S NH Arylamination of 3-Nitropyridine: A Competitive Formation of 2-Arylamino-5-nitropyridines and 2-Arylamino-5-nitrosopyridines

Article abstract of DOI:10.1055/s-0037-1610173

Arylamination of 3-nitropyridine via the nucleophilic substitution of hydrogen leads to a mixture of 2-arylamino-5-nitropyridines and novel 2-arylamino-5-nitrosopyridines, with the latter as the major product. The proposed mechanism includes the formation of σ ^H -adducts and their further aromatization proceeding either through an oxidative pathway or intramolecular Red/Ox pathway of the S _N^H reaction. Moreover, we have shown that nitroso compounds can be selectively oxidized with m -chloroperbenzoic acid to give the corresponding nitro derivatives or their N -oxides, depending on the reaction temperature and the amount of oxidant.

Full text of DOI:10.1055/s-0037-1610173

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2018, 50, A–K
paper
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en
I. V. Borovlev et al.
Paper
Synthesis
H
SN Arylamination of 3-Nitropyridine: A Competitive Formation of
2-Arylamino-5-nitropyridines and 2-Arylamino-5-nitrosopyridines
Ivan V. Borovlev*
Oleg P. Demidov
0
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0-
9
5
7
7-
2
0
7
mCPBA, CH2Cl2, rt
Gulminat A. Amangasieva
Elena K. Avakyan
NO2
NO2
NO2
mCPBA, (CH2Cl)2
1. ArNH2, NaH,
DMSO, rt
N
O
+
ArNH
ArNH
N+
O–
2. H2O
N
N
Anastasia A. Borovleva
Diana Yu. Pobedinskaya
ArNH
N
reflux
Department of Chemistry, North Caucasus Federal University,
Pushkin st. 1, Stavropol, 355009, Russia
ivborovlev@rambler.ru
Received: 07.03.2018
Accepted after revision: 04.05.2018
Published online: 19.06.2018
operations or expensive catalysts and ligands, can be used.8
Its mechanism involves the formation of a σH adduct and its
further aromatization in the presence of an oxidant (oxida-
tive SNH reaction).9
DOI: 10.1055/s-0037-1610173; Art ID: ss-2018-t0157-op
Abstract Arylamination of 3-nitropyridine via the nucleophilic substi-
tution of hydrogen leads to a mixture of 2-arylamino-5-nitropyridines
and novel 2-arylamino-5-nitrosopyridines, with the latter as the major
product. The proposed mechanism includes the formation of σH-ad-
ducts and their further aromatization proceeding either through an oxi-
As the result of a cooperative electron-withdrawing ef-
fect of the nitro group and the N-heteroatom in the 3-nitro-
pyridine molecule, the latter possesses strong electrophilic
properties and can participate in different reactions with a
variety of nucleophilic reagents. For example, oxidative am-
ination of 3-nitropyridine employing liquid NH3/KMnO4
proceeded nonselectively, giving a mixture of three isomer-
ic amino derivatives, the products of ortho- and para-sub-
stitution.10 Additionally, the amination reactions of 3-nitro-
pyridines with ammonia in aqueous KMnO4 solution or
DMSO/KMnO4 were reported.11 In these experiments, sub-
stitution at the position 6 of 3-nitropyridine was observed.
The oxidative SNH alkylamination reaction of 3-nitropyr-
idines has also been well-studied.12 Usually, these reactions
are performed employing an excess of alkyl- or dialkyl-
amines in the presence of an oxidant. In 2010 Verbeeck and
co-workers showed that such transformations in the pres-
ence of a complex oxidant, namely dipyridine silver per-
manganate AgPy2MnO4, are the most efficient.12c 3-Nitro-
pyridines also participate in VNS reactions. For instance,
amination reactions with hydroxylamine,13a 4-aminо-1,2,4-
triazole,13a О-methylhydroxylamine,13b and sulfenamides
have been reported.8b VNS reactions with alkylamines and
arylamines8b,13c have also been described, but they are less-
well studied. Oxidative SNH and VNS transformations usual-
ly proceeded regioselectively, affording the products of
para-substitution towards the nitro group, exclusively.
The key features of SNH arylamination are the inapplica-
bility of amination and alkylamination protocols, due to the
low nucleophilicity of arylamines, and their high suscepti-
bility to oxidation. This is why the reactions of this type are
almost unstudied. Until recently, there were only a few re-
H
dative pathway or intramolecular Red/Ox pathway of the SN reaction.
Moreover, we have shown that nitroso compounds can be selectively
oxidized with m-chloroperbenzoic acid to give the corresponding nitro
derivatives or their N-oxides, depending on the reaction temperature
and the amount of oxidant.
H
Key words C–H functionalization, SN arylamination, 3-nitropyridine,
metal-free synthesis
Aromatic and heteroaromatic amines are widely used as
building blocks for various pharmaceuticals, drugs, agro-
chemicals, polymers, and materials.1 Many methods for
their synthesis employ halogenated starting materials un-
der noncatalytic2 or catalytic conditions.3 This approach
usually requires additional derivatization, that does not
correspond the principle of atom economy.4 Over the last
few decades, significant progress in C–N bond formation
through the activation of C–H bonds of aromatic and het-
eroaromatic compounds by transition metals has been
achieved.5 However, this approach cannot be applied to the
synthesis of pharmaceuticals6a and organic dyes for solar
cells6b as, for these purposes, metal traces are not tolerated.
Nucleophilic aromatic substitution of hydrogen (SN
can be considered as an attractive alternative to the transi-
tion-metal approach. The SN methods include cine-, tele-,
and vicarious nucleophilic substitution (VNS), which re-
quire a good leaving group presence in the substrate or in
the reagent. Additionally, the oxidative nucleophilic substi-
tution of hydrogen, which does not require any preparatory
H
7
)
H
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–K

B
I. V. Borovlev et al.
Paper
Synthesis
ported examples of intermolecular arylamination: arylami-
nation of 5-azacinnoline,14 1,2,4-triazines,15 and 3-nitropy-
ridines.16,17 These experiments were performed in the pres-
ence of strong bases; in fact, arylamide anions acted as
nucleophiles in these transformations.
Table 1 Optimization of the Reaction Conditions for SNH Phenylamina-
tion of 3-Nitropyridine (Method A, 15 min)
Entry
Aniline (equiv)
NaH (equiv)
Yields (%)a
2a
3a
Recently, we have demonstrated that even such weak N-
nucleophiles as arylamino, acylamino, and carbamoyl ami-
no groups, can be introduced into the 1,3,7-triazapyrene18
1
2
3
4
5
6
7
1.1
2
1.1
2
16
16
9b
8
22
1.5b
and acridine19 molecules via the SN process at room tem-
H
2
2
perature. The reactions were performed, employing sodium
hydride as the base in dry DMSO. This solvent is known to
enhance the nucleophilicity of different anions. Hereby, the
aim of the present work was to study the arylamination of
3-nitropyridine under the same conditions and to establish
the scope of the reaction.
3
3
16
22
25c
–
31
33
33c
–
4
4
4
4
6
6
a Isolated yields after column chromatography.
b The reaction was performed under argon.
c The reaction was performed with bubbling O2.
First, we performed the amination of 3-nitropyridine
(1) with aniline as a model reaction. Sodium anilide (1.1
equiv) was prepared by the treatment of aniline with sodi-
um hydride in dry DMSO at room temperature. Then, 3-nit-
ropyridine (1.1 equiv) was added, and the reaction mixture
was stirred under air (Table 1, Method A); complete conver-
sion was observed in 15 minutes. Surprisingly, we could
isolate two products with a similar structure. According to
NMR and HRMS data, these compounds were N-(5-nitro-
pyridin-2-yl)aniline (2a)17 and new N-(5-nitrosopyridin-2-
yl)aniline (3a) (Scheme 1, Table 1, entry 1). Increasing of the
amount of aniline and NaH gave compounds 2a and 3a in
higher yields with a predominance of the nitroso product
3a (entries 2, 4, and 5). However, the reaction with 6 equiv-
alents of sodium anilide resulted in the formation of a com-
plex mixture of oligomerization products (entry 7). Heating
the reaction mixture at 60 °C led to its decomposition. The
use of 4 equivalents of sodium anilide at room temperature
was found to be optimal.
obtained the both products in lower yields (Table 1, entry
3). On other hand, when the reaction was performed with
bubbling oxygen, nearly the same outcome was observed
(cf. entries 5 and 6). Thus, both 3-nitropyridine and oxygen
could oxidize the σH adducts 4 into the nitro compound 2a
(Scheme 2). This is why the total yield of compounds 2a and
3a, which was calculated from the starting 3-nitropyridine,
was low. It is known that oxygen can be an efficient oxidant
only when anionic σH adducts are further deprotonated
with a base; thus, actually, the corresponding dianion un-
dergoes the oxidation8d (Scheme 2).
