Reactions of 3-R-5-nitropyridines with nucleophiles: Nucleophilic substitution vs conjugate addition

Article abstract of DOI:10.1016/j.tet.2019.130659

A number of 3-R-5-nitropyridines were synthesized and their reactions with various types of nucleophiles were investigated. The reaction outcome depends on the nature of a nucleophile: in case of anionic O-, N- and S-nucleophiles the previously unreported substitution of non-activated nitro group occurred while carbon nucleophiles underwent dearomatization of the pyridine ring with the formation of products of 1,2- and 1,4-addition.

Full text of DOI:10.1016/j.tet.2019.130659

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Reactions of 3-R-5-nitropyridines with nucleophiles: Nucleophilic substitution vs
conjugate addition
Maxim A. Bastrakov, Vladislav V. Nikol'skiy, Alexey M. Starosotnikov, Ivan V.
Fedyanin, Svyatoslav A. Shevelev, Daniil A. Knyazev
PII:
S0040-4020(19)31028-2
https://doi.org/10.1016/j.tet.2019.130659
TET 130659
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 4 August 2019
Revised Date: 24 September 2019
Accepted Date: 27 September 2019
Please cite this article as: Bastrakov MA, Nikol'skiy VV, Starosotnikov AM, Fedyanin IV, Shevelev SA,
Knyazev DA, Reactions of 3-R-5-nitropyridines with nucleophiles: Nucleophilic substitution vs conjugate
addition, Tetrahedron (2019), doi: https://doi.org/10.1016/j.tet.2019.130659.
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Graphical Abstract

Reactions of 3-R-5-nitropyridines with nucleophiles: nucleophilic
substitution vs conjugate addition.
1
*
1,2
1
3
Maxim A. Bastrakov , Vladislav V. Nikol’skiy , Alexey M. Starosotnikov , Ivan V. Fedyanin ,
1
1
Svyatoslav A. Shevelev , Daniil A. Knyazev
1
N.D. Zelinsky Institute of Organic Chemistry RAS; Leninsky prosp. 47, 119991 Moscow, Russia
Chemistry Department Lomonosov Moscow State University, 119991, Moscow, Leniskie gory, 1/3
A.N. Nesmeyanov Institute of Organoelement Compounds, Vavilova str. 28, Moscow 119991, Russia
2
3
E-mail: b_max82@mail.ru
Abstract:
A number of 3-R-5-nitropyridines were synthesized and their reactions with various types of
nucleophiles were investigated. The reaction outcome depends on the nature of a nucleophile: in case
of anionic O-, N- and S-nucleophiles the previously unreported substitution of non-activated nitro
group occurred while carbon nucleophiles underwent dearomatization of the pyridine ring with the
formation of products of 1,2- and 1,4-addition.
Keywords: nitro group, nitropyridines, nucleophilic substitution, dihydropyridines, oxidative
nucleophilic substitution, nucleophilic addition.
Introduction
Nitropyridines represent an important class of organic compounds that are used in the synthesis
of biologically active compounds [1] possessing antitumor [2,3] or anti-HIV activity [4-6]. Other
applications of nitropyridines include herbicides [7], pesticides [8], energetic compounds [9] and
highly efficient organic optical materials [10]. Due to numerous useful properties, there is a challenge
to develop methods for the synthesis of new functionalized nitropyridine derivatives. At the same time
the number of general approaches for the functionalization of nitropyridines is quite limited. For
example, nucleophilic aromatic substitution is one of the most popular ways to functionalize nitro
(het)arenes [11-15]. The nitro group is considered as one of the best activating groups as well as good
leaving group which can be replaced under the action of nucleophiles of different nature. However,
nucleophilic substitution of non-activated nitro groups is rare and described mostly in
polynitrobenzene series [16-20]. For nitropyridines containing non-activated nitro groups, such
reactions have not been studied before. Only one example of the substitution of a nitro group in 3,5-
dinitropyridine is known so far [21].
1

