph*4
1
Ph*5
0.5
2
4-MeC6H4
4-MeOC6H4
4-O2NC6H4
1.5
4
* All experiments were performed with 2 equiv of the respective aromatic
amide and 2 equiv of NaH.
** Yield after chromatographic separation.
*** The experiment was performed under argon atmosphere.
*4 The experiment was performed in the presence of K3Fe(CN)6 (2 equiv).
*5 The reaction was performed at 65–70°C.
propionic, and isobutyric acids) was found to be
ineffective, as it led to intractable product mixtures.
The formation of nitroso compounds 3a–c represents the
first example of an alternative route for the aromatization
H
of σH-adducts during oxidative SN amidation reactions.
H
This route competes with oxidative SN reactions and is
well known in the series of nitroarenes. It proceeds via
dehydration of σH-intermediates to the respective nitroso
compounds or products of their subsequent transforma-
tions.2,7e,24 Similar reactions in the series of nitrohetarenes
were recently observed during arylamination of 5-nitro-
indole24e and 3-nitropyridine,23a as well as upon
carbamoylamination of the latter.23b In the case of
amidation of 5-nitroquinoline (1), the nucleophile was
added in the first step at the ortho and para positions
relative to the NO2 group, while para-σH-adduct 5 under-
went further oxidative aromatization with the formation of
nitroamides 2a–d (Scheme 2, path a), but its ortho-analog
6 was aromatized by a sequence of steps including proton
transfer and elimination of a water molecule, giving
nitrosoamides 3a–c (Scheme 2, path b).
The anions of p-methyl- and p-methoxybenzamides
reacted analogously, leading to the formation of the
respective nitroamides 2b,с and nitrosoamides 3b,с with a
significant predominance of the latter (Scheme 1, Table 1,
entries 5, 6). However, p-nitrobenzamide gave not only the
expected nitroamide 2d, but also its isomer at position 6 –
4-nitro-N-(5-nitroquinolin-6-yl)benzamide (4) (Scheme 1,
Table 1, entry 7). It is likely that p-nitrobenzamide itself
showed oxidizing properties toward the respective
intermediates (o-nitrobenzamide formed a complex product
mixture). Using amides of aliphatic acids (acetic,
A characteristic feature in 1H NMR spectra of
nitrosoamides 3a–c in CDCl3 was the strong downfield
shift of NH proton signals (13.5–13.6 ppm), providing
evidence of a strong intramolecular NH···O=N hydrogen
bond. In the case of their nitro analog 4, the intramolecular
624

Chemistry of Heterocyclic Compounds 2019, 55(7), 623–631
Scheme 2
Figure 1. The molecular structure of compound 3a with atoms
represented by thermal vibration ellipsoids of 50% probability.
The intramolecular O···HN hydrogen bond (1.808 Å) is shown by
a dotted line.
hydrogen bond was weaker (the NH proton signal was
observed at δ 10.41 ppm). The structures of N-(5-nitroso-
quinolin-6-yl)benzamide (3a) and 4-nitro-N-(5-nitro-
quinolin-6-yl)benzamide (4) were confirmed by X-ray
structural analysis (Figs. 1, 2). According to X-ray diffrac-
tion data, the length of the O···HN hydrogen bond for
nitro product 4 in crystalline state (2.098 Å) was
substantially longer than for nitroso compound 3a (1.808 Å).
It is known that in the absence of a free para position
relative to the NO2 group, as, for example, in the case of
Figure 2. The molecular structure of compound 4 with atoms
represented by thermal vibration ellipsoids of 50% probability.
The intramolecular O···HN hydrogen bond (2.098 Å) is shown by
a dotted line.
position 8, with the formation of N-(7-nitrosoquinolin-8-yl)-
benzamides 11a–с (Scheme 3, Table 2, entries 5–7).
However, similarly to the example of 5-nitroquinoline,
the use of p-nitrobenzamide in both cases led to the
respective dinitro compounds as amidation products:
4-nitro-N-(6-nitroquinolin-5-yl)benzamide (9) and 4-nitro-
N-(7-nitroquinolin-8-yl)benzamide (12) (Scheme 3, Table 2,
entries 4 and 8). It should be noted that compound 12 has
been synthesized earlier by the nitration of N-(quinolin-
8-yl)benzamide.25
H
p-substituted nitrobenzenes24a or 5-nitroindole,24e the SN
arylamination leads only to the respective o-nitrosoamines
or products of their subsequent transformations. Therefore,
similar disproportionation products were also expected
from the amidation of 6- and 7-nitroquinolines. Indeed,
when using benzamide and its p-methyl and p-methoxy
derivatives, the reaction with these nitroquinolines led
exclusively to the formation of nitroso compounds in low
or moderate yields, and only one of the two ortho positions
relative to the nitro group was involved in the reaction.
Interestingly, in contrast to nitrosoamides 3a–c, the
H
1
Thus, 6-nitroquinoline (7) participated in SN amidation
signals of NH protons in H NMR spectra of their analogs
reaction exclusively at position 5, forming the respective
N-(6-nitrosoquinolin-5-yl)benzamides 8a–с (Scheme 3,
Table 2, entries 1–3), while 7-nitroquinoline (10) reacted at
8a–c and 11a–c in CDCl3 showed much weaker downfield
shifts. In our opinion, the reason for this was steric
hindrance by the hydrogen atom or lone electron pair of
Scheme 3
NHC(O)Ar
NHC(O)C6H4NO2-p
O2N
ArC(O)NH2, NaH, O2
DMSO, rt
ON
ON
O2N
or
or
N
N
N
N
9
7
8a–c
ArC(O)NH2, NaH, O2
DMSO, rt
N
O2N
N
O2N
NHC(O)Ar
NHC(O)C6H4NO2-p
10
11a–c
12
NHC(O)Ar
ArC(O)NH2, NaH, K3Fe(CN)6
DMSO, rt
N
N
NO2
NO2
13
14a–d
625

Chemistry of Heterocyclic Compounds 2019, 55(7), 623–631
Table 2. Reaction conditions and product yields from
The benzamide anions used in this study clearly were
weaker nucleophiles than the NH2– anion, but were more
nucleophilic than ammonia. Thus, the regioselectivity
SNH amidation of 6-nitroquinoline (7),
7-nitroquinoline (10), and 8-nitroquinoline (13)
H
Starting
material
Reaction
time, h
Yield,
%
observed in oxidative SN amination of 5-, 6-, and
Entry
Ar
Product
7-nitroquinolines (compounds 1, 7, 10) in liquid NH3 –
1
2
7*
7*
Ph
1
1.5
2
73
67
77
43
66
74
80
39
63
78
72
84
KMnO4 system16b was practically the same as the
8a
8b
H
regioselectivity of SN amidation. However, 8-nitro-
4-MeC6H4
4-MeOC6H4
4-O2NC6H4
Ph
quinoline (13) could not be aminated under those
conditions, while products 14a–d from its amidation were
obtained by us in high yields.
We further found that our synthesized N-(5-nitroso-
quinolin-6-yl)benzamides 3a–c were readily deacylated as
a result of alcoholysis in MeOH–K2CO3 system at room
temperature, forming the expected single product –
5-nitrosoquinolin-6-amine (15) (Scheme 4).
3
7*
8c
4
7*
3
9
5
10*
10*
10*
10*
13**
13**
13**
13**
1
11a
11b
11c
12
6
4-MeC6H4
4-Me3OC6H4
4-O2NC6H4
Ph
1
7
1
8
6
9
20
8
14a
14b
14c
14d
Scheme 4
10
11
12
4-MeC6H4
4-MeOC6H4
4-O2NC6H4
12
6
* Amide (1.5 equiv) and NaH (1.5 equiv) were used.