The reaction is accompanied by resinification, probably,
due to the formation of some reduced products of 3-nitro-
pyridine or due to the insufficient stability of intermediates
4.
Arylamine anions bearing either electron-donating or
electron-withdrawing substituents on the benzene ring, re-
act with 3-nitropyridine under the same conditions to form
a mixture of compounds 2 and 3 in different ratios, general-
ly, with the predominance of the nitroso compound 3
(Scheme 1, Table 2, entries 3, 5, 7, and 9–12). The only ex-
ception was 4-nitroaniline, which afforded the nitro com-
pound 2i as the sole product even under an inert atmo-
sphere (Table 2, entry 14). Obviously, the nitro group of this
reagent is able to oxidize the corresponding σH adduct 4 in
the final step of the transformation. Notably, the products
of nucleophilic substitution at positions 2 and 4 of 3-nitro-
pyridine were not detected. This can be explained by the in-
stability of the corresponding σH adducts or their insuffi-
1. ArNH2, NaH,
DMSO, rt
NO2
Ν
NO2
O
+
2. H2O
ArNH
Ν
ArNH
Ν
Ν
minor
2a–i
major
3a–h
1
Scheme 1 SNH Arylamination of 3-nitropyridine
In 2011, Gulevskaya and co-workers reported that 3-nit-
ropyridine has a dual role, as a substrate and an oxidant, in
such reactions.17 To examine, if 3-nitropyridine is the only
oxidant in this reaction, or oxygen from the air is also in-
volved, we performed the transformation under argon and
O–
N+
NO2
NO2
H
O–
NO2
1 or O2
H
ArNH–
– (H+ + 2e)
ArNH
N–
ArNH
N
N
ArNH
N
1
4
2a–i
Scheme 2 Proposed pathway for the synthesis of nitro compounds 2a–i
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–K

C
I. V. Borovlev et al.
Paper
Synthesis
cient concentration in the reaction mixture. In the latter
case, a stronger oxidant is required, which is not possible
for a number of reasons (cf. with data10).
The formation of nitroso compounds from nitroarenes
via the nucleophilic substitution is a well-known process.8a
For example, anions of primary arylamines upon reaction
with nitrobenzenes give ortho-σH-adducts which afford N-
aryl-2-nitrosoanilines under basic conditions.20 Interesting-
Table 2 Products of the SNH Arylamination Reaction of 3-Nitropyridine Using ArNH2/NaH/DMSO at Room Temperaturea
Entry
Amine
Methodb
Yield (%)
2
3
NO2
NO
1
2
3
4
5
6
7
8
9
PhNH2
A
B
A
B
A
B
A
B
A
Ν
NH
Ν
NH
3a (33)
3a (52)
2a (22)
2a (1)
PhNH2
NO2
NO
4-MeC6H4NH2
4-MeC6H4NH2
4-MeOC6H4NH2
4-MeOC6H4NH2
4-FC6H4NH2
4-FC6H4NH2
4-CF3C6H4NH2
NH
Ν
NH
Ν
2b (16)
2b (11)
MeO
3b (32)
3b (44)
NO2
NO
MeO
NH
Ν
Ν
NH
2c (13)
2c (17)
3c (41)
3c (30)
NO2
F
NO
F
Ν
NH
Ν
NH
2d (12)
2d (12)
F3C
3d (36)
3d (53)
NO2
NO
F3C
NH
Ν
NH
Ν
2e (6)
3e (47)
NO2
Br
NO
Br
10
11
4-BrC6H4NH2
A
A
Ν
NH
Ν
NH
2f (20)
3f (43)
NO2
NO
Br
Br
2,4-Br2C6H3NH2
NH
Ν
NH
Ν
Br
Br
2g (22)
3g (44)
NO2
NO
12
2-ClC6H4NH2
A
NH
Ν
NH
Ν
Cl
Cl
3h (20)
2h (22)
13
14
15
2-ClC6H4NH2
B
A
B
2h (7)
3h (14)
NO2
O2N
4-NO2C6H4NH2
–
–
NH
Ν
2i (57)
2i (59)
4-NO2C6H4NH2
a Isolated yields after column chromatography.
b Method A: one-time addition of 3-nitropyridine (1 equiv) to the solution of sodium arylamide (4 equiv) in DMSO, rt, 15 min; Method B: gradual addition of 3-
nitropyridine (1 equiv) to a preformed solution of sodium arylamide (2 equiv) in DMSO, rt, 2.5 h.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–K

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I. V. Borovlev et al.
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ly, the formation of both ortho and para σH adducts was ob-
served, but only the ortho isomers of nitrosoanilines were
isolated. According to the data reported by Wróbel and
Kwast,20b para σH adducts can be oxidized to give the corre-
sponding N-aryl-4-nitroanilines. The proposed mechanism
for the synthesis of the nitroso compounds does not in-
volve an external oxidant, which could be an alternative
pathway for the aromatization of σH-adducts. The last step
of the reaction proceeds as an intramolecular Red/Ox-pro-
cess. The plausible mechanism for the formation of the ni-
troso compounds 3 is presented in Scheme 3.
X
ArNH–
1
ArNH– Na+
[ ArN=NAr ]
N
H
DMSO, rt
SN
NH
X
N
5a,b
Ar = Ph, 2-ClC6H4
X
5: X = H (a, 1%), X = Cl (b, 7%)
Scheme 4 Proposed mechanism for the formation of byproducts 5a,b
Although azobenzene can be generated via the aerobic
oxidation of aniline under basic conditions,22 without 3-nit-
ropyridine, no formation of compound 5b was observed.
The structure of the product was established by X-ray crys-
tal structure determination23 (see the Supporting Informa-
tion).
O–
N+
NO2
ArNH–
NO2
O–
~H+
H
H
In contrast to nitro products 2, in the 1H NMR spectra of
nitroso compounds 3 in DMSO-d6, we observed broad pro-
ton signals of the pyridine ring. Additionally, 13C NMR spec-
tra of compounds 3c,d,e,h demonstrated an incomplete set
of signals at room temperature, which can be explained by
the prototropic tautomerism of the nitroso compounds 3a–
h in DMSO-d6 (Scheme 5).
N–
ArNH
N
N
ArNH
1
4
OH
N
N
O
O–
– HO–
ArNH
N
3a–h
ArNH
N
Scheme 3 Proposed mechanism for the synthesis of compounds 3a–h
N
N
N
OH
O
O
i
ii
Thus, the aromatization of σH adducts 4 can proceed ac-
cording to 2 pathways, leading to the products of two com-
petitive reactions with comparable rates. To the best of our
knowledge, the intramolecular disproportionation of σH ad-
ducts with N-nucleophiles has not previously been de-
scribed for 3-nitropyridine. It should be noted, the products
of the condensation of anilines with nitroso compounds
were not detected, and this can be explained by the fact
that the compounds 3 formed inactive anions in the reac-
tion mixture.