This work is a part of our ongoing research on the chemistry of nitropyridines. Earlier, we have
developed efficient methods for the annulations of different heterocyclic rings to nitropyridine core. As
a result, a number of new derivatives of decahydrodipyrrolo[3,4-b:3',4'-d]pyridine [22-23], pyrido[3,2-
b][1,4]benzoxazine [24], 1,4-dihydropyridine fused with furoxan or selenadiazole [25-26] and
[
1,2,4]triazolo[1,5-a]pyridine [27] were synthesized. Herein we report on reactions of 3-R-5-
nitropyridines with nucleophilic reagents.
Results and discussion.
The starting substituted 5-nitropyridines were synthesized according to the scheme 1. The
chlorine atom in commercially available compounds 1a-d is readily substituted under the action of
hydrazine hydrate. Next, pyridines 2 were oxidized in the presence of silver nitrate to give target 3-R-
5-nitropyridines in good yields.
Scheme 1. Synthesis of 3-R-5-nitropyridines 3a-d
3
,5-Dinitropyridine 3a was selected as a model compound to study the reactions with number
of anionic nucleophiles. Interaction of 3a with equimolar amounts of the corresponding alkanethiols in
the presence of K CO resulted in substitution of one of the nitro groups to give 3-alkylthio-5-
2
3
nitropyridines 4a-d, scheme 2, table 1 (entries 1-4). Using the excess of nucleophilic reagent at the
same temperature or under more drastic conditions did not affect the reaction outcome: the substitution
of the second nitro group was not observed. Similarly, reactions of 3a with NaN in DMF at 100°C or
3
MeONa in boiling MeOH led to the products of displacement of the nitro group 4e and 4f respectively
(table 1, entries 5 and 6). We have also found that the nitro group in compound 3a can be replaced
under the action of acetophenone oxime salt giving rise to pyridine 4g, table 1, entry 7. Interestingly,
when 2-aminothiophenol was taken as a nucleophilic reagent, the substitution product underwent in
situ cyclization, apparently, via oxidative nucleophilic substitution of hydrogen in position 2.
Compound 4h showed spectral characteristics similar to those described previously [13].
2

Scheme 2. Nucleophilic substitution of non-activated nitro group in 3,5-dinitropyridine
Table 1. Reaction conditions and isolated yields of compounds 4a-h
Entry
Nu
Reaction conditions
Product
Yield, %
34
o
1
BnS
K CO , N-MP, 50 C, 4h
2
3
4a
o
2
K CO , N-MP, 50 C, 4h
36
2
3
4b
O N
S
2
o
3
4
cyclo-C H S
K CO , N-MP, 50 C, 4h
59
48
6
11
2
3
N
4c
o
i-BuS
K CO , N-MP, 50 C, 4h
2 3
4d
o
MeONa, MeOH, 65 C,
5
6
MeO
N3
30
48
24h
4
f
e
o
DMF, 100 C, 3h
4
o
7
8
NaH, DMF, 20 C, 24h
67
85
4g
o
K CO , N-MP, 50 C, 4h
2
3
4h
3

It is known that the nitro group in 1,3,5-trinitrobenzene (TNB) is readily substituted under the
action of various S-, N-, O-nucleophiles in aprotic dipolar solvents (N-MP, DMF) at 50-100°C [22-
2
6]. Compounds 4a-h were obtained in moderate to good yields under almost similar conditions.
However, evaluation of the reaction temperature resulted in considerable tarring. These results indicate
that the nitrogen atom of the pyridine ring has an activating effect close to that of NO2.
Our attempts to substitute the nitro group in 3a with OPh group failed. Application of standard
conditions (PhOH, K CO , N-MP, 50-100°C) led solely to significant resinification; formation of
2
3
compound 5 was not observed. Surprisingly, reaction with phenol in the presence of sodium hydride in
DMF or DMSO gave the dearomatization product 6, scheme 3.
Scheme 3. Interaction of 3,5-dinitropyridine 3a with phenol.
In this case the reaction pattern changed apparently due to ambidency of phenoxide ion: it can
act either as an oxygen or as a carbon nucleophile. The interaction of TNB with phenoxide ion was
studied using NMR monitoring of the reaction mixture [28,29]. It was found that anionic adduct 7a
was initially formed, which then gradually converted to thermodynamically more stable complex 7b.
In addition, the authors noted that on acidifying of solutions of 7a, TNB was recovered. Unlike 7a,
acidification of complex 7b did not lead to its destruction.
Scheme 4. Ambidency of phenoxide ion in reaction with TNB
4

It should be noted that nucleophilic dearomatization of the pyridine nucleus usually requires
activation to proceed since pyridine itself is not electrophilic enough. The quaternization of nitrogen
atom is generally employed to prepare pyridinium salts that display enhanced electrophilic character
[
30,31]. At the same time the direct dearomatization of pyridines is a significant challenge in modern
organic chemistry. Direct addition of phenol to pyridine ring is the first example of such process in the
case of nitropyridine derivatives.
The structure of compound 6 was confirmed by spectral methods, as well as X-ray diffraction
data. The molecule 6 crystallizes with a solvate water molecule (Fig 1).
Fig. 1. General view of 6 and solvate water molecule in the crystal. Anisotropic displacement
parameters are drawn at the 50% probability level.
Some other π-excessive aromatics such as substituted phenols or indoles react with 3a similarly
giving rise to 2-substituted 1,2-dihydropyridines 8a-d, scheme 5. However in case of 2,4-
dimethylphenol, the addition product 8d could not be isolated due to its spontaneous oxidative
rearomatization to give compound 9:
5