** Amide (6 equiv), NaH (6 equiv), and K3Fe(CN)6 (6 equiv) were used.
nitrogen atom at the peri positions, resulting in
acoplanarity of the amide group and quinoline ring. Such
interpretation was confirmed by X-ray structural analysis
of 4-methoxy-N-(6-nitrosoquinolin-5-yl)benzamide (8c)
(Fig. 3).
The presence of an NH2 group was observed from
1H NMR spectrum of compound 15 in CDCl3 as two one-
proton signals at 11.94 and 5.54 ppm, the first of which
belonged to the proton involved in strong intramolecular
hydrogen bond. In our opinion, compound 15, similarly to
We later found that, in contrast to the 5-, 6-, and
7-isomers (compounds 1, 7, and 10, respectively),
SN amidation of 8-nitroquinoline (13) under the same
amides 3a–c, is
a
convenient object for further
functionalization of quinolines. However, it should be noted
that analogs of compounds 3a–c – nitroso compounds 8a
and 11a – reacted quite slowly under the same conditions,
giving intractable product mixtures.
Taking into account the reversibility of the first step
involving the addition of nucleophile, such contrasting
H
conditions proceeded exceedingly slowly and remained
incomplete after 48 h. The use of K3Fe(CN)6 as external
single-electron oxidant in this case was successful, even
though a 6-fold excess of the amidating agent was
necessary to complete the reaction, as well as the reaction
duration was substantially longer (Table 2, entries 9–12).
8-Nitroquinoline (13) reacted with aromatic amide anions
at the para position relative to the nitro group, forming
products from oxidative nucleophilic substitution of
hydrogen – N-(8-nitroquinolin-5-yl)benzamides 14a–d as
the only reaction products (Table 2, entries 9–12).
H
results in the SN amidation reaction of isomeric
nitroquinolines can be explained by the different
thermodynamic stability of the σH-adducts, as well as the
ratio of their aromatization rates according to the two
routes (the kinetic factor). In comparison to nitroarenes, the
π-electron-poor pyridine ring certainly facilitated the
addition step, but was not expected to substantially
stabilize the σH-intermediate, since the delocalization of
negative charge that is possible in the case of 6- and
8-nitroquinolines with the participation of the pyridine
nitrogen atom would imply simultaneous disruption of
aromaticity in two rings. As a polar aprotic solvent, DMSO
does not substantially solvate anionic species, thus
enhancing the nucleophilicity of arylamide ions, but not
stabilizing the anionic intermediates. It is possible that the
strongly polar nature of DMSO promoted the formation of
more polar anionic σH-adducts, thus influencing the
regioselectivity of the reaction.
Thus, the use of amide anions of aromatic acids as
nucleophilic agents in the reaction with 8-nitroquinoline in
anhydrous DMSO led to the formation of products from
H
SN amidation at position 5. Furthermore, 5-nitroquinoline
formed a mixture of 6- and 8-aroylamino derivatives of
5-nitro- and 5-nitrosoquinoline. In the case of 6- and
Figure 3. The molecular structure of compound 8c with atoms
represented by thermal vibration ellipsoids of 50% probability.
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Chemistry of Heterocyclic Compounds 2019, 55(7), 623–631
7-isomers, the products were amides derived from 6- and
(54%), green crystals, mp 181–182°C (decomp., PhH –
7-nitrosoquinolines, respectively. The regioselectivity of
reactions in all cases was determined exclusively by the
nitro group.
petroleum ether). IR spectrum, ν, cm–1: 3059, 1694, 1585,
1
1498, 1354. H NMR spectrum (CDCl3), δ, ppm (J, Hz):
7.63–7.73 (3H, m, H-3,4,5 Ph); 7.81 (1H, dd, J = 8.6,
J = 4.2, H-3); 8.20 (2H, d, J = 7.7, H-2,6 Ph); 8.53 (1H, d,
J = 9.6, H-8); 9.05 (1H, d, J = 4.2, H-2); 9.39 (1H, d,
J = 9.6, H-7); 9.80 (1H, d, J = 8.6, H-4); 13.45 (1H, br. s,
Experimental
IR spectra were recorded on a Shimadzu IRTracer-100
1
1
FTIR spectrometer for samples as thin films. H and 13C
NH). H NMR spectrum (DMSO-d6), δ, ppm (J, Hz): 7.67–
NMR spectra were acquired on a Bruker Avance HD 400
spectrometer (400 and 100 MHz, respectively). The
internal standards were residual DMSO-d6 signals (2.50 ppm
7.80 (3H, m, H-3,4,5 Ph); 7.94 (1H, dd, J = 8.5, J = 4.1, H-3);
8.14 (2H, br. d, J = 6.8, H-2,6 Ph); 8.60 (1H, d, J = 9.4,
H-8); 9.03–9.10 (2H, m, H-2,7); 9.49 (1H, br. d, J = 8.2,
H-4); 12.81 (1H, br. s, NH). 13C NMR spectrum (DMSO-d6),
δ, ppm: 122.9 (C-7); 124.6 (C-4a); 126.5 (C-6); 126.7 (C-3);
128.0 (C-2,6 Ph); 129.3 (C-3,5 Ph); 130.7 (C-4); 133.3 (C-1,4
Ph); 143.1 (C-8); 143.6 (C-8a); 149.0 (C-5); 151.0 (C-2);
167.6 (C=O). Found, m/z: 300.0749 [М+Na]+.
C16H11N3NaO2. Calculated, m/z: 300.0743.
1
for H nuclei, 40.5 ppm for 13С nuclei)26 and TMS when
CDCl3 was used as solvent. The structures of the key
products (compounds 2a, 3a, 4, 12a) were confirmed by
1
2D NMR experiments (1H–1H COSY, H–13C HSQC, and
1H–13C HMBC) on the same instrument (see the Sup-
plementary information file). Mass spectra were recorded
on a Bruker UHR-TOF maXis spectrometer (electrospray
ionization). Melting points were determined on a REACH
Devices RD-MP digital melting point apparatus. The
reaction progress was controlled by TLC on Silufol UV-254
plates. The nitroquinolines and NaH (60% suspension in
paraffin oil, abcr GmbH) were obtained from commercial
sources and used without additional purification.
4-Methyl-N-(5-nitroquinolin-8-yl)benzamide (2b). The
first pale-yellow fraction, eluent PhH. Yield 20 mg (13%),
pale-yellow crystals, mp 245–246°C (decomp., PhH –
petroleum ether) (mp 210–211°C28b). IR spectrum, ν, cm–1:
3348, 1689, 1570, 1504, 1394. 1H NMR spectrum (CDCl3),
δ, ppm (J, Hz): 2.47 (3H, s, CH3); 7.38 (2H, d, J = 8.1, H-3,5
Ar); 7.76 (1H, dd, J = 8.8, J = 4.2, H-3); 7.99 (2H, d,
J = 8.1, H-2,6 Ar); 8.61 (1H, d, J = 8.8, H-7); 8.96 (1H, dd,
J = 4.2, J = 1.4, H-2); 9.01 (1H, d, J = 8.8, H-6); 9.31 (1H,
Amidation of 5-nitroquinoline (1). A solution of the
appropriate amide (1 mmol) in anhydrous DMSO (4 ml)
was treated at room temperature by adding a suspension of
NaH in paraffin oil (40 mg, 1 mmol of NaH) and 5-nitro-
quinoline (1) (87 mg, 0.5 mmol). The mixture was
vigorously stirred at room temperature for the duration
indicated in Table 1. The reaction mixture was then poured
onto ice (50 g) and after warming to room temperature was
acidified with dilute HCl solution to pH ~7. The precipitate
that formed was filtered off, washed with water, and dried.