To minimize the consumption of 3-nitropyridine as an
oxidant, we performed an additional experiment, where a
diluted solution of 3-nitropyridine (1 equiv) in DMSO was
slowly added (micro drops via a syringe) over 2.5 hours to
the preformed solution of the aniline anion (2 equiv) in
DMSO (Method B). In this experiment, the nitroso product
3a was isolated in 52% yield, whereas the yield of the nitro
compound 2a was 1% (Table 1, cf. entries 1 and 2). Employ-
ing Method B, this tendency was observed for other aryl-
amines as well. Moreover, the yields of nitro compounds
2b–d,h were higher than those for 2a (Table 2, entries 4, 6,
8). Notably, the yield of the sole product 2i of the reaction
with 4-nitroaniline was the same (entry 15). However,
when a sixfold excess of sodium anilide was used, a com-
plex mixture of reaction products was obtained. We were
able to isolate only one side product, namely (E)-N-[4-
(phenyldiazenyl)phenyl]aniline (5a)21 (Scheme 4). The
same reaction with 2-chloroaniline afforded previously un-
known (E)-2-chloro-N-[3-chloro-4-(2-chlorophenyldiaze-
nyl)phenyl]aniline (5b) under the same conditions.
ArN
N
ArNH
3a–h
N
ArN
N
H
Scheme 5 Prototropic tautomerism of nitroso compounds 3 in DMSO-
d6
1
In contrast, in the H NMR spectra of the products 3 at
60 °C, we observed narrow proton signals. Moreover, a
complete set of signals of the pyridine ring was found in the
13C NMR spectra of the compounds 3c,d,e,h at 60 °C. Appar-
ently, the tautomerization rate at room temperature for
these compounds is rather slow on an NMR timescale.
Figure 1 ORTEP diagram of nitro compound 2a
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–K

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I. V. Borovlev et al.
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Synthesis
The structures of the compounds 2a (Figure 1) and 3a
Table 3 Synthesis of N-(5-Nitropyridin-2-yl)arylamines 2 and N-(5-Ni-
tro-1-oxypyridin-2-yl)arylamines 6
(Figure 2) were confirmed by X-ray determination.23
Entry
Starting compound Product
Yielda (%)
1
2
3a
3a
2a
78
40
NO2
Ν+
O–
NH
3
4
2a
3b
41
73
6a
2b
NO2
Ν+
O–
5
6
3b
3c
3c
3d
3d
3e
3e
3f
56
76
44
67
40
80
45
53
39
71
41
78
40
NH
6b
2c
Figure 2 ORTEP diagram of nitroso compound 3a
NO2
MeO
NH Ν+
7
For further studies of these related compounds, we tried
to transform the nitroso derivatives 3a–h into the nitro
products 2a–h. The reaction was performed in dichloro-
methane solution at room temperature, using m-chloroper-
benzoic acid (mCPBA) as an oxidant. The corresponding
nitro compounds 2a–h were obtained in 53–80% yields
(Scheme 6). However, when N-(5-nitrosopyridin-2-yl)aryl-
amines 3a–h were refluxed with an excess of the same oxi-
dant in the 1,2-dichloroethane, the reaction proceeded fur-
ther, leading to new N-(5-nitro-1-oxypyridin-2-yl)aryl-
amines 6a–h in moderate yields (Scheme 6, Table 3).
Obviously, the nitroso group of compounds 3 is more easily
oxidized than the pyridine nitrogen.
O–
6c
8
2d
NO2
F
NH Ν+
9
O–
6d
2e
10
11
12
13
14
15
16
17
NO2
F3C
NH Ν+
O–
6e
2f
NO2
mCPBA (1.5 equiv)
CH2Cl2, rt
NO2
Br
ArNH
N
N
mCPBA
for a
O
2a–h
Ν+
O–
3f
NH
NO2
ArNH
N
3a–h
mCPBA (3 equiv)
6f
ClCH2CH2Cl, reflux
ArNH
N+
6a–h O–
3g
3g
3h
3h
2g
NO2
Br
Scheme 6 Oxidation of nitroso and nitro compounds with m-chloro-
perbenzoic acid
Ν+
O–
NH
Br
Oxidation of nitro compound 2a under same conditions
also gave the corresponding N-oxide 6a (Scheme 6). The
formation of N-oxides 6a–h can take place due to the elec-
tron-donor effect of the substituent at the 2-position of the
pyridine ring. Thus, no reaction was observed using 3-nit-
ropyridine as the starting compound. We also failed to ob-
tain the N-oxide from the nitro compound 2i even using a
large excess of oxidant. The structure of N-oxide 6b was
confirmed by X-ray crystal structure determination23 (see
the Supporting Information).
6g
2h
NO2
Ν+
O–
NH
Cl
6h
a Isolated yields after column chromatography.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–K

F
I. V. Borovlev et al.
Paper
Synthesis
In summary, we have shown that sodium arylamides
can be used as nucleophiles in SNH reactions with 3-nitropy-
ridine, affording new 2-arylamino-5-nitrosopyridines along
with the expected 2-arylamino-5-nitropyridines. Aromati-
zation of σH-adducts, which are formed in the first step of
the reaction, proceeds via two possible pathways. Thus, an
oxidative SNH process, in which both 3-nitropyridine and at-
mospheric oxygen act as oxidants, affords nitro compounds.
Alternatively, an intramolecular Red/Ox process, which is
well-known for VNS reactions, gives the corresponding ni-
troso derivatives. The first example of the synthesis of ni-
troso compounds via attack on the para-position to the ni-
tro group by the arylamide anion is described. Finally, we
have demonstrated that nitroso compounds can be trans-
formed into the corresponding nitro products or their N-ox-
ides, depending on the reaction temperature and the
amount of m-chloroperbenzoic acid. The obtained products
represent versatile precursors for valuable pyridine deriva-
tives.
rt, the solution was acidified with dil HCl to pH ~7. The precipitate
obtained was filtered off, washed with water, and dried. The separa-
tion of nitro 2 and nitroso compounds 3 was performed as indicated
in Method A.
N-(5-Nitropyridin-2-yl)aniline (2a)
Yellow solid; yield: 24 mg (22%, Method A); 1.08 mg (1%, Method B);
mp 138–139 °C (CH2Cl2) (Lit.17 135–136 °C).
IR (thin film): 3235, 3035, 2939, 1582, 1547, 1464, 1328 cm–1
.
1H NMR (400 MHz, DMSO-d6): δ = 10.13 (br s, 1 H, NH), 9.03 (d, J = 2.8
Hz, 1 H, H-6 Py), 8.29 (dd, J = 9.3, 2.8 Hz, 1 H, H-4 Py), 7.70 (d, J = 7.9
Hz, 2 H, H-2′,6′ Ph), 7.36 (br t, J = 7.9 Hz, 2 H, H-3′,5′ Ph), 7.08 (br t, J =
7.4 Hz, 1 H, H-4′ Ph), 6.91 (d, J = 9.3 Hz, 1 H, H-3 Py).
13C NMR (100 MHz, DMSO-d6): δ = 159.0, 146.0, 139.4, 136.1, 132.5,
128.9, 123.2, 120.2, 110.0.
HRMS (DART): m/z [M + H]+ calcd for C11H10N3O2: 216.0768; found:
216.0766.
N-(5-Nitrosopyridin-2-yl)aniline (3a)
Dark green solid; yield: 33 mg (33%, Method A); 51.7 mg (52%, Meth-
od B); mp 167–168 °C (CH2Cl2).
IR (thin film): 3294, 3205, 3042, 1588, 1526 cm–1
.
1H and 13C NMR spectra were recorded on a Bruker Avance HD 400
spectrometer in the solvent indicated relative to residual DMSO sig-
nals24 or TMS as internal standard when CDCl3 was used as solvent.
HRMS were registered on a Bruker UHR-TOF MaxisTM Impact instru-
ment using the DART technique (carrier gas He, 300 °C). IR spectra
were recorded on a Shimadzu IRTracer-100. All melting points were
determined in glass capillaries using REACH Devices RD-MP and Elec-
trothermal IA 9200 instruments and are uncorrected. The identity of
the compounds prepared by various methods was established by
comparison of their IR spectra. The progress of the reactions was
monitored by TLC using Silufol UV-254 silica gel plates; petroleum
ether = PE. m-Chloroperbenzoic acid containing 77% of active ingredi-
ent (abcr GmbH & Co. KG) and NaH as 60% w/w dispersion in mineral
oil was used as such (Merck). Other commercially available chemicals
were used also without additional purification.