Scheme 5. Reaction of 3,5-dinitropyridine 3a with substituted phenols and indoles.
Another interesting result was obtained using methyl ketones as C-nucleophiles which react
smoothly with 3,5-dinitropyridine 3a in the presence of DBU leading to the mixtures of 1,4- and 1,2-
adducts, scheme 6, table 2. 1,4-Dihydropyridines 10a-g were found to be the major products in all
cases, while 1,2-adducts 11 in some cases were formed in trace amounts and could be detected only by
NMR of the reaction mixture, table 2. The ratio of isomers 10 and 11 (determined by NMR of crude
products) is correlated to some extent with pKa of the corresponding ketone [32]. However, the
reasons of such selectivity require additional study.
Scheme 6. Reaction of 3,5-dinitropyridine 3a with methyl ketones
Table 2. Yields and isomer ratio of compounds 10a-h, 11a-h
R
Products
Yield of the Isomer ratio Isolated
minor
pKa
mixture (%) 10:11*
yield of
major
isomer
50
isomer
(DMSO)
Me
10a+11a
10b+11b
62
85
5.9
5.0
-
26.5
-
cyclopropyl
69
12
6

t-Bu
Ph
10c+11c
10d+11d
10e+11e
10f+11f
10g+10g
65
88
69
83
71
4.7
3.6
3.6
3.3
2.1
52
67
52
62
47
-
27.7
24.7
25.7
25.2
23.2
17
13
17
21
4
4
2
*
-MeO-C H4
6
-Me-C H4
6
-Cl-C H4
6
determined by NMR spectroscopy
The structures of adducts 10 and 11 were established on the basis of NMR spectroscopy, and
for compound 10e it was also confirmed by X-Ray data. (Fig. 2).
Fig. 2 General view of one of crystallographically independent molecules in the crystal of 10e. Anisotropic
displacement parameters are drawn at the 50% probability level.
The above mentioned functionalization methods of the pyridine ring were extended to 3-R-5-
nitropyridines 3b-d. These compounds were found to undergo nucleophilic substitution of the nitro
group with BnSH to form sulfides 12b-d in moderate yields. In case of compounds 3b,c the reactions
also proceeded selectively and the substitution of halogen was not observed, scheme 7. On the other
hand, compounds 3b-d as well as 3-nitropyridine 3e reacted with 2,6-disubstituted phenols leading to
2-aryl-5-nitropyridines 13a-e, scheme 7. Interestingly, in some cases oxidative re-aromatization under
the action of air oxygen occurred (compounds 13a-c), while compounds 13d,e were proved to be 1,2-
dihydropyridines.
7

Scheme 7. Reactions of 3-R-5-nitropyridines 3b-d with nucleophiles.
Conclusion
In conclusion, reactions of 3-R-5-nitropyridines with variety of anionic nucleophiles were
studied. Direction of the process was found to be dependent on the nature of certain nucleophile. In
case of O-, N- and S-nucleophiles the substitution of non-activated nitro group takes place. Such
reactivity resembles that of polynitroarenes with meta-positioned nitro groups. At the same time
ambident nucleophiles (phenoxide ions, indoles, ketone enolates) gave products of nucleophilic 1,2- or
1,4-addition to the pyridine ring. On this basis a number of novel or hardly accessible pyridines and
their dihydro derivatives were synthesized. The crystal structure of adducts was studied.
Functionalization methods of nitropyridines developed in this work can be applied to the synthesis of
wide range of polyfunctionalized pyridines and related compounds.
Experimental section
All chemicals were of commercial grade and used directly without purification. Melting points
were measured on a Stuart SMP 20 apparatus. 1H and 13C NMR spectra were recorded on Bruker AC-
8