The obtained mixture was separated into fractions by the
dry silica gel flash chromatography.27
1
dd, J = 8.8, J = 1.4, H-4); 11.06 (1H, br. s, NH). H NMR
spectrum (DMSO-d6), δ, ppm (J, Hz): 2.44 (3H, s, CH3);
7.46 (2H, d, J = 7.8, H-3,5 Ar); 7.95–8.00 (3H, m, H-2,6
Ar, H-3); 8.66 (1H, d, J = 8.8, H-7); 8.87 (1H, d, J = 8.8,
H-6); 9.11–9.17 (2H, m, H-2,4); 10.98 (1H, br. s, NH).
13C NMR spectrum (DMSO-d6), δ, ppm: 20.9; 113.3; 120.9;
125.2; 127.1; 127.3; 129.5; 130.8; 132.7; 137.0; 138.4;
140.2; 142.9; 149.9; 164.7. Found, m/z: 330.0856 [М+Na]+.
C17H13N3NaO3. Calculated, m/z: 330.0849.
4-Methyl-N-(5-nitrosoquinolin-6-yl)benzamide (3b).
The second yellow fraction, eluent PhH–EtOAc, 5:1. Yield
103 mg (71%), yellowish-green crystals, mp 170–171°C
(decomp., PhH – petroleum ether). IR spectrum, ν, cm–1:
3360, 3036, 1688, 1580, 1347. 1H NMR spectrum (CDCl3),
δ, ppm (J, Hz): 2.50 (3H, s, CH3); 7.45 (2H, d, J = 8.0,
H-3,5 Ar); 7.80 (1H, dd, J = 8.5, J = 4.2, H-3); 8.10 (2H, d,
J = 8.0, H-2,6 Ar); 8.52 (1H, J = 9.6, H-8); 9.03 (1H, d,
J = 4.2, H-2); 9.39 (1H, d, J = 9.6, H-7); 9.79 (1H, d,
N-(5-Nitroquinolin-8-yl)benzamide (2a). The first
yellow fraction, eluent PhH. Yield 18 mg (12%), pale-
yellow crystals, mp 213–214°C (decomp., PhH – petroleum
ether) (mp 215–216°C28a, 209–210°C28b, 212–213°C28c).
IR spectrum, ν, cm–1: 3356, 2921, 1687, 1498, 1382.
1H NMR spectrum (CDCl3), δ, ppm (J, Hz): 7.50–7.67 (3H,
m, H-3,4,5 Ph); 7.77 (1H, dd, J = 8.8, J = 4.1, H-3); 8.10
(2H, d, J = 7.6, H-2,6 Ph); 8.63 (1H, d, J = 8.8, H-6); 8.97
(1H, d, J = 4.1, H-2); 9.03 (1H, d, J = 8.8, H-7); 9.32 (1H,
1
J = 8.5, H-4); 13.49 (1H, br. s, NH). H NMR spectrum
1
d, J = 8.8, H-4); 11.10 (1H, br. s, NH). H NMR spectrum
(DMSO-d6), δ, ppm (J, Hz): 2.45 (3H, s, CH3); 7.51 (2H, d,
J = 8.0, H-3,5 Ar); 7.93 (1H, dd, J = 8.5, J = 4.1, H-3); 8.03
(2H, d, J = 8.0, H-2,6 Ar); 8.58 (1H, d, J = 9.5, H-8); 9.03
(1H, d, J = 4.1, H-2); 9.08 (1H, d, J = 9.5, H-7); 9.50 (1H,
d, J = 8.5, H-4); 12.87 (1H, br. s, NH). 13C NMR spectrum
(DMSO-d6), δ, ppm: 21.2; 122.7; 125.2; 126.0; 126.6;
128.1; 129.9; 130.4; 130.7; 143.2; 143.5; 143.8; 148.9;
151.0; 167.5. Found, m/z: 314.0901 [М+Na]+.
C17H13N3NaO2. Calculated, m/z: 314.0900.
(DMSO-d6), δ, ppm (J, Hz): 7.66 (2H, br. d, J = 7.3, H-3,5
Ph) 7.72 (1H, br. t, J = 7.1, H-4 Ph); 7.97 (1H, dd, J = 8.6,
J = 4.4, H-3); 8.07 (2H, br. d, J = 7.7, H-2,6 Ph); 8.67 (1H,
d, J = 8.8, H-6); 8.87 (1H, d, J = 8.8, H-7); 9.11–9.17 (2H,
m, H-2,4); 11.03 (1H, br. s, NH). 13C NMR spectrum
(DMSO-d6), δ, ppm: 113.9 (C-7); 122.0 (C-4a); 124.9
(C-3); 127.6 (C-2,6 Ph); 128.1 (C-6); 129.2 (C-3,5 Ph);
132.8 (C-4 Ph); 133.6 (C-4); 134.3 (C-1 Ph); 137.9 (C-8a);
138.8 (C-5); 141.0 (C-8); 149.2 (C-2); 165.9 (C=O).
Found, m/z: 316.0701 [М+Na]+. C16H11N3NaO3.
Calculated, m/z: 316.0693.
4-Methoxy-N-(5-nitroquinolin-8-yl)benzamide
(2c).25,28d,e The first pale-yellow fraction, eluent PhH. Yield
31 mg (19%), pale-yellow crystals, mp 255–256°C
(decomp., PhH – petroleum ether). IR spectrum, ν, cm–1:
3326, 2854, 1680, 1502, 1350. 1H NMR spectrum (CDCl3),
N-(5-Nitrosoquinolin-6-yl)benzamide (3a). The second
yellow fraction, eluent PhH–EtOAc, 5:1. Yield 75 mg
627

Chemistry of Heterocyclic Compounds 2019, 55(7), 623–631
δ, ppm (J, Hz): 3.85 (3H, s, OCH3); 7.01 (2H, d, J = 8.5,
Ar); 144.9 (C-8a); 150.5 (C-4 Ar); 151.1 (C-2); 163.8
(CO). Found, m/z: 339.0727 [М+H]+. C16H11N4O5.
Calculated, m/z: 339.0724. Found, m/z: 361.0533 [М+Na]+.
C16H10N4NaO5. Calculated, m/z: 361.0543.
H-3,5 Ar); 7.70 (1H, dd, J = 8.7, J = 4.0, H-3); 8.01 (2H, d,
J = 8.5, H-2,6 Ar); 8.56 (1H, d, J = 8.8, H-7); 8.90 (1H, d,
J = 4.0, H-2); 8.94 (1H, d, J = 8.8, H-8); 9.26 (1H, d,
1
J = 8.7, H-4); 10.97 (1H, br. s, NH). H NMR spectrum
Amidation of 6- and 7-nitroquinolines 7, 10 (General
method). A solution of the appropriate amide (0.75 mmol)
in anhydrous DMSO (4 ml) was stirred at room
temperature and treated by adding NaH suspension in
paraffin oil (30 mg, 0.75 mmol NaH) and 6- or 7-nitro-
quinoline (87 mg, 0.5 mmol, compounds 7 or 10,
respectively). The mixture was vigorously stirred at room
temperature for the duration indicated in Table 2. The
reaction mixture was then poured onto ground ice (50 g)
and after warming to room temperature was acidified with
dilute HCl solution to pH ~7. The precipitate that formed
was filtered off, washed with water, and dried. The product
was recrystallized from a suitable solvent.