1H NMR (400 MHz, DMSO-d6): δ = 10.50 (br s, 1 H, NH), 9.78 (br s, 1 H,
H-6 Py), 7.82 (d, J = 7.9 Hz, 2 H, H-2′,6′ Ph), 7.41 (br t, J = 7.9 Hz, 2 H,
H-3′,5′ Ph), 7.12 (br t, J = 7.4 Hz, 1 H, H-4′ Ph), 7.07 (br s, 1 H, H-4 Py),
6.82 (d, J = 9.2 Hz, 1 H, H-3 Py).
13C NMR (100 MHz, DMSO-d6): δ = 160.9, 159.2, 138.9, 129.0 (2 C),
124.1, 120.9, 111.19, 111.15.
HRMS (DART): m/z [M + H]+ calcd for C11H10N3O: 200.0818; found:
200.0802.
4-Methyl-N-(5-nitropyridin-2-yl)aniline (2b)
Yellow solid; yield: 18 mg (16%, Method A); 12.6 mg (11%, Method B);
mp 140–141 °C (CH2Cl2).
IR (thin film): 3227, 3178, 3030, 2921, 1594, 1581, 1540, 1330 cm–1
.
1H NMR (400 MHz, DMSO-d6): δ = 10.05 (br s, 1 H, NH), 9.01 (d, J = 2.8
Hz, 1 H, H-6 Py), 8.26 (dd, J = 9.3, 2.8 Hz, 1 H, H-4 Py), 7.57 (d, J = 8.3
Hz, 2 H, H-2′,6′ C6H4), 7.17 (d, J = 8.3 Hz, 2 H, H-3′,5′ C6H4), 6.85 (d, J =
9.3 Hz, 1 H, H-3 Py), 2.28 (s, 3 H, CH3).
13C NMR (100 MHz, DMSO-d6): δ = 159.1, 146.1, 136.8, 135.8, 132.4,
129.3 (2 C), 120.4, 109.6, 20.5.
N-(5-Nitropyridin-2-yl)arylamines 2a–i and N-(5-Nitrosopyridin-
2-yl)arylamines 3a–h; General Procedures
Method A: To a solution of the arylamine (2 mmol) in anhyd DMSO (2
μL), NaH (2 mmol) was added at rt. When H2 bubbling ceased, 3-nitro-
pyridine 1 (0.5 mmol) was added. The mixture was stirred vigorously
at rt for 0.25 h. Then it was poured onto well-milled ice (~50 g). Upon
reaching rt, the solution was acidified with dil HCl to pH ~7. The pre-
cipitate obtained was filtered off, washed with water, and dried. The
crude products were separated by column flash chromatography
(silica gel, CH2Cl2/PE 1:1 then CH2Cl2) to give a first yellow fraction
(CH2Cl2/PE 1:1) and then a second yellow-green fraction (CH2Cl2). Af-
ter evaporation of the solvent, the corresponding nitro 2 and nitroso
compounds 3 were obtained from the first and the second fractions,
respectively. In the case of nitro compound 2i, the separation was
performed by elution with CH2Cl2 collecting the second yellow frac-
tion. The products were then purified by recrystallization from an ap-
propriate solvent.
HRMS (DART): m/z [M + H]+ calcd for C12H12N3O2: 230.0924; found:
230.0905.
4-Methyl-N-(5-nitrosopyridin-2-yl)aniline (3b)
Dark green solid; yield: 34 mg (32%, Method A); 47 mg (44%, Method
B); mp 170–171 °C (CH2Cl2).
IR (thin film): 3232, 3023, 2930, 1600, 1571, 1532, 1506 cm–1
.
1H NMR (400 MHz, DMSO-d6): δ = 10.45 (br s, 1 H, NH), 9.75 (br s, 1 H,
H-6 Py), 7.69 (br d, 2 H, H-2′,6′ C6H4), 7.22 (d, J = 8.3 Hz, 2 H, H-3′,5′
C6H4), 7.05 (br s, 1 H, H-4 Py), 6.77 (d, J = 9.3 Hz, 1 H, H-3 Py), 2.31 (s,
3 H, CH3).
13C NMR (100 MHz, DMSO-d6): δ = 165.2, 161.4, 159.6, 136.8, 133.8,
134.0, 130.1, 129.9, 121.5, 21.0.
HRMS (DART): m/z [M + H]+ calcd for C12H12N3O: 214.0975; found:
214.0970.
Method B: To a solution of the arylamine (1 mmol) in anhyd DMSO
(1.5 μL), NaH (1 mmol) was added at rt. When H2 bubbling ceased, the
solution of 3-nitropyridine 1 (0.5 mmol) in DMSO (1.5 μL) was added
gradually by micro drops via a syringe over 2.5 h with vigorous stir-
ring. Then it was poured onto well-milled ice (~50 g). Upon reaching
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–K

G
I. V. Borovlev et al.
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Synthesis
1
4-Methoxy-N-(5-nitropyridin-2-yl)aniline (2c)
13C NMR (100 MHz, DMSO-d6, 60 °C): δ = 159.8 (d, JC,F = 187.7 Hz),
3
4
159.6, 159.1, 157.2, 135.1, 122.8 (d, JC,F = 7.9 Hz), 119.5 (d, JC,F = 2.4
Dark red solid; yield: 16 mg (13%, Method A); 21 mg (17%, Method B);
mp 162–163 °C (CH2Cl2).
IR (thin film): 3230, 3180, 2923, 1598, 1549, 1510, 1328 cm–1
1H NMR (400 MHz, DMSO-d6): δ = 10.00 (br s, 1 H, NH), 8.99 (d, J = 2.8
Hz, 1 H, H-6 Py), 8.24 (dd, J = 9.3, 2.8 Hz, 1 H, H-4 Py), 7.56 (d, J = 8.9
Hz, 2 H, H-3′,5′ C6H4), 6.95 (d, J = 8.9 Hz, 2 H, H-2′,6′ C6H4), 6.79 (d, J =
9.3 Hz, 1 H, H-3 Py), 3.75 (s, 3 H, OCH3).
Hz), 115.2 (d, 2JC,F = 22.3 Hz), 110.6.
HRMS (DART): m/z [M + H]+ calcd for C11H9FN3O: 218.0724; found:
.
218.0726.
N-(5-Nitropyridin-2-yl)-4-(trifluoromethyl)aniline (2e)
Yellow solid; yield: 8.5 mg (6%, Method A); mp 137–138 °C (CH2Cl2).
IR (thin film): 3344, 3231, 3098, 1589, 1552, 1520, 1360 cm–1
.
13C NMR (100 MHz, DMSO-d6): δ = 159.2, 155.6, 146.3, 135.5, 132.4,
1H NMR (400 MHz, DMSO-d6): δ = 10.45 (br s, 1 H, NH), 9.09 (d, J = 2.8
Hz, 1 H, H-6 Py), 8.37 (dd, J = 9.3, 2.8 Hz, 1 H, H-4 Py), 7.96 (d, J = 8.5
Hz, 2 H, H-3′,5′ C6H4), 7.71 (d, J = 8.5 Hz, 2 H, H-2′,6′ C6H4), 7.01 (d, J =
9.3 Hz, 1 H, H-3 Py).
132.2, 122.4, 114.1 (2 C), 55.2.
HRMS (DART): m/z [M + H]+ calcd for С12Н12N3О2: 246.0873; found:
246.0870.
4-Methoxy-N-(5-nitrosopyridin-2-yl)aniline (3c)
13C NMR (100 MHz, DMSO-d6): δ = 158.5, 145.6, 143.3, 137.0, 132.9,
124.5 (q, 1JC,F = 269.7 Hz), 126.1 (q, 3JC,F = 3.8 Hz), 122.5 (q, 2JC,F = 31.8
Hz), 119.3, 111.2.
HRMS (DART): m/z [M + H]+ calcd for C12H9F3N3O2: 284.0641; found:
284.0643.
Black solid; yield: 47 mg (41%, Method A); 34 mg (30%, Method B); mp
158–159 °C (CH2Cl2).
IR (thin film): 3218, 3000, 2825, 1600, 1505 cm–1
.
1H NMR (400 MHz, CDCl3, 20 °C): δ = 9.62 (br s, 1 H, NH), 7.53 (br s, 1
H, H-6 Py), 7.25 (d, J = 8.8 Hz, 2 H, H-3′,5′ C6H4), 7.04–6.97 (m, 1 H, H-
4 Py), 6.91 (d, J = 8.8 Hz, 2 H, H-2′,6′ C6H4), 6.47 (d, J = 9.2 Hz, 1 H, H-3
Py), 3.78 (s, 3 H, OCH3).