2
00 (at 200 and 50 MHz, respectively), Bruker AM-300 (at 300.13 and 75.13 MHz, respectively),
Bruker Avance DRX 500 (at 500 and 125 MHz, respectively) or Bruker Avance II 600 spectrometer
at 600 and 150 MHz, respectively) in DMSO-d6 or CDCl with TMS as internal standard. IR spectra
(
3
were recorded on BrukerAlpha spectrometer, and the samples were prepared as KBr pellets. HRMS
spectra were recorded on a Bruker micrOTOF II mass spectrometer using ESI. All reactions were
monitored by TLC analysis using ALUGRAM SIL G/UV254 plates, which were visualized by UV
light. Compounds 1a-d were purchased from commercial suppliers. Data collection for all samples
was performed on a Bruker APEX DUO diffractometer equipped with CCD detector (graphite-
monochromated MoKα radiation with λ = 0.71073 Å or CuKα radiation with λ =1.54178 Å). A
semiempirical absorption correction was applied with the SADABS [33] program using the intensity
data of the equivalent reflections. The structures were solved with dual-space approach with SHELXT
2
program [34] and refined by the full-matrix least-squares technique against F hkl in anisotropic
approximation with SHELXL program [35] software package. Hydrogen atoms connected to N and O
atoms were found from difference Fourier synthesis and refined isotropically. Other hydrogen atoms
were placed in calculated positions and refined in a riding model with U (H ) = 1.5U (C ) for
iso
m
eq
m
methyl groups and U (H) = 1.2U (C) for all other hydrogen atoms. Detailed crystallographic
iso
eq
information is provided in Table 3. Structures were deposited to Cambridge Structural Database,
CCDC 1919417-1919420 and 1938068-1938069 contain the supplementary crystallographic data for
this paper. These data can be obtained free of charge via https://www.ccdc.cam.ac.uk/structures.
9

General procedure for the synthesis of compounds 2a-d. A solution of an appropriate 2-
chloropyridine (5 mmol) in methanol (15 mL) was added dropwise to a pre-cooled solution of
hydrazine hydrate (2.42 mL, 50 mmol, 10 eq.) in methanol (10 mL).( 2d was added in small portions
as a suspension due to low solubility). The reaction mixture was stirred at room temperature for 1-2 h
until the starting compound was completely consumed (TLC). The precipitate was filtered off, washed
with water and dried on air.
2-Hydrazino-3,5-dinitropyridine (2a)
о
o
1
Violet solid; yield 75%; m.p. 177 С (lit. 173 C)[36]; H NMR (300 MHz, DMSO-d6): δ= 9.19 (s, 1H),
8.88 (s, 1H), 7.38 ( br.s, 3H).
5-Chloro-2-hydrazino-3-nitropyridine (2b)
o
o
1
Orange solid; yield 78%; m.p. 136-137 C (lit. 134-135 C)[37]; H NMR (300 MHz, DMSO-d6): δ=
9.46 (br. s, 1H), 8.56 (s, 1H), 8.45 (s, 1H), 4.90 (s, 2H).
5-Bromo-2-hydrazino-3-nitropyridine (2c)
1
Red solid; yield 89%; m.p. 151 °С; H NMR (300 MHz, DMSO-d6): δ= 9.39 (br. s, 1H), 8.60 (s, 1H),
8.52 (s, 1H), 4.90 (s, 2H).
Methyl 6-hydrazino-5-nitronicotinate (2d)
o
o
1
Red solid; yield 84%; m.p. 167 C (lit. 169-170 C)[37]; H NMR (300 MHz, DMSO-d6): δ= 10.12
(br.s, 1H), 8.88 (s, 1H), 8.68 (s, 1H), 5.26 (s, 2H), 3.84 (s, 3H).
General procedure for the synthesis of compounds 3a-d. An appropriate 2-hydrazinopyridine (10
mmol) was added to a solution of silver nitrate (5.1 g, 30 mmol) in distilled water (100 mL). The
suspension was heated to 80°C with vigorous stirring to prevent excessive foaming. After the
evolution of nitrogen ceased, the reaction mixture was heated additionally for 1-2 hours until the
starting compound was completely consumed (TLC). A precipitate of metallic silver was filtered off
and washed with chloroform. The filtrate was extracted with chloroform, combined extracts were
washed with brine, dried over anhydrous Na SO and evaporated. Traces of colored impurities, if
2
4
present, can be removed from chloroform solution by shaking with activated charcoal.
,5-Dinitropyridine (3a)
Pale yellow solid; Yield 70%; m.p. 108-109 C (lit.106 C) [37]; H NMR (300 MHz, DMSO):
δ= 9.73(s, 2H), 9.13 (s, 1H).
3
o
o
1
3-Chloro-5-nitropyridine (3b)
o
1
White fluffy crystals; yield 62%; m.p. 88-89 C (lit.88) [37]; H NMR (300 MHz, CDCl ): δ=
3
1
3
9
1
3
.36 (s, 1H), 8.91 (s, 1H), 8.51 (s, 1H); C NMR (75.47 MHz, DMSO): δ= 154.2, 145.0, 143.4, 131.9,
31.8.
-Bromo-5-nitropyridine (3c)
1
0