(DMSO-d6), δ, ppm (J, Hz): 3.88 (3H, s, OCH3); 7.19 (2H,
d, J = 8.5, H-3,5 Ar); 7.99 (1H, dd, J = 8.5, J = 4.4, H-3);
8.06 (2H, d, J = 8.5, H-2,6 Ar); 8.68 (1H, d, J = 8.9, H-7);
8.87 (1H, d, J = 8.9, H-8); 9.12–9.18 (2H, m, H-2,4); 10.98
(1H, br. s, NH). 13C NMR spectrum (DMSO-d6), δ, ppm:
54.5; 112.5; 113.2; 120.9; 123.7; 125.3; 127.1; 128.5; 132.4;
136.7; 137.4; 140.1; 148.0; 162.1; 164.2. Found, m/z:
346.0804 [М+Na]+. C17H13N3NaO4. Calculated, m/z:
346.0798.
4-Methoxy-N-(5-nitrosoquinolin-8-yl)benzamide (3c).
The second yellow fraction, eluent PhH–EtOAc, 5:1. Yield
80 mg (52%), orange crystals, mp 185–186°C (decomp.,
PhH – petroleum ether). IR spectrum, ν, cm–1: 3366, 3069,
N-(6-Nitrosoquinolin-5-yl)benzamide (8a). Yield 101 mg
(73%), light-green crystals, mp 175–176°C (decomp., EtOAc –
petroleum ether). IR spectrum, ν, cm–1: 3233, 1657, 1613,
1
1688, 1585, 1357. H NMR spectrum (CDCl3), δ, ppm
(J, Hz): 3.95 (3H, s, OCH3); 7.12 (2H, d, J = 8.6, H-2,6
Ar); 7.78 (1H, dd, J = 8.5, J = 4.1, H-3); 8.18 (2H, d,
J = 8.6, H-3,5 Ar); 8.49 (1H, d, J = 9.6, H-8); 9.03 (1H, d,
J = 4.1, H-2); 9.37 (1H, d, J = 9.6, H-7); 9.78 (1H, d,
1
1500, 1386. H NMR spectrum (CDCl3), δ, ppm (J, Hz):
6.95 (1H, d, J = 9.2, H-8); 7.55–7.62 (3H, m, H-3, H-3,5
Ph); 7.68 (1H, t, J = 7.4, H-4 Ph); 7.88 (1H, d, J = 9.2,
H-7); 8.15 (2H, d, J = 7.4, H-2,6 Ph); 8.71 (1H, br. d, J = 8.5,
H-4); 9.11 (1H, dd, J = 4.2, J = 1.5, H-2); 10.74 (1H, br. s,
NH). 13C NMR spectrum (CDCl3), δ, ppm: 110.4; 122.0;
124.6; 128.1; 128.6; 129.3; 133.3 (2C); 136.7; 142.8;
152.4; 154.9; 155.5; 167.3. Found, m/z: 300.0737 [М+Na]+.
C16H11N3NaO2. Calculated, m/z: 300.0743.
1
J = 8.5, H-4); 13.56 (1H, br. s, NH). H NMR spectrum
(DMSO-d6), δ, ppm (J, Hz): 3.91 (3H, s, OCH3); 7.25 (2H,
d, J = 8.8, H-2,6 Ar); 7.94 (1H, dd, J = 8.5, J = 4.1, H-3);
8.12 (2H, d, J = 8.8, H-3,5 Ar); 8.58 (1H, d, J = 9.5, H-8);
9.03 (1H, dd, J = 4.1, J = 1.2, H-2); 9.09 (1H, d, J = 9.5,
H-7); 9.53 (1H, br. d, J = 8.5, H-4); 12.97 (1H, br. s, NH).
13C NMR spectrum (DMSO-d6), δ, ppm: 56.2; 115.1;
123.1; 125.6; 126.0; 126.4; 126.9; 130.7; 131.0; 143.7;
143.9; 149.3; 151.3; 163.7; 167.4. Found, m/z: 308.1037
[М+H]+. C17H14N3O3. Calculated, m/z: 308.1030.
4-Methyl-N-(6-nitrosoquinolin-5-yl)benzamide (8b).
Yield 97 mg (67%), yellowish-green crystals, mp 167–168°C
(decomp., PhH). IR spectrum, ν, cm–1: 3301, 1671, 1537,
1
1493, 1321. H NMR spectrum (CDCl3), δ, ppm (J, Hz):
4-Nitro-N-(5-nitroquinolin-8-yl)benzamide
(2d).25
2.48 (3H, s, CH3); 6.95 (1H, d, J = 9.2, H-8); 7.38 (2H, d,
J = 8.0, H-3,5 Ar); 7.58 (1H, dd, J = 8.5, J = 4.2, H-3);
7.87 (1H, d, J = 9.2, H-7); 8.04 (2H, d, J = 8.0, H-2,6 Ar);
8.70 (1H, br. d, J = 8.5, H-4); 9.10 (1H, br. d, J = 4.2, H-2);
10.75 (1H, br. s, NH). 13C NMR spectrum (CDCl3), δ, ppm:
21.8; 110.5; 121.9; 124.6; 128.1; 128.4; 129.9; 130.4;
136.9; 143.0; 144.2; 152.4; 154.8; 155.6; 167.2. Found, m/z:
314.0916 [М+Na]+. C17H13N3NaO2. Calculated, m/z:
314.0900.
The first light-yellow fraction, eluent PhH. Yield 12 mg
(7%), light-brown crystals, mp 264–265°C (decomp., PhH –
petroleum ether). IR spectrum, ν, cm–1: 3311, 3114, 1687,
1
1538, 1305. H NMR spectrum (CDCl3), δ, ppm (J, Hz):
7.81 (1H, dd, J = 8.8, J = 4.2, H-3); 8.27 (2H, d, J = 8.8,
H-2,6 Ar); 8.45 (2H, d, J = 8.8, H-3,5 Ar); 8.64 (1H, d,
J = 8.8, H-7); 8.99 (1H, dd, J = 4.2, J = 1.5, H-2); 9.01
(1H, d, J = 8.8, H-6); 9.33 (1H, dd, J = 8.8, J = 1.5, H-4);
11.15 (1H, br. s, NH). 13C NMR spectrum (DMSO-d6), δ,
ppm: 114.3; 121.9; 124.4; 125.1; 127.8; 128.8; 133.8;
137.9; 139.7; 140.1; 149.5; 150.3; 160.3; 163.7. Found,
m/z: 339.0714 [М+H]+. C16H11N4O5. Calculated, m/z:
339.0724.
4-Nitro-N-(5-nitroquinolin-6-yl)benzamide (4). The
second yellow fraction, eluent PhH–EtOAc, 5:1. Yield 78 mg
(46%), yellow crystals, mp 234–235°C (decomp., PhH –
petroleum ether). IR spectrum, ν, cm–1: 3368, 3105, 1692,
1588, 1418. 1H NMR spectrum (CDCl3), δ, ppm (J, Hz): 7.63
(1H, dd, J = 8.8, J = 4.2, H-3); 8.17 (2H, d, J = 6.9, H-2,6 Ar);
8.40–8.44 (3H, m, H-3,5 Ar, H-8); 8.58 (1H, dd, J = 8.8,
J = 1.5, H-4); 8.95 (1H, d, J = 9.4, H-7); 8.99 (1H, dd,
J = 4.2, J = 1.5, H-2); 10.41 (1H, br. s, NH). 13C NMR
spectrum (DMSO-d6), δ, ppm: 121.9 (C-4a); 123.7 (C-7);
124.3 (C-3); 124.5 (C-3,5 Ar); 128.9 (C-2,6 Ar); 131.4
(C-4); 132.5 (C-6); 134.5 (C-5); 136.7 (C-8); 138.9 (C-1
4-Methoxy-N-(6-nitrosoquinolin-5-yl)benzamide (8c).