1H NMR (400 MHz, DMSO-d6, 60 °C): δ = 10.25 (br s, 1 H, NH), 9.63 (br
s, 1 H, H-6 Py), 7.67 (d, J = 8.9 Hz, 2 H, H-3′,5′ C6H4), 7.08 (dd, J = 8.9,
1.6 Hz, 1 H, H-4 Py), 6.99 (d, J = 8.9 Hz, 2 H, H-2′,6′ C6H4), 6.73 (d, J =
9.3 Hz, 1 H, H-3 Py), 3.79 (s, 3 H, OCH3).
N-(5-Nitrosopyridin-2-yl)-4-(trifluoromethyl)aniline (3e)
Dark green solid; yield: 63 mg (47%, Method A); mp 171–172 °C (CH2-
Cl2).
IR (thin film): 3299, 3184, 3088, 1590, 1516, 1501 cm–1
.
1H NMR (400 MHz, DMSO-d6, 20 °C): δ = 10.75 (br s, 1 H, NH), 9.88 (br
s, 1 H, H-6 Py), 8.10 (d, J = 8.6 Hz, 2 H, H-3′,5′ C6H4), 7.77 (d, J = 8.6 Hz,
2 H, H-2′,6′ C6H4), 7.12 (br d, J = 8.7 Hz, 1 H, H-4 Py), 6.91 (d, J = 9.2 Hz,
1 H, H-3 Py).
13C NMR (100 MHz, DMSO-d6, 60 °C): δ = 160.8, 159.6, 159.1, 156.1,
131.6, 122.8, 119.4, 114.1, 110.1, 55.1.
1H NMR (400 MHz, DMSO-d6, 60 °C): δ = 10.58 (br s, 1 H, NH), 9.77 (d,
J = 2.4 Hz, 1 H, H-6 Py), 8.07 (d, J = 8.6 Hz, 2 H, H-3′,5′ C6H4), 7.73 (d, J =
8.6 Hz, 2 H, H-2′,6′ C6H4), 7.17 (dd, J = 9.2, 2.4 Hz, 1 H, H-4 Py), 6.92 (d,
J = 9.2 Hz, 1 H, H-3 Py).
13C NMR (100 MHz, DMSO-d6, 60 °C): δ = 160.5, 158.6, 157.9, 142.6,
125.8 (q, 3J = 11.3 Hz), 124.2 (q, 1J = 269.6 Hz), 123.2 (q, 2J = 95.7 Hz),
120.0, 119.6, 111.6.
HRMS (DART): m/z [M + H]+ calcd for С12Н12N3О: 230.0924; found:
230.0914.
4-Fluoro-N-(5-nitropyridin-2-yl)aniline (2d)
Orange solid; yield: 14 mg (12%, Method A); 14 mg (12%, Method B);
mp 188–189 °C (CH2Cl2).
IR (thin film): 3351, 3259, 3164, 2925, 1627, 1549, 1508, 1326 cm–1
.
HRMS (DART): m/z [M + H]+ calcd for C12H9F3N3O: 268. 0708; found:
268. 0692.
1H NMR (400 MHz, DMSO-d6): δ = 10.14 (br s, 1 H, NH), 9.02 (d, J = 2.7
Hz, 1 H, H-6 Py), 8.28 (dd, J = 9.3, 2.7 Hz, 1 H, H-4 Py), 7.74–7.68 (m, 2
H, H-3′,5′ C6H4), 7.24–7.18 (m, 2 H, H-2′,6′ C6H4), 6.86 (d, J = 9.3 Hz, 1
H, H-3 Py).
4-Bromo-N-(5-nitropyridin-2-yl)aniline (2f)
Pale brown solid; yield: 29 mg (20%, Method A); mp 148–149 °C (CH2-
Cl2/PE).
1
13C NMR (100 MHz, DMSO-d6): δ = 158.9, 158.1 (d, JC,F = 158.1 Hz),
146.0, 136.1, 135.8, 132.6, 122.1 (d, 3JC,F = 7.8 Hz), 115.5 (d, 2JC,F = 22.2
IR (thin film): 3348, 3219, 3138, 2921, 2850, 1620, 1581, 1536, 1358
Hz), 109.9.
cm–1
.
HRMS (DART): m/z [M + H]+ calcd for C11H9FN3O2: 234.1100; found:
234.1094.
1H NMR (400 MHz, DMSO-d6): δ = 10.22 (br s, 1 H, NH), 9.05 (d, J = 2.7
Hz, 1 H, H-6 Py), 8.31 (dd, J = 9.3, 2.8 Hz, 1 H, H-4 Py), 7.71 (d, J = 8.9
Hz, 2 H, H-3′,5′ C6H4), 7.53 (d, J = 8.9 Hz, 2 H, H-2′,6′ C6H4), 6.92 (d, J =
9.3 Hz, 1 H, H-3 Py).
13C NMR (100 MHz, DMSO-d6): δ = 158.6, 145.8, 138.9, 136.4, 132.6,
131.6, 121.7, 114.5, 110.6.
4-Fluoro-N-(5-nitrosopyridin-2-yl)aniline (3d)
Brown solid; yield: 39 mg (36%, Method A); 57.5 mg (53%, Method B);
mp 201–202 °C (CH2Cl2).
IR (thin film): 3225, 3049, 2923, 2852, 1600, 1502 cm–1
1H NMR (400 MHz, DMSO-d6, 20 °C): δ = 10.53 (br s, 1 H, NH), 9.77 (br
s, 1 H, H-6), 7.87–7.80 (m, 2 H, H-3′,5′ C6H4), 7.30–7.21 (m, 2 H, H-2′,6′
C6H4), 7.10–7.06 (m, 1 H, H-4 Py), 6.78 (d, J = 9.2 Hz, 1 H, H-3 Py).
1H NMR (400 MHz, DMSO-d6, 60 °C): δ = 10.35 (br s, 1 H, NH), 9.68 (d,
J = 2.0 Hz, 1 H, H-6 Py), 7.82 (dd, J = 9.1 Hz, JC,F = 5.0 Hz, 2 H, H-3′,5′
C6H4), 7.23 (d, J = 9.1 Hz, JC,F = 2.3 Hz, 2 H, H-2′,6′ C6H4), 7.12 (dd, J =
9.3, 2.0 Hz, 1 H, H-4 Py), 6.79 (dd, J = 9.3 Hz, JC,F = 0.3 Hz, 1 H, H-3 Py).
.
HRMS (DART): m/z [M + H]+ calcd for C11H979BrN3O2: 293.9873;
found: 293.9873.
4-Bromo-N-(5-nitrosopyridin-2-yl)aniline (3f)
Brown solid; yield: 60 mg (43%, Method A); mp 185–186 °C (CH2Cl2).
IR (thin film): 3297, 3196, 3013, 2925, 2851, 1604, 1581, 1524 cm–1
.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–K

H
I. V. Borovlev et al.
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Synthesis
1H NMR (400 MHz, DMSO-d6): δ = 10.57 (br s, 1 H, NH), 9.81 (br s, 1 H,
H-6 Py), 7.84 (d, J = 8.8 Hz, 2 H, H-3′,5′ C6H4), 7.59 (d, J = 8.8 Hz, 2 H, H-
2′,6′ C6H4), 7.10–7.05 (m, 1 H, H-4 Py), 6.83 (d, J = 9.2 Hz, 1 H, H-3 Py).
13C NMR (100 MHz, DMSO-d6): δ = 160.8, 158.8, 138.4, 131.7, 122.5,
115.5, 111.6.
1H NMR (400 MHz, DMSO-d6, 60 °C): δ = 10.02 (br s, 1 H, NH), 9.59 (br
s, 1 H, H-2 Py), 7.76 (d, J = 8.0 Hz, 1 H, H-3′ C6H4), 7.58 (dd, J = 8.1, 1.2
Hz, 1 H, H-6′ C6H4), 7.43 (ddd, J = 8.0, 7.6, 1.2 Hz, 1 H, H-4′ C6H4), 7.32
(ddd, J = 8.1, 7.6, 1.4 Hz, 1 H, H-5′ C6H4), 7.15 (dd, J = 9.2, 2.0 Hz, 1 H,
H-4 Py), 6.79 (d, J = 9.2 Hz, 1 H, H-3 Py).