o
1
Off-white solid; yield 84%; m.p. 113-114 °С (lit. 110 C) [38]; H NMR (300 MHz, CDCl ): δ=
3
1
3
9
.38 (s, 1H), 9.00 (s, 1H), 8.65 (s, 1H); C NMR (150 MHz, CDCl ): δ= 156.8, 145.1, 143.8, 134.4,
3
1
21.3. HRMS (ESI): m/z calcd for C H BrN O [M+H]: 202.9451 ; found: 202.9448.
5
3
2
2
Methyl 5-nitronicotinate (3d)
o
1
Yellow solid; Yield 51%; m.p. 88 °С (lit 87 C) [39]; H NMR (300 MHz, CDCl ): δ= 9.60 (s,
3
1H), 9.50 (s, 1H), 9.05 (s, 1H), 4.05 (s, 3H).
General procedure for the synthesis of compounds 4a-c, 12b-d. To a solution of appropriate 3-
nitropyridine (1 mmol) in DMF or NMP (5 mL) was added an appropriate thiol (1.5 mmol), K CO3
2
(0.138 g, 1 mmol) and the reaction mixture was stirred at 70°C until the starting compound was
completely consumed (TLC), then poured into water, acidified to pH 2~3 with concentrated
hydrochloric acid and extracted with chloroform. Organic phase was washed several times with water,
dried over anhydrous Na SO and evaporated. The residue was purified by flash-chromatography on
2
4
silica gel with chloroform as eluent.
-(Benzylthio)-5-nitropyridine (4a)
Beige solid; yield 34%; m.p. 72-73 °C; H NMR (200 MHz, DMSO-d6): δ= 9.12 (s, 1H) 8.87
3
1
1
3
(
s, 1H), 8.48 (s, 1H), 7.42-7.25 (m, 5H), 4.47 (s, 2H); C NMR (75 MHz, DMSO-d6): δ= 153.5,
1
42.3, 136.3, 135.3, 129.9, 129.3, 128.9, 128.6, 127.4, 35.9. HRMS (ESI): m/z calcd for C H N O S
12
10
2
2
[
M+H]: 247.0536; found: 247.0532.
3-[(2-Furylmethyl)thio]-5-nitropyridine (4b)
1
Brown crystals; yield 36%; m.p. 70-71 °C; H NMR (300 MHz, DMSO-d6): δ= 9.17 (s, 1H),
1
3
8
.91 (s, 1H), 8.55 (s, 1H), 7.61 (s, 1H), 6.38 (s, 1H), 6.33 (s, 2H), 4.55 (s, 2H); C NMR (75 MHz,
DMSO-d6): δ= 154.0, 149.6, 144.2, 143.1, 141.6, 134.5, 130.5, 110.7, 108.9, 28.7. (ESI): m/z calcd for
C H N O S [M+H]: 237.0328; found: 237.0328.
10
8
2
3
3-(Cyclohexylthio)-5-nitropyridine (4c)
1
Beige solid; yield 59%; m.p. 72 °C; H NMR (300 MHz, DMSO-d6): δ= 9.18 (s, 1H), 8.93 (s,
H), 8.49 (s, 1H), 3.55-3.63 (m, 1H), 1.97 (s, 2H), 1.72 (s, 2H), 1.60 (d, J = 11.7 Hz, 1H), 1.47-1.25
1
13
(
m, 5H); C NMR (75 MHz, DMSO-d6): δ 155.0, 144.3, 141.7, 134.1, 131.4, 44.6, 32.4, 25.1. HRMS
(
ESI): m/z calcd for C H N O S [M+H]: 239.0849; found: 239.0844.
1
1
14
2
2
3-(Isobutylthio)-5-nitropyridine (4d)
1
Brown solid; yield 48%; m.p. 60 °C; H NMR (300 MHz, DMSO-d6): δ= 9.13 (d, J = 2.1 Hz,
1
1
H), 8.91 (d, J = 1.8 Hz, 1H), 8.45 (s, 1H), 3.10 (d, J = 6.6 Hz, 2H), 1.92-1.83 (m, 1H), 1.05 (s, 3H),
1
3
.02 (s, 3H); C NMR (150 MHz, DMSO-d6): δ= 154.2, 145.6, 141.9, 137.6, 130.2, 41.1, 28.8, 22.8.
HRMS (ESI): m/z calcd for C H N O S [M+H]: 213.0692; found: 213.0692.
8
10
2
2
3-(Benzylthio)-5-chloropyridine (12b)
1
1