Yield 118 mg (77%), light-green crystals, mp 188–189°C
(decomp., EtOAc). IR spectrum, ν, cm–1: 3083, 2929, 1632,
1
1578, 1381. H NMR spectrum (CDCl3), δ, ppm (J, Hz):
3.92 (3H, s, OCH3); 6.97 (1H, d, J = 9.2, H-8); 7.06 (2H, d,
J = 8.7, H-2,6 Ar); 7.57 (1H, dd, J = 8.6, J = 4.2, H-3);
7.86 (1H, d, J = 9.2, H-7); 8.12 (2H, d, J = 8.7, H-3,5 Ar);
8.70 (1H, br. d, J = 8.6, H-4); 9.11 (1H, br. d, J = 4.2, H-2);
10.75 (1H, br. s, NH). 13C NMR spectrum (CDCl3), δ, ppm:
55.8; 110.6; 114.5; 121.8; 124.6; 125.4; 128.2; 130.2;
137.0; 143.1; 152.4; 154.8; 155.6; 163.7; 166.8. Found, m/z:
330.0856 [М+Na]+. C17H13N3NaO3. Calculated, m/z:
330.0849.
4-Nitro-N-(6-nitroquinolin-5-yl)benzamide (9). The
second yellow fraction, eluent PhH–EtOAc, 5:1. Yield
73 mg (43%), yellow crystals, mp 242–243°C (decomp.,
EtOAc). IR spectrum, ν, cm–1: 3240, 1661, 1600, 1514,
628

Chemistry of Heterocyclic Compounds 2019, 55(7), 623–631
1
1345. H NMR spectrum (CDCl3), δ, ppm (J, Hz): 7.59
(1H, dd, J = 8.7, J = 4.2, H-3); 8.20 (1H, d, J = 9.4, H-8);
8.25 (2H, d, J = 8.7, H-2,6 Ar); 8.36 (1H, br. d, J = 8.7,
H-4); 8.40 (1H, d, J = 9.4, H-7); 8.45 (2H, d, J = 8.7, H-3,5
Ar); 9.13 (1H, br. d, J = 4.2, H-2); 10.14 (1H, br. s, NH).
13C NMR spectrum (CDCl3), δ, ppm: 122.5; 123.9, 124.3;
124.5; 129.1; 129.9; 130.8; 135.7; 138.3; 140.3; 150.1;
150.6; 154.3; 164.7. Found, m/z: 361.0537 [М+Na]+.
C16H10N4NaO5. Calculated, m/z: 361.0543.
J = 8.8, H-2,6 Ar); 8.43 (2H, d, J = 8.8, H-3,5 Ar); 8.61
(1H, dd, J = 8.3, J = 1.5, H-4); 9.13 (1H, dd, J = 4.1,
J = 1.5, H-2); 11.30 (1H, br. s, NH). 13C NMR spectrum
(CDCl3), δ, ppm: 122.4; 123.9; 124.3; 124.4; 127.6; 129.3;
129.8; 136.8; 138.9; 140.5; 141.0; 150.4; 150.8; 163.5.
Found, m/z: 361.0532 [М+Na]+. C16H10N4NaO5.
Calculated, m/z: 361.0543.
Amidation of 8-nitroquinoline (13). A solution of the
appropriate amide (3 mmol) in anhydrous DMSO (4 ml) was
stirred at room temperature and treated with a suspension
of NaH in paraffin oil (120 mg, 3 mmol NaH),
8-nitroquinoline (13) (87 mg, 0.5 mmol), and K3Fe(CN)6
(987 mg, 3 mmol). The mixture was vigorously stirred at
room temperature for the duration indicated in Table 2. The
crude products were further purified by recrystallization
from EtOAc.
N-(7-Nitrosoquinolin-8-yl)benzamide (11a). Yield
104 mg (75%), beige crystals, mp 159–160°C (decomp.,
EtOAc). IR spectrum, ν, cm–1: 3317, 2921, 1684, 1510,
1
1408. H NMR spectrum (CDCl3), δ, ppm (J, Hz): 6.77
(1H, d, J = 9.0, H-5); 7.51 (1H, d, J = 9.0, H-6); 7.56–7.61
(2H, m, H-3,5 Ph); 7.62–7.67 (2H, m, H-3, H-4 Ph); 8.20
(1H, br. d, J = 8.8, H-4); 8.22 (2H, d, J = 8.2, H-2,6 Ph);
9.00 (1H, br. d, J = 4.1, H-2); 10.42 (1H, br. s, NH).
13C NMR spectrum (CDCl3), δ, ppm: 109.1; 123.3; 124.8;
128.3; 129.0; 131.7; 132.9; 134.0; 136.7; 139.7; 142.7;
150.5; 152.5; 168.8. Found, m/z: 300.0746 [М+Na]+.
C16H11N3NaO2. Calculated, m/z: 300.0743.
4-Methyl-N-(7-nitrosoquinolin-8-yl)benzamide (11b).
Yield 108 mg (74%), yellowish-green crystals, mp 169–
170°C (decomp., EtOAc). IR spectrum, ν, cm–1: 3297,
1682, 1516, 1480, 1397. 1H NMR spectrum (CDCl3), δ, ppm
(J, Hz): 2.48 (3H, s, CH3); 6.77 (1H, d, J = 9.0, H-5); 7.38
(2H, d, J = 8.2, H-3,5 Ar); 7.49 (1H, d, J = 9.0, H-6); 7.64
(1H, dd, J = 8.3, J = 4.2, H-3); 8.12 (2H, d, J = 8.2, H-2,6 Ar);
8.19 (1H, dd, J = 8.3, J = 1.6, H-4); 8.99 (1H, dd, J = 4.2,
J = 1.6, H-2); 10.41 (1H, br. s, NH). 13C NMR spectrum
(CDCl3), δ, ppm: 21.8; 109.2; 123.1; 124.7; 128.3; 129.7;
131.1; 131.7; 136.7; 139.8; 142.7; 143.6; 150.4; 152.5;
168.7. Found, m/z: 314.0896 [М+Na]+. C17H13N3NaO2.
Calculated, m/z: 314.0900.
4-Methoxy-N-(7-nitrosoquinolin-8-yl)benzamide
(11c). Yield 123 mg (80%), yellowish-green crystals,
mp 165–166°C (decomp., PhH). IR spectrum, ν, cm–1:
3320, 3078, 1682, 1505, 1395. 1H NMR spectrum (CDCl3),
δ, ppm (J, Hz): 3.92 (3H, s, OCH3); 6.76 (1H, d, J = 9.0,
H-5); 7.06 (2H, d, J = 8.7, H-2,6 Ar); 7.47 (1H, d, J = 9.0,
H-6); 7.62 (1H, dd, J = 8.2, J = 4.2, H-3); 8.17–8.19 (3H,
m, H-4, H-3,5 Ar); 8.98 (1H, br. d, J = 4.2, H-2); 10.37
(1H, br. s, NH). 13C NMR spectrum (CDCl3), δ, ppm: 55.7;
109.2; 114.2; 123.0; 124.7; 126.1; 130.3; 131.7; 136.7;
140.0; 142.7; 150.3; 152.5; 163.4; 168.3. Found, m/z:
330.0857 [М+Na]+. C17H13N3NaO3. Calculated, m/z:
330.0849.