13C NMR (100 MHz, DMSO-d6, 60 °C): δ = 161.0, 160.0, 158.3, 135.1,
129.6, 128.7, 127.6, 127.5, 127.2, 120.1, 109.4.
HRMS (DART): m/z [M + H]+ calcd for C11H979BrN3O: 277.9924; found:
277.9928.
HRMS (DART): m/z [M + H]+ calcd for C11H9N3O35Cl: 234.0429; found:
234.0435.
2,4-Dibromo-N-(5-nitropyridin-2-yl)aniline (2g)
Yellow solid; yield: 41 mg (22%, Method A); mp 162–163 °C (CH2-
Cl2/PE).
4-Nitro-N-(5-nitropyridin-2-yl)aniline (2i)
Yellow solid; yield: 74 mg (57%, Method A); 77 mg (59%, Method B);
mp 272–273 °C (EtOH).
IR (thin film): 3356, 3079, 2919, 2854, 1607, 1568, 1528, 1349 cm–1
.
1H NMR (400 MHz, DMSO-d6): δ = 9.75 (br s, 1 H, NH), 8.93 (d, J = 2.8
Hz, 1 H, H-6 Py), 8.32 (dd, J = 9.3, 2.8 Hz, 1 H, H-4 Py), 7.97 (d, J = 1.5
Hz, 1 H, H-3′ C6H3), 7.65–7.58 (m, 2 H, H-5′,6′ C6H3), 6.90 (d, J = 9.3 Hz,
1 H, H-3 Py).
13C NMR (100 MHz, DMSO-d6): δ = 159.6, 145.9, 136.7, 136.6, 134.9,
133.1, 131.3, 129.2; 120.4, 118.3, 109.2.
IR (thin film): 3347, 3237, 3093, 1594, 1577, 1555, 1394, 1315 cm–1
.
1H NMR (400 MHz, DMSO-d6): δ = 10.71 (br s, 1 H, NH), 9.13 (d, J = 2.0
Hz, 1 H, H-6 Py), 8.43 (dd, J = 9.1, 2.0 Hz, 1 H, H-4 Py), 8.24 (d, J = 8.9
Hz, 2 H, H-3′,5′ C6H4), 8.01 (d, J = 8.9 Hz, 2 H, H-2′,6′ C6H4), 7.08 (d, J =
9.1 Hz, 1 H, H-3 Py).
13C NMR (100 MHz, DMSO-d6): δ = 158.0, 146.1, 145.3, 141.3, 137.6,
133.1, 125.1, 118.6, 112.0.
HRMS (DART): m/z [M + H]+ calcd for C11H849Br2N3O2: 371.8978;
found: 371.8974.
HRMS (DART): m/z [M + H]+ calcd for C11H9N4O4: 261.0618; found:
261.0617.
2,4-Dibromo-N-(5-nitrosopyridin-2-yl)aniline (3g)
Green solid; yield: 78 mg (44%, Method A); mp 189–190 °C (CH2Cl2).
Side-Products 5a,b; General Procedure
IR (thin film): 3253, 3156, 3077, 1607, 1515 cm–1
.
To a solution of the aniline or o-chloroaniline (3 mmol) in anhyd
DMSO (1.5 mL), NaH (3 mmol) was added at rt. When H2 bubbling
ceased, a solution of 3-nitropyridine (0.5 mmol) in DMSO (1.5 mL)
was added gradually by micro drops via a syringe over 2.5 h with vig-
orous stirring. Then it was poured onto well-milled ice (~50 g). Upon
reaching rt, the solution was acidified with dilute HCl to pH ~7. The
aqueous solution was extracted with CH2Cl2 (3 × 10 mL) and the sol-
vent was distilled off on a rotary evaporator under reduced pressure.
The dried residue was purified by flash chromatography (silica gel,
CH2Cl2) collecting the first orange fraction.
1H NMR (400 MHz, DMSO-d6): δ = 10.17 (br s, 1 H, NH), 9.66 (br s, 1 H,
H-6 Py), 8.00 (s, 1 H, H-3′ C6H4), 7.68–7.63 (m, 2 H, H-5′,6′ C6H3), 7.11
(br d, J = 7.9 Hz, 1 H, H-4 Py), 6.81 (d, J = 9.2 Hz, 1 H, H-3 Py).
13C NMR (100 MHz, DMSO-d6): δ = 161.2, 159.9, 136.3, 134.9 (2C),
131.3 (2C), 129.9, 120.9, 119.1, 110.0.
HRMS (DART): m/z [M + H]+ calcd for C11H879Br2N3O: 355.9029;
found: 355.9021.
2-Chloro-N-(5-nitropyridin-2-yl)aniline (2h)
Yellow solid; yield: 27 mg (22%, Method A); 9 mg (7%, Method B); mp
130–131 °C (CH2Cl2).
(E)-N-[4-(Phenyldiazenyl)phenyl]aniline (5a)
Orange solid; yield: 3 mg (1%); mp 80–81 °C (PE) (Lit.21 80–81 °C).
HRMS (DART): m/z [M + H]+ calcd for С18Н16N3: 274.1339; found:
274.1350.
IR (thin film): 3404, 3177, 3099, 2937, 1600, 1575, 1530, 1365 cm–1
.
1H NMR (400 MHz, DMSO-d6): δ = 9.78 (br s, 1 H, NH), 8.94 (d, J = 2.8
Hz, 1 H, H-6 Py), 8.31 (dd, J = 9.3, 2.8 Hz, 1 H, H-4 Py), 7.70 (dd, J = 7.8,
1.5 Hz, 1 H, H-3′ C6H4Cl), 7.55 (dd, J = 8.0, 1.3 Hz, 1 H, H-6′ C6H4Cl),
7.39 (ddd, J = 6.7, 8.0, 1.5 Hz, 1 H, H-5′ C6H4Cl), 7.27 (ddd, J = 7.8, 6.7,
1.3 Hz, 1 H, H-4′ C6H4Cl), 6.88 (d, J = 9.3 Hz, 1 H, H-3 Py).
(E)-2-Chloro-N-[3-chloro-4-(2-chlorophenyldiazenyl)phenyl]ani-
line (5b)
Orange solid; yield: 26 mg (7%); mp 142–143 °C (PE).
13C NMR (100 MHz, DMSO-d6): δ = 159.8, 145.9, 136.4, 135.6, 133.0,
IR (thin film): 3404, 3065, 2921, 2854, 1601, 1581, 1512, 1418, 1340
129.9, 128.3, 127.7, 127.3, 126.9, 109.0.
HRMS (DART): m/z [M + H]+ calcd for C11H9N3O235Cl: 250.0378; found:
250.0380.
cm–1
.
1H NMR (400 MHz, DMSO-d6): δ = 8.93 (s, 1 H, NH), 7.73 (d, J = 9.0 Hz,
1 H), 7.68 (dd, J = 7.8, 1.4 Hz, 1 H), 7.63 (dd, J = 7.7, 2.0 Hz, 1 H), 7.58
(dd, J = 8.1, 1.2 Hz, 1 H), 7.53–7.44 (m, 3 H), 7.39 (ddd, J = 8.2, 7.7, 1.3
Hz, 1 H), 7.23 (ddd, J = 8.0, 7.8, 1.4 Hz, 1 H), 7.03 (d, J = 2.3 Hz, 1 H),
6.96 (dd, J = 9.0, 2.4 Hz, 1 H).
13C NMR (100 MHz, DMSO-d6): δ = 149.6, 148.3, 140.4, 137.7, 137.0,
133.4, 131.8, 130.7, 130.5, 128.3, 128.1, 127.7, 126.1, 125.2, 119.0,
117.7, 114.5, 114.0.
2-Chloro-N-(5-nitrosopyridin-2-yl)aniline (3h)
Green solid; yield: 23 mg (20%, Method A); 16.3 mg (14%, Method B);
mp 121–122 °C (CH2Cl2).