1
Red oil; yield 21%; H NMR (300 MHz, DMSO-d6): δ= 8.43 (s, 1H), 8.40 (d, J = 1.5 Hz, 1H),
1
3
7
1
2
3
.93 (s, 1H), 7.37-7.22 (m, 5H), 4.36 (s, 2H); C NMR (75 MHz, DMSO-d6): δ= 147.0, 145.1, 136.6,
35.0, 128.8, 128.4, 127.3, 36.0. HRMS (ESI): m/z calcd for C H ClNS [M+H]: 236.0295; found:
1
2
10
36.0303.
-(Benzylthio)-5-bromopyridine (12c)
1
Red oil; yield 47%; H NMR (300 MHz, DMSO-d6): δ= 8.48 (s, 1H), 8.46 (s, 1H), 8.04 (s,
1
3
1
H), 7.41-7.22 (m, 5H), 4.36 (s, 2H); C NMR (75 MHz, DMSO-d6): δ= 147.8, 138.3, 137.1, 135.9,
1
29.4, 129.1, 129.0, 127.8, 120.7, 36.6. HRMS (ESI): m/z calcd for C H BrNS [M+H]: 279.9790;
1
2
10
found: 279.9792.
Methyl 5-(benzylthio)nicotinate (12d)
o
1
Light-brown solid; yield 50%; m.p. 69-70 C; H NMR (300 MHz, DMSO-d6): δ= 8.84 (s, 1H),
1
3
8
.71 (s, 1H), 8.14 (s, 1H), 7.36-7.23 (m, 5H), 4.37 (s, 2H), 3.87 (s, 3H); C NMR (75 MHz, DMSO-
d6): δ= 165.2, 153.3, 147.5, 137.2, 136.7, 134.2, 129.4, 129.0, 127.8, 126.1, 53.0, 36.9. HRMS (ESI):
m/z calcd for C H NO S [M+H]: 260.0740; found: 260.0740.
1
4
13
2
3-Methoxy-5-nitropyridine (4e)
To a solution of 3,5-dinitropyridine (0.169 g, 1 mmol) in MeOH (10 mL) was added powdered
MeONa (0.162 g, 3 mmol) and the reaction mixture was refluxed until the starting compound was
completely consumed (TLC), then poured into water and extracted with ethyl acetate. Organic phase
was washed several times with water, dried over anhydrous Na SO and evaporated. The residue was
2
4
purified by flash-chromatography on silica gel with chloroform as eluent.
1
Light-brown solid; yield 30%; m.p. 72-73 °C; H NMR (300 MHz, DMSO-d6): δ= 8.99 (s,
1
3
1
1
3
H), 8.72 (s, 1H), 8.11 (s, 1H), 3.97 (s, 3H); C NMR (75 MHz, DMSO-d6): δ= 155.6, 144.8, 144.1,
36.2, 114.7, 56.5. HRMS (ESI): m/z calcd for C H N O [M+H]: 155.0451; found: 155.0455.
6
6
2
3
-Azido-5-nitropyridine (4f)
To a solution of 3,5-dinitropyridine (0.169 g, 1 mmol) in DMF (5 mL) was added NaN (0.195
3
g, 3 mmol) and the reaction mixture was stirred at 85°C until the starting compound was completely
consumed (TLC), then poured into water and extracted with ethyl acetate. Organic phase was washed
several times with water, dried over anhydrous Na SO and evaporated. The residue was purified by
2
4
flash-chromatography on silica gel with chloroform as eluent.
o
1
Light-yellow solid; yield 48%; m.p. 36 C; H NMR (300 MHz, DMSO-d6): δ= 9.16 (d, J = 2.1
1
3
Hz, 1H), 8.81 (d, J = 2.2 Hz, 1H), 8.34 (t, J = 2.2 Hz, 1H). C NMR (125 MHz, DMSO-d6): δ= 146.7,
1
2
1
44.5, 140.3, 138.0, 121.8. IR (KBr, νmax/cm-1 ): 682, 814, 900, 1175, 1288, 1317, 1357, 1530, 1568,
138. HRMS (ESI): m/z calcd for C H N O [M+H]: 166.0360; found: 166.0366.
5
3
5
2
-Phenylethan-1-one O-(5-nitropyridin-3-yl) oxime (4g)
1
2