N-(8-Nitroquinolin-5-yl)benzamide
(14a).
Yield
92 mg (63%), beige crystals, mp 233–234°C (decomp.,
EtOAc). IR spectrum, ν, cm–1: 3268, 3068, 1652, 1519,
1390. 1H NMR spectrum (DMSO-d6), δ, ppm (J, Hz): 7.59–
7.61 (2H, m, H-3,5 Ph); 7.67 (1H, t, J = 7.2, H-4 Ph); 7.76
(1H, dd, J = 8.6, J = 4.1, H-3); 7.95 (1H, d, J = 8.2, H-6);
8.11 (2H, d, J = 7.7, H-2,6 Ph); 8.35 (1H, d, J = 8.2, H-7);
8.65 (1H, dd, J = 8.6, J = 1.5, H-4); 9.08 (1H, dd, J = 4.1,
J = 1.5, H-2); 10.85 (1H, br. s, NH). 13C NMR spectrum
(DMSO-d6), δ, ppm: 121.5 (C-6); 122.7 (C-3); 123.5 (C-7);
123.9 (C-4a); 128.1 (C-2,6 Ph); 128.6 (C-3,5 Ph); 132.2 (C-4
Ph); 133.1 (C-4); 133.9 (C-1' Ph); 137.8 (C-5); 139.1
(C-8a); 145.4 (C-8); 152.7 (C-2); 166.6 (C=O). Found, m/z:
316.0702 [М+Na]+. C16H11N3NaO3. Calculated, m/z:
316.0693.
4-Methyl-N-(8-nitroquinolin-5-yl)benzamide (14b).
Yield 120 mg (78%), beige crystals, mp 234–235°C
(decomp., EtOAc). IR spectrum, ν, cm–1: 3263, 3050, 1649,
1527, 1360. 1H NMR spectrum (DMSO-d6), δ, ppm
(J, Hz): 2.42 (3H, s, CH3); 7.40 (2H, d, J = 8.0, H-3,5 Ar);
7.75 (1H, dd, J = 8.6, J = 4.0, H-3); 7.95 (1H, d, J = 8.2,
H-6); 8.01 (2H, d, J = 8.0, H-2,6 Ar); 8.34 (1H, d, J = 8.2,
H-7); 8.63 (1H, br. d, J = 8.6, H-4); 9.05 (1H, br. d, J = 4.0,
H-2); 10.76 (1H, br. s, NH). 13C NMR spectrum (DMSO-d6),
δ, ppm: 21.1; 121.5; 122.6; 123.6; 123.9; 128.2; 129.1;
131.0; 133.1; 138.0; 139.1; 142.3; 145.2; 152.7; 166.4. Found,
m/z: 330.0858 [М+Na]+. C17H13N3NaO3. Calculated, m/z:
330.0849.
4-Methoxy-N-(8-nitroquinolin-5-yl)benzamide (14c).
Yield 116 mg (72%), beige crystals, mp 235–236°C
(decomp., EtOAc). IR spectrum, ν, cm–1: 3262, 1649, 1604,
1530, 1381. 1H NMR spectrum (DMSO-d6), δ, ppm (J, Hz):
3.87 (3H, s, OCH3); 7.12 (2H, d, J = 8.7, H-3,5 Ar); 7.75 (1H,
dd, J = 8.6, J = 4.1, H-3); 7.92 (1H, d, J = 8.2, H-6); 8.10
(2H, d, J = 8.7, H-2,6 Ar); 8.33 (1H, d, J = 8.2, H-7); 8.62
(1H, br. d, J = 8.6, H-4); 9.06 (1H, br. d, J = 3.8, H-2);
10.68 (1H, br. s, NH). 13C NMR spectrum (DMSO-d6),
δ, ppm: 55.6; 113.8; 121.4; 122.6; 123.6; 123.9; 125.9;
130.2; 133.2; 138.1; 139.1; 145.2; 152.7; 162.4; 165.9. Found,
m/z: 346.0783 [М+Na]+. C17H13N3NaO4. Calculated, m/z:
346.0798.
4-Nitro-N-(7-nitroquinolin-8-yl)benzamide
(12).25
The first yellow fraction, eluent 1:1 petroleum ether – EtOAc
mixture. Yield 66 mg (39%), yellow crystals, mp 255–256°C
(decomp., EtOAc). IR spectrum, ν, cm–1: 3290, 3074, 1697,
1
1524, 1343. H NMR spectrum (CDCl3), δ, ppm (J, Hz):
7.68 (1H, dd, J = 8.3, J =4.2, H-3); 7.76 (1H, d, J = 9.1,
H-5); 8.08 (1H, d, J = 9.1, H-6); 8.27 (2H, d, J = 8.6, H-2,6
Ar); 8.31 (1H, br. d, J = 8.3, H-4); 8.41 (2H, d, J = 8.6,
H-3,5 Ar); 8.98 (1H, br. d, J = 4.2, H-2); 10.45 (1H, br. s,
1
NH). H NMR spectrum (DMSO-d6), δ, ppm (J, Hz): 7.76
(1H, d, J = 9.1, H-5); 7.83 (1H, dd, J = 8.3, J = 4.1, H-3);
8.14 (2H, s, H-5,6); 8.08 (1H, d, J = 9.1, H-6); 8.33 (2H, d,
4-Nitro-N-(8-nitroquinolin-5-yl)benzamide
Yield 142 mg (84%), yellow crystals, mp 247–248°C
(14d).
629

Chemistry of Heterocyclic Compounds 2019, 55(7), 623–631
(decomp., EtOAc). IR spectrum, ν, cm–1: 3424, 2924, 1693,
This work received financial support from the Ministry
of Education and Science of the Russian Federation within
1516, 1345. 1H NMR spectrum (DMSO-d6), δ, ppm
(J, Hz): 7.77 (1H, dd, J = 8.7, J = 4.2, H-3); 7.98 (1H, d,
J = 8.2, H-6); 8.33 (2H, d, J = 8.8, H-2,6 Ar); 8.36 (1H, d,
J = 8.2, H-7); 8.43 (2H, d, J = 8.8, H-3,5 Ar); 8.69 (1H, br. d,
J = 8.7, H-4); 9.09 (1H, br. d, J = 3.6, J = 1.3, H-2); 11.14
(1H, br. s, NH). 13C NMR spectrum (DMSO-d6), δ, ppm:
121.8; 122.8; 123.5; 123.7; 123.9; 129.7; 133.1; 137.2;
139.0; 139.6; 145.7; 149.5; 152.8; 165.1. Found, m/z:
361.0548 [М+Na]+. C16H10N4NaO5. Calculated, m/z:
361.0543.
the
framework
of
State
Assignment
(project
No. 4.6306.2017/8.9).
References
1. (a) Michael, J. P. Nat. Prod. Rep. 1997, 14, 605. (b) Kumar, S.;
Bawa, S.; Gupta, H. Mini-Rev. Med. Chem. 2009, 9, 1648.
(c) Puskullu, M. O.; Tekiner, B.; Suzen, S. Mini-Rev. Med.
Chem. 2013, 13, 365. (d) Taylor, R. D.; MacCoss, M.;
Lawson, A. D. G. J. Med. Chem. 2014, 57, 5845. (e) Gopaul, K.;
Shintre, S. A.; Koorbanally, N. A. Anticancer Agents Med.