IR (thin film): 3242, 3148, 3077, 1601, 1514, 1503 cm–1
1H NMR (400 MHz, CDCl3, 20 °C): δ = 9.81 (br s, 1 H, NH), 8.16 (d, J =
8.1 Hz, 1 H, H-3′ C6H4), 7.63 (br s, 1 H, H-6 Py), 7.49 (dd, J = 8.0, 1.0 Hz,
1 H, H-6′ C6H4), 7.35–7.32 (m, 1 H, H-4′ C6H4), 7.18–7.14 (m, 1 H, H-5′
C6H4), 7.13 (br d, J = 8.4 Hz, 1 H, H-4 Py), 6.68 (d, J = 9.1 Hz, 1 H, H-3
Py).
.
HRMS (DART): m/z [M + H]+ calcd for С18Н13N3Cl3: 376.0170; found:
376.0171.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–K

I
I. V. Borovlev et al.
Paper
Synthesis
N-(5-Nitropyridin-2-yl)arylamines 2a–h from N-(5-Nitrosopyri-
din-2-yl)arylamines 3a–h; General Procedure
4-Methyl-N-(5-nitro-1-oxypyridin-2-yl)aniline (6b)
Pale brown solid; yield: 27 mg (56%); mp 171–172 °C (benzene/PE).
IR (thin film): 3170, 3152, 1624, 1573, 1326, 1271 cm–1
1H NMR (400 MHz, DMSO-d6): δ = 10.25 (br s, 1 H, NH), 9.09 (d, J = 2.4
Hz, 1 H, H-6 Py), 8.00 (dd, J = 9.5, 2.4 Hz, 1 H, H-4 Py), 7.27 (s, 4 H,
C6H4), 7.01 (d, J = 9.5 Hz, 1 H, H-3 Py), 2.33 (s, 3 H, CH3).
A solution of mCPBA (1.5 mmol) and N-(5-nitrosopyridin-2-yl)aryl-
amine 3 (1 mmol) in CH2Cl2 (5 mL) was stirred at rt for 0.5 h. After
evaporation of the solvent, the crude products were separated by col-
umn flash chromatography (silica gel, benzene then benzene/EtOAc)
to give a first colorless fraction (benzene) and then a second yellow
fraction (benzene/EtOAc 5:1). N-(5-Nitropyridin-2-yl)arylamines 2a–
h were obtained from the second fraction.
.
13C NMR (100 MHz, DMSO-d6): δ = 152.5, 135.7, 134.8, 134.2, 134.0,
130.1, 124.1, 123.3, 104.9, 20.6.
HRMS (DART): m/z [M + H]+ calcd for С12Н12N3O3: 246.0873; found:
N-(5-Nitropyridin-2-yl)aniline (2a)
246.0880.
Yield: 168 mg (78%).
4-Methoxy-N-(5-nitro-1-oxypyridin-2-yl)aniline (6c)
4-Methyl-N-(5-nitropyridin-2-yl)aniline (2b)
Orange solid; yield: 23 mg (44%); mp 173–174 °C (benzene/PE).
IR (thin film): 3075, 1618, 1563, 1499, 1328, 1275 cm–1
.
Yield: 167 mg (73%).
1H NMR (400 MHz, DMSO-d6): δ = 10.19 (br s, 1 H, NH), 9.08 (d, J = 2.4
Hz, 1 H, H-6 Py), 7.99 (dd, J = 9.6, 2.4 Hz, 1 H, H-4 Py), 7.31 (dd, J = 8.9,
3.3 Hz, 2 H, H-2′,6′ C6H4), 7.03 (dd, J = 8.9, 3.3 Hz, 2 H, H-3′,5′ C6H4),
6.89 (d, J = 9.6 Hz, 1 H, H-3 Py), 3.78 (s, 3 H, CH3).
4-Methoxy-N-(5-nitropyridin-2-yl)aniline (2c)
Yield: 186 mg (76%).
13C NMR (100 MHz, DMSO-d6): δ = 157.7, 152.9, 134.6, 133.9, 129.4,
4-Fluoro-N-(5-nitropyridin-2-yl)aniline (2d)
126.1, 123.3, 114.8, 104.7, 55.4.
Yield: 156 mg (67%).
HRMS (DART): m/z [M + H]+ calcd for С12Н12N3O4: 262.0822; found:
N-(5-Nitropyridin-2-yl)-4-(trifluoromethyl)aniline (2e)
262.0820.
Yield: 226 mg (80%).
4-Fluoro-N-(5-nitro-1-oxypyridin-2-yl)aniline (6d)
4-Bromo-N-(5-nitropyridin-2-yl)aniline (2f)
Brown solid; yield: 20 mg (40%); mp 251–252 °C (benzene/PE).
IR (thin film): 3190, 3131, 1631, 1580, 1500, 1330, 1274 cm–1
.
Yield: 155 mg (53%).
1H NMR (400 MHz, DMSO-d6): δ = 10.32 (br s, 1 H, NH), 9.11 (d, J = 2.4
Hz, 1 H, H-6 Py), 8.01 (dd, J = 9.5, 2.4 Hz, 1 H, H-4 Py), 7.47–7.41 (m, 2
H, H-3′,5′ C6H4), 7.35–7.28 (m, 2 H, H-2′,6′ C6H4), 7.00 (d, J = 9.5 Hz, 1
H, H-3 Py).
2,4-Dibromo-N-(5-nitropyridin-2-yl)aniline (2g)
Yield: 263 mg (71%).
1
13C NMR (100 MHz, DMSO-d6): δ = 160.1 (d, JC,F = 241.8 Hz), 152.6,
2-Chloro-N-(5-nitropyridin-2-yl)aniline (2h)
135.1, 134.0, 133.2, 126.3 (d, 3JC,F = 8.6 Hz), 123.3, 116.4 (d, 2JC,F = 22.6
Yield: 194 mg (78%).
Hz), 105.0.
N-(5-Nitro-1-oxypyridin-2-yl)arylamines 6a–h; General Procedure
HRMS (DART): m/z [M + H]+ calcd for С11Н9FN3O3: 250.0622; found:
250.0630.
A solution of mCPBA (0.6 mmol) and N-(5-nitrosopyridin-2-yl)aryl-
amine 3 (0.2 mmol) or nitro compound 2a (0.2 mmol) in 1,2-dichlo-
roethane (10 mL) was refluxed for 1 h. After evaporation of the sol-
vent, the crude products were separated by column flash chromatog-
raphy (silica gel, benzene then benzene/EtOAc) to give a first maize
yellow fraction (benzene), and then a second yellow fraction (ben-
zene/EtOAc, 10:1). N-(5-Nitro-1-oxypyridin-2-yl)arylamines 6a–h
were obtained from the second fraction.
N-(5-Nitro-1-oxypyridin-2-yl)-4-(trifluoromethyl)aniline (6e)
Yellow solid; yield: 27 mg (45%); mp 187–188 °C (benzene/PE).
IR (thin film): 3075, 1614, 1569, 1508, 1320, 1275 cm–1
1H NMR (400 MHz, DMSO-d6): δ = 10.57 (br s, 1 H, NH), 9.15 (d, J = 2.3
Hz, 1 H, H-6 Py), 8.04 (dd, J = 9.5, 2.3 Hz, 1 H, H-4 Py), 7.81 (d, J = 8.4
Hz, 2 H, H-3′,5′ C6H4), 7.64 (d, J = 8.4 Hz, 2 H, H-2′,6′ C6H4), 7.34 (d, J =
9.5 Hz, 1 H, H-3 Py).
.
N-(5-Nitro-1-oxypyridin-2-yl)aniline (6a)
13C NMR (100 MHz, DMSO-d6): δ = 151.6, 141.8, 136.1, 134.2, 126.6
Pale brown solid; yield: 18.5 mg (40% from 3a), 19 mg (41%, 2a); mp
176–177 °C (benzene/PE).
3
1
2
(q, JC,F = 3.7 Hz), 124.2 (q, JC,F = 270.1 Hz), 125.5 (q, JC,F = 31.9 Hz),
123.4, 123.0, 106.2.