3
,5-dinitropyridine (0.169 g, 1 mmol) and acetophenone oxime (0.135 g, 1 mmol) were
dissolved in DMSO (10 mL) and NaH (60% in mineral oil, 0.04 g, 1 mmol) was added. The reaction
mixture was stirred at room temperature for 24 hours until the starting compound was completely
consumed (TLC), then poured into water and acidified to pH 2~3 with hydrochloric acid. A precipitate
was filtered off, washed with water and dried on air.
o
1
Yellow solid; yield 67%; m.p. 90 C; H NMR (300 MHz, DMSO-d6): δ= 9.11 (s, 1H), 9.00 (s,
1
3
1
H), 8.41 (s, 1H), 7.87 (d, J = 6.5 Hz, 2H), 7.54 (m, 3H), 2.55 (s, 3H); C NMR (75 MHz, DMSO-
d6): δ= 161.6, 155.2, 144.7, 142.8, 138.0, 134.3, 130.7, 128.8, 126.8, 116.3, 13.7. HRMS (ESI): m/z
calcd for C H N O [M+H]: 258.0873; found: 258.0861.
1
3
11
3
3
General procedure for the synthesis of compounds 6,8a,9,14a-e To a solution of sodium phenoxide
prepared from substituted phenol (1 mmol) and NaH (60% in mineral oil, 0.04 g, 1 mmol) in DMSO
(10 mL), was added an appropriate 3-nitropyridine (1 mmol). The reaction mixture was stirred at room
temperature for 1-24 hours until the starting compound was completely consumed (TLC), then poured
into water and acidified to pH 2~3 with hydrochloric acid. A precipitate was filtered off, washed with
water and dried in air.
4-(3,5-Dinitro-1,2-dihydropyridin-2-yl)phenol (6)
o
1
Red crystals; yield 15%; m.p. 222 C; H NMR (300 MHz, DMSO-d6): δ= 10.82 (br.s, 1H),
.67 (s, 1H), 8.64 (s, 1H), 8.32 (s, 1H), 7.23 (d, J = 8.4 Hz, 2H), 6.78 (d, J = 8.4 Hz, 2H), 6.04 (s, 1H);
C NMR (75 MHz, DMSO-d6): δ= 158.1, 147.8, 130.7, 130.1, 128.6, 125.3, 118.9, 115.6, 55.1;
9
1
3
HRMS (ESI): m/z calcd for C H N O [M+Na]: 286.0434 ; found: 286.0441.
1
1
9
3
5
4-(3,5-Dinitro-1,2-dihydropyridin-2-yl)-2,6-dimethylphenol (8a)
o
1
Orange powder; yield 91%; m.p. 264 C; H NMR (300 MHz, DMSO-d6): δ= 10.79 (br.s., 1H),
1
3
8
.60 (s, 1H), 8.49 (s, 1H), 8.32 (s, 1H), 6.97 (s, 2H), 5.97 (s, 1H), 2.16 (s, 6H); C NMR (75 MHz,
DMSO-d6): δ= 154.0, 147.7, 130.6, 130.2, 127.1, 125.4, 124.7, 118.9, 55.4, 16.5; HRMS (ESI): m/z
calcd for C H N O [M+H]: 292.0928 ; found: 292.0929.
1
3
13
3
5
2-(3,5-Dinitropyridin-2-yl)-4,6-dimethylphenol (9)
o
1
Red crystals; yield 20%; m.p. 172 C; H NMR (300 MHz, DMSO-d6): δ= 9.38 (s, 1H), 8.90 (s,
1
3
1
1
H), 7.81 (s, 1H), 7.41 (s, 1H), 2.53 (s, 3H), 2.47 (s, 3H); C NMR (150 MHz, DMSO-d6): δ= 158.0,
49.7, 148.8, 143.4, 142.1, 135.5, 135.0, 123.3, 122.0, 119.9, 116.1, 21.9, 15.6; HRMS (ESI): m/z
calcd for C H N O [M+H]: 290.0771 ; found: 290.0770.
1
3
11
3
5
2,6-Dimethyl-4-(5-nitropyridin-2-yl)phenol (13a)
o
1
Brown solid; yield 21%; m.p. 186-187 C; H NMR (300 MHz, DMSO-d6): δ= 9.33 (s, 1H),
1
3
8
.94 (s, 1H), 8.53 (d, J = 9.0 Hz, 1H), 8.11 (d, J = 8.5 Hz, 1H), 7.85 (s, 2H), 2.56 (s, 6H); C NMR
(
150 MHz, DMSO-d6): δ= 161.4, 156.5, 144.8, 142.0, 132.3, 128.1, 127.3, 124.8, 119.1, 16.8; HRMS
ESI): m/z calcd for C H N O [M+H]: 245.0921 ; found: 245.0921.
(
1
3
12
2
3
1
3