Chem. 2015, 15, 631. (f) Hussaini, S. M. Expert Opin. Ther.
Pat. 2016, 26, 1201. (g) Jain, S.; Chandra, V.; Jain, P. K.;
Pathak, K.; Pathak, D.; Vaidya, A. Arab. J. Chem. 2016.
DOI:10.1016/j.arabjc.2016.10.009. (h) Sharma, V.; Mehta, D. K.;
Das, R. Mini-Rev. Med. Chem. 2017, 17, 1557. (i) Musiol, R.
Expert Opin. Drug Discovery 2017, 12, 583.
Alcoholysis of nitroso compounds 3a–c (General
method). A solution of the appropriate amide 3a–c
(0.3 mmol) in MeOH (15 ml) was treated by adding K2CO3
(248.4 mg, 1.8 mmol), followed by vigorous stirring for
0.5 h. The mixture was then poured into cold water
(100 ml) and acidified with dilute HCl solution to pH ~7.
The product was extracted with EtOAc (3×15 ml), and the
solvent was evaporated to dryness at reduced pressure.
Further purification was performed by the dry silica gel
flash chromatography,27 eluting with 5:1 PhH–EtOAc
mixture and collecting the first (yellowish-green) fraction.
After the removal of solvent, pure nitroso product 15 was
obtained.
2. Mąkosza, M.; Wojciechowski, K. Top. Heterocycl. Chem.
2014, 37, 51.
3. (a) Baeten, M.; Maes, B. U.W. Adv. Organomet. Chem. 2017,
67, 401. (b) C–H Bond Activation and Catalytic Functiona-
lization. I and II; Dixneuf, P. H.; Doucet, H., Eds.; Springer:
Berlin, 2016. (c) Metal Free C–H Functionalization of
Aromatics. Nucleophilic Displacement of Hydrogen;
Charushin, V.; Chupakhin, O., Eds.; Springer: Cham, 2014.
4. (a) Arends, I.; Sheldon, R.; Hanefeld, U. Green Chemistry and
Catalysis; Wiley-VCH: Weinheim, 2007. (b) Constable, D. J. C.;
Dunn, P. J.; Hayler, J. D.; Humphrey, G. R.; Leazer, J. L.;
Linderman, R. J.; Lorenz, K.; Manley, J.; Pearlman, B. A.;
Wells, A.; Zaks, A.; Zhang, T. Y. Green Chem. 2007, 9, 411.
(c) Utepova, I. A.; Trestsova, M. A.; Chupakhin, O. N.;
Charushin, V. N.; Rempel, A. A. Green Chem. 2015, 17,
4401. (d) Lancaster, M. Green Chemistry. An Introductory Text;
2nd ed.; RSC Publishing: Cambridge, 2010. (e) Sheldon, R. A.
Chem. Soc. Rev. 2012, 41, 1437.
5-Nitrosoquinolin-6-amine (15). Yield 33 mg (64%,
from compound 3a), 41 mg (79%, from compound 3b),
36 mg (71%, from compound 3c), green crystals, mp 190–
191°C (decomp., PhH) (mp 176°C29). IR spectrum, ν, cm–1:
3248, 2923, 1628, 1505, 1297. 1H NMR spectrum (CDCl3),
δ, ppm (J, Hz): 5.54 (1H, br. s, NH); 7.03 (1H, d, J = 9.4,
H-8); 7.63 (1H, dd, J = 8.4, J = 4.3, H-3); 8.06 (1H, d,
J = 9.4, H-7); 8.84 (1H, dd, J = 4.3, J = 1.5, H-2); 9.59
13
(1H, d, J = 8.4, H-4); 11.94 (1H, br. s, NH···O). C NMR
5. (a) Kim, J.; Kim, J.; Chang, S. Chem.–Eur. J. 2013, 19, 7328.
(b) Ryu, J.; Shin, K.; Park, S. H.; Kim, J. Y.; Chang, S.
Angew. Chem. 2012, 124, 10042. (c) Shi, J.; Zhou, B.; Yang, Y.;
Li, Y. Org. Biomol. Chem. 2012, 10, 8953.
6. (a) Verbitskiy, E. V.; Cheprakova, E. M.; Slepukhin, P. A.;
Kravchenko, M. A.; Skornyakov, S. N.; Rusinov, G. L.;
Chupakhin, O. N.; Charushin, V. N. Eur. J. Med. Chem. 2015,
97, 225. (b) Verbitskiy, E. V.; Cheprakova, E. M.;
Subbotina, J. O.; Schepochkin, A. V.; Slepukhin, P. A.;
Rusinov, G. L.; Charushin, V. N.; Chupakhin, O. N.;
Makarova, N. I.; Metelitsa, A. V.; Minkin, V. I. Dyes Pigm.
2014, 100, 201.
7. (a) Chupakhin, O. N.; Charushin, V. N.; van der Plas, H. C.
Nucleophilic Aromatic Substitution of Hydrogen; Academic
Press: San Diego, 1994. (b) Chupakhin, O. N.; Charushin, V. N.
Tetrahedron Lett. 2016, 57, 2665. (c) Charushin, V. N.;
Chupakhin, O. N. Top. Heterocycl. Chem. 2014, 37, 1.
(d) Gulevskaya, A. V.; Pozharskii, A. F. Top. Heterocycl.
Chem. 2014, 37, 179. (e) Mąkosza, M. Synthesis 2017, 3247.
(f) Suwiński, J. W. ARKIVOC 2017, (i), 402. (g) Czaban-
Jóźwiak, J.; Loska, R.; Mąkosza, M. J. Org. Chem. 2016, 81,
11751. (h) Varaksin, M. V.; Utepova, I. A.; Chupakhin, O. N.
Chem. Heterocycl. Compd. 2012, 48, 1213. [Khim.
Geterotsikl. Soedin. 2012, 1301.] (i) Varaksin, M. V.;
Utepova, I. A.; Chupakhin, O. N.; Charushin, V. N.
Tetrahedron 2015, 71, 7077.
spectrum (CDCl3), δ, ppm: 123.1; 124.7; 129.5; 130.7;
132.9; 142.2; 142.6; 148.6; 149.1. Found, m/z: 174.0654
[М+H]+. C9H8N3O. Calculated, m/z: 174.0662.
X-ray structural analysis of compounds 3a, 4, and 8с
was performed on an Agilent SuperNova diffractometer
equipped with a microfocus X-ray source containing a
copper anode and Atlas S2 CCD matrix detector. Crystals
suitable for X-ray structural analysis were obtained by slow
evaporation of a solution in 1:1 petroleum ether – CH2Cl2
system (compound 3a), EtOAc (compound 4), or MeOH
(compound 8с) at room temperature. The reflections were
collected, unit cell parameters were determined and refined
by using the specialized CrysAlisPro 1.171.38.41 software
suite (Rigaku Oxford Diffraction, 2015).30 The structures
were solved using ShelXT program (Sheldrick, 2015)31 and
refined with ShelXL program (Sheldrick, 2015),32
Molecular graphics were rendered and prepared for
publication using the Olex2 version 1.2.10 software suite.33
The complete X-ray diffraction datasets were deposited at
the Cambridge Crystallographic Data Center (deposits
CCDC 1871005 (compound 3a), CCDC 1874185
(compound 4), and CCDC 1904646 (compound 8с)).
1
Supplementary information file containing Н and 13С
8. (a) Matern, A. I.; Charushin, V. N.; Chupakhin, O. N. Russ.