HRMS (DART): m/z [M + H]+ calcd for С12Н9F3N3О3: 300.0591; found:
300.0591.
IR (thin film): 3074, 1624, 1564, 1499, 1329, 1274 cm–1
.
1H NMR (400 MHz, DMSO-d6): δ = 10.33 (br s, 1 H, NH), 9.11 (d, J = 2.4
Hz, 1 H, H-6 Py), 8.02 (dd, J = 9.5, 2.4 Hz, 1 H, H-4 Py), 7.47 (dd, J = 7.4,
7.3 Hz, 2 H, H-3′,5′ Ph), 7.41 (d, J = 7.4 Hz, 2 H, H-2′,6′ Ph), 7.29 (t, J =
7.3 Hz, 1 H, H-4′ Ph), 7.09 (d, J = 9.5 Hz, 1 H, H-3 Py).
13C NMR (100 MHz, DMSO-d6): δ = 152.3, 136.9, 135.1, 134.0, 129.6,
126.1, 124.0, 123.3, 105.1.
4-Bromo-N-(5-nitro-1-oxypyridin-2-yl)aniline (6f)
Pale brown solid; yield: 24 mg (39%); mp 211–212 °C (benzene/PE).
IR (thin film): 3071, 1619, 1563, 1327, 1274 cm–1
.
HRMS (DART): m/z [M + H]+ calcd for С11Н10N3O3: 232.0717; found:
232.0737.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–K

J
I. V. Borovlev et al.
Paper
Synthesis
1H NMR (400 MHz, DMSO-d6): δ = 10.37 (br s, 1 H, NH), 9.12 (d, J = 2.4
Hz, 1 H, H-6 Py), 8.01 (dd, J = 9.5, 2.4 Hz, 1 H, H-4 Py), 7.64 (d, J = 8.6
Hz, 2 H, H-2′,6′ C6H4), 7.38 (d, J = 8.6 Hz, 2 H, H-3′,5′ C6H4), 7.14 (d, J =
9.5 Hz, 1 H, H-3 Py).
Chemistry and Technology of Aromatic Compounds); Khimia:
Moscow, 1992.
(3) de Meijere, A.; Diederich, F. Metal-Catalyzed Cross-Coupling
Reactions; Wiley-VCH: Weinheim, 2004, 2nd ed..
(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) Xu, J.; Wei, Z.; Li, J. Chin. J.
Org. Chem. 2012, 32, 1208.
13C NMR (100 MHz, DMSO-d6): δ = 152.0, 136.5, 135.4, 134.0, 132.4,
125.9, 123.2, 118.2, 105.5.
HRMS (DART): m/z [M + H]+ calcd for С11Н979BrN3O3: 309.9813;
found: 309.9823.
2,4-Dibromo-N-(5-nitro-1-oxypyridin-2-yl)aniline (6g)
Yellow solid; yield: 32 mg (41%); mp 208–209 °C (benzene/PE).
(5) (a) Tsang, W. C. P.; Zheng, N.; Buchwald, S. L. J. Am. Chem. Soc.
2005, 127, 14560. (b) Kim, J. Y.; Cho, S. H.; Joseph, J.; Chang, S.
Angew. Chem. Int. Ed. 2010, 49, 9899. (c) Kim, J. Y.; Park, S. H.;
Ryu, J.; Cho, S. H.; Kim, S. H.; Chang, S. J. Am. Chem. Soc. 2012,
134, 9110. (d) Kim, J.; Kim, S. H.; Chang, S. Chem. Eur. J. 2013, 19,
7328. (e) Ryu, J.; Shin, K.; Park, S. H.; Kim, J. Y.; Chang, S. Angew.
Chem. Int. Ed. 2012, 51, 9904.
(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) Chupakhin, O. N.; Charushin, V. N.; van der Plas, H. C. Nucleop-
hilic Aromatic Substitution of Hydrogen; Academic Press: San
Diego, 1994.
(8) (a) Mąkosza, M.; Wojciechowski, K. Top. Heterocycl. Chem. 2014,
37, 51. (b) Mąkosza, M.; Białecki, M. J. Org. Chem. 1998, 63, 4878.
(c) Mąkosza, M. Chem. Soc. Rev. 2010, 39, 2855. (d) Mąkosza, M.;
Wojciechowski, K. Chem. Rev. 2004, 104, 2631. (e) Chupakhin, O.
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IR (thin film): 3076, 1621, 1565, 1329, 1274 cm–1
.
1H NMR (400 MHz, DMSO-d6): δ = 10.17 (br s, 1 H, NH), 9.13 (d, J = 2.4
Hz, 1 H, H-6 Py), 8.09 (d, J = 2.1 Hz, 1 H, H-3′ C6H3), 8.00 (dd, J = 9.4,
2.4 Hz, 1 H, H-4 Py), 7.72 (dd, J = 8.5, 2.1 Hz, 1 H, H-5′ C6H3), 7.47 (d,
J = 8.5 Hz, 1 H, H-6′ C6H3), 6.68 (d, J = 9.4 Hz, 1 H, H-3 Py).
13C NMR (100 MHz, DMSO-d6): δ = 152.0, 135.7, 135.6, 135.1, 134.0,
132.2, 130.0, 123.1, 122.2, 120.6, 105.8.
HRMS (DART): m/z [M + H]+ calcd for С11Н879Br2N3O3: 387.8927;
found: 387.8932.
2-Chloro-N-(5-nitro-1-oxypyridin-2-yl)aniline (6h)
Pale brown solid; yield: 21 mg (40%); mp 162–163 °C (benzene/PE).
IR (thin film): 3085, 1619, 1566, 1329, 1267 cm–1
.
1H NMR (400 MHz, DMSO-d6): δ = 10.21 (br s, 1 H, NH), 9.13 (d, J = 2.4
Hz, 1 H, H-6 Py), 8.02 (dd, J = 9.4, 2.4 Hz, 1 H, H-4 Py), 7.68 (dd, J = 7.8,
1.2 Hz, 1 H, H-3′ C6H4Cl), 7.54 (dd, J = 7.7, 1.7 Hz, 1 H, H-6′ C6H4Cl),
7.49 (dd, J = 7.5, 7.8 Hz, 1 H, H-4′ C6H4Cl), 7.42 (dd, J = 7.7, 7.5 Hz, 1 H,
H-5′ C6H4Cl), 6.64 (d, J = 9.4 Hz, 1 H, H-3 Py).
13C NMR (100 MHz, DMSO-d6): δ = 152.2, 135.5, 134.0, 133.9, 130.5,
130.0, 128.9, 128.7, 128.3, 123.2, 105.5.
HRMS (DART): m/z [M + H]+ calcd for С11Н935ClN3О3: 266.0327; found:
266.0327.
(9) (a) van der Plas, H. C. Adv. Heterocycl. Chem. 2004, 86, 1.
(b) Charushin, V. N.; Chupakhin, O. N. Top. Heterocycl. Chem.
2014, 37, 1. (c) Gulevskaya, A. V.; Pozharskii, A. F. Top. Hetero-
cycl. Chem. 2014, 37, 179. (d) Mattijs, B.; Maes, B. U. W. Adv.
Organomet. Chem. 2017, 67, 401.
(10) Wozniak, M.; Baranski, A.; Szpakiewicz, B. Liebigs Ann. Chem.
1991, 875.
(11) (a) Bakke, J. M.; Svensen, H. Tetrahedron Lett. 2001, 42, 4393.
(b) Bakke, J. M. J. Heterocycl. Chem. 2005, 42, 463.
Funding Information
This project received financial support from the Ministry of Education
and Science of the Russian Federation in the framework of the State
Assignment to the Higher Education Institutions № 4.6306.2017/8.9.
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(12) (a) Szpakiewicz, B.; Wozniak, M. J. Prakt. Chem. 1999, 341, 75.
(b) Gulevskaya, A. V.; Maes, B. U. W.; Meyers, C.; Herrebout, W.;
van der Veken, B. J. Eur. J. Org. Chem. 2006, 5305. (c) Verbeeck,
S.; Herrebout, W. A.; Gulevskaya, A. V.; van der Veken, B. J.;
Maes, B. U. W. J. Org. Chem. 2010, 75, 5126.
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5039.
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1610173.
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–K