Chem. Rev. 2007, 76, 23. [Usp. Khim. 2007, 76, 27.]
(b) Chupakhin, O. N.; Charushin, V. N.; van der Plas, H. C.
NMR spectra of all synthesized compounds is available from
the journal website at http://link.springer.com/journal/10593.
630

Chemistry of Heterocyclic Compounds 2019, 55(7), 623–631
Tetrahedron 1988, 44, 1. (c) Berberova, N. T.;
Okhlobystin, O. Yu. Chem. Heterocycl. Compd. 1984, 20,
817. [Khim. Geterotsikl. Soedin. 1984, 1011.]
21. Demidov, O. P.; Borovlev, I. V.; Amangasieva, G. A.;
Avakyan, E. K. Chem. Heterocycl. Compd. 2016, 52, 104.
[Khim. Geterotsikl. Soedin. 2016, 52, 104.]
9. Budyka, M. F.; Terent'ev, P. B.; Kost, A. N. Chem.
Heterocycl. Compd. 1978, 14, 663. [Khim. Geterotsikl.
Soedin. 1978, 809.]
22. Amangasieva, G. A.; Borovlev, I. V.; Demidov, O. P.;
Avakyan, E. K.; Borovleva, A. A. Russ. J. Org. Chem. 2018,
54, 867. [Zh. Org. Khim. 2018, 54, 865.]
10. Borovlev, I. V.; Demidov, O. P.; Saigakova, N. A.;
Amangasieva, G. A. Eur. J. Org. Chem. 2014, 7675.
11. (a) Shchepochkin, A. V.; Chupakhin, O. N.; Charushin, V. N.;
Steglenko, D. V.; Minkin, V. I.; Rusinov, G. L.; Matern, A. I.
RSC Adv. 2016, 6, 77834. (b) Makhaeva, G. F.; Lushchekina, S. V.;
Boltneva, N. P.; Serebryakova, O. G.; Rudakova, E. V.;
Ustyugov, A. A.; Bachurin, S. O.; Shchepochkin, A. V.;
Chupakhin, O. N.; Charushin, V. N.; Richardson, R. J. Bioorg.
Med. Chem. 2017, 25, 5981. (c) Shchepochkin, A. V.;
Chupakhin, O. N.; Charushin, V. N.; Rusinov, G. L.;
Subbotina, Yu. O.; Slepukhin, P. A.; Budnikova, Yu. G. Russ.
Chem. Bull., Int. Ed. 2013, 62, 773. [Izv. Akad. Nauk, Ser. Khim.
2013, 772.]
12. Gulevskaya, A. V.; Tyaglivaya, I. N.; Verbeeck, S.;
Maes, B. U. W.; Tkachuk, A. V. ARKIVOC 2011, (ix), 238.
13. Garnier, E.; Audoux, J.; Pasquinet, E.; Suzenet, F.; Poullain, D.;
Lebret, B.; Guillaumet, G. J. Org. Chem. 2004, 69, 7809.
14 (a) Bashkin, J. K.; Rains, R.; Stern, M. Green Chem. 1999, 1,
G41. (b) Triplett, R. D.; Rains, R. K. US Patent 7504539.
15. Patriciu, O.-I.; Fînaru, A.-L.; Săndulescu, I.; Guillaumet, G.
Synthesis 2007, 3868.
16. (a) Tondys, H.; van der Plas, H. C.; Wozniak, M. J.
Heterocycl. Chem. 1985, 22, 353. (b) Wozniak, M.; Baranski, A.;
Nowak, K.; van der Plas, H. C. J. Org. Chem. 1987, 52, 5643.
17. Demidov, O. P.; Pobedinskaya, D. Yu.; Avakyan, E. K.;
Amangasieva, G. A.; Borovlev, I. V. Chem. Heterocycl. Compd.
2018, 54, 875. [Khim. Geterotsikl. Soedin. 2018, 54, 875].
18. (a) Grzegożek, M. J. Heterocycl. Chem. 2008, 45, 1879.
(b) Grzegożek, M.; Szpakiewicz, B.; Kowalski, P. ARKIVOC
2009, (vi), 84.
23. (a) Borovlev, I. V.; Demidov, O. P.; Amangasieva, G. A.;
Avakyan, E. K.; Borovleva, A. A.; Pobedinskaya, D. Yu.
Synthesis 2018, 3520. (b) Avakyan, E. K.; Borovlev, I. V.;
Demidov, O. P.; Amangasieva, G. A.; Pobedinskaya, D. Yu.
Chem. Heterocycl. Compd. 2017, 53, 1207. [Khim.
Geterotsikl. Soedin. 2017, 53, 1207.]
24. (a) Wróbel, Z.; Kwast, A. Synlett 2007, 1525. (b) Wróbel, Z.;
Kwast, A. Synthesis 2010, 3865. (c) Kwast, A.; Stachowska, K.;
Trawczyński, A.; Wróbel, Z. Tetrahedron Lett. 2011, 52,
6484. (d) Wróbel, Z.; Stachowska, K.; Grudzień, K.; Kwast, A.
Synlett 2011, 1439. (e) Wróbel, Z.; Więcław, M.; Bujok, R.;
Wojciechowski, K. Monatsh. Chem. 2013, 144, 1847.
25. Khan, B.; Khan, A. A.; Bora, D.; Verma, D.; Koley, D.
ChemistrySelect 2017, 2, 260.
26. Gottlieb, H. E.; Kotlyar, V.; Nudelman, A. J. Org. Chem.
1997, 62, 7512.
27. Sharp, J. T.; Gosney, I.; Rowley, A. G. Practical Organic
Chemistry; Chapman and Hall: London, 1989.
28. (a) Zhu, X.; Qiao, L.; Ye, P.; Ying, B.; Xu, J.; Shen, C.;
Zhang, P. RSC Adv. 2016, 6, 89979. (b) He, Y.; Zhao, N.;
Qiu, L.; Zhang, X.; Fan, X. Org. Lett. 2016, 18, 6054.
(c) Mondal, S.; Samanta, S.; Hajra, A. Adv. Synth. Catal.
2018, 360, 1026. (d) Whiteoak, C. J.; Planas, O.; Company, A.;
Ribas, X. Adv. Synth. Catal. 2016, 358, 1679. (e) Wang, Y.;
Yu, F.; Han, X.; Li, M.; Tong, Y.; Ding, J.; Hou, H. Inorg.
Chem. 2017, 56, 5953.
29. Ma̧ kosza, M.; Białecki, M. J. Org. Chem. 1998, 63, 4878.
30. CrysAlisPro, version 1.171.38.41; Rigaku Oxford Diffraction,
2015. https://www.rigaku.com/en/products/smc/crysalis.
31. Sheldrick, G. M. Acta Crystallogr., Sect. A: Found. Adv.
2015, 71, 3.
32. Sheldrick, G. M. Acta Crystallogr., Sect. C: Struct. Chem.
2015, 71, 3.
19. (a) Stern, M. K.; Cheng, B. K. J. Org. Chem. 1993, 58, 6883.
(b) Esser, F.; Pook, K.-H. Synthesis 1992, 596.
20. Borovlev, I. V.; Demidov, O. P.; Kurnosova, N. A.;
Amangasieva, G. A.; Avakyan, E. K. Chem. Heterocycl. Compd.
2015, 51, 170. [Khim. Geterotsikl. Soedin. 2015, 51, 170.]
33. Dolomanov, O. V.; Bourhis, L. J.; Gildea, R. J.; Howard, J. A. K.;
Puschmann, H. J. Appl. Crystallogr. 2009, 42, 339.
631