4-(3-Chloro-5-nitropyridin-2-yl)-2,6-dimethylphenol (13b)
o
1
Yellow solid; yield 40%; m.p. 145-147 C; H NMR (300 MHz, DMSO-d6): δ= 9.32 (s, 1H),
1
3
8
.89 (s, 1H), 8.75 (s, 1H), 7.44 (s, 2H), 2.24 (s, 6H); C NMR (150 MHz, DMSO-d6): δ= 160.5,
55.5, 142.5, 142.2, 133.5, 129.9, 128.4, 127.0, 123.9, 16.7; HRMS (ESI): m/z calcd for C H ClN O
3
1
13
11
2
[
M+H]: 279.0531 ; found: 279.0530.
4-(3-Bromo-5-nitropyridin-2-yl)-2,6-dimethylphenol (13c)
1
H NMR spectrum contains trace signals ( 5%) of 4a as a minor product. Yellow solid; yield
o
1
7
7
1
3
1%; m.p. 140-143 C; H NMR (300 MHz, DMSO-d6): δ= 9.33 (s, 1H), 8.85 (s, 1H), 8.83 (s, 1H),
1
3
.38 (s, 2H), 2.23 (s, 6H); C NMR (150 MHz, DMSO-d6): δ= 162.2, 155.2, 142.9, 142.1, 136.5,
29.9, 128.4, 123.8, 117.8, 16.7; HRMS (ESI): m/z calcd for C H BrN O [M+H]: 323.0026 ; found:
1
3
11
2
3
23.0026.
Methyl 2-(4-hydroxy-3,5-dimethylphenyl)-5-nitro-1,2-dihydropyridine-3-carboxylate (13d)
o
1
Light-red crystals; yield 44%; m.p. 235 C; H NMR (300 MHz, DMSO-d6): δ= 9.99 (bs, 1H),
1
3
8
.41 (s, 1H), 8.40 (bs, 1H), 7.81 (s, 1H), 6.85 (s, 2H), 5.49 (s, 1H), 3.61 (s, 3H), 2.13 (s, 6H); C NMR
(75 MHz, DMSO-d6): δ= 164.9, 153.5, 146.6, 132.3, 127.1, 126.8, 124.4, 120.0, 112.5, 54.9, 51.6,
1
6.6; HRMS (ESI): m/z calcd for C H N O [M+H]: 305.1132 ; found: 305.1132.
15 16 2 5
4-(3-Bromo-5-nitro-1,2-dihydropyridin-2-yl)-2,6-diisopropylphenol (13e)
o
1
Yellow solid; yield 75%; m.p. 166 C; H NMR (300 MHz, DMSO-d6): δ= 9.53 (br. s. 1H), 8.26 (s,
1
3
1
H), 7.15 (s, 1H), 6.98 (s, 2H), 5.46 (s, 1H), 3.24-3.29 (m, 2H), 1.12 (d, J= 6.6 Hz, 12H); C NMR
75.47 MHz, DMSO-d6): δ 151.8, 143.6, 136.0, 131.8, 122.8, 121.0, 119.9, 109.5, 62.8, 26.7, 23.4,
3.3; HRMS (ESI): m/z calcd for C H BrN O [M+H]: 381.0808 ; found: 381.0799.
(
2
1
7
21
2
3
General procedure for the synthesis of compounds 8b-c. An appropriate indole (1 mmol) was added
to a solution of 3,5-dinitropyridine (0.169 g, 1 mmol) in DMF (5 mL), followed by Cs CO (0.326 g, 1
2
3
mmol). The reaction mixture was stirred at 70°C for 2-3 hours until the starting compound was
completely consumed (TLC), then poured into diluted hydrochloric acid and extracted several times
with ethyl acetate. Combined extracts were washed with brine, dried over anhydrous Na SO and
2
4
evaporated. The residue was recrystallized from ethanol.
3-(3,5-Dinitro-1,2-dihydropyridin-2-yl)-1H-indole (8b)
o
1
Red powder; yield 47%.; m.p. 236-237 C; H NMR (300 MHz, DMSO-d6): δ= 11.30 (s, 1H),
1
1
1
0.85 (bs, 1H), 8.61 (s, 1H), 8.31 (s, 1H), 7.59 (d, J = 7.8 Hz, 1H), 7.46 (s, 1H), 7.40 (d, J = 8.1 Hz,
1
3
H), 7.16-7.04 (m, 2H), 6.47 (s, 1H); C NMR (150 MHz, DMSO-d6): δ= 147.5, 136.4, 130.1, 125.5,
25.4, 124.7, 121.7, 119.6, 119.1, 118.5, 113.8, 112.1, 48.7; HRMS (ESI): m/z calcd for C H N O
4
1
3
10
4
[
M+H]: 287.0775; found: 287.0779.
3-(3,5-Dinitro-1,2-dihydropyridin-2-yl)-5-methoxy-1H-indole (8c)
1
4

o
1
Red powder; yield 53%; m.p. 208 C; H NMR (300 MHz, DMSO-d6): δ= 11.19 (s, 1H), 10.86
bs,1H), 8.65 (s, 1H), 8.34 (s, 1H), 7.41 (s, 1H), 7.32 (d, J = 9 Hz, 1H), 7.09 (s, 1H), 6.80 (d, J = 8.7
(
1
3
Hz, 1H), 6.45 (s, 1H), 3.74 (s, 3H); C NMR (75 MHz, DMSO-d6): δ= 153.6, 147.4, 131.5, 129.7,
25.8, 125.0, 124.6, 119.2, 113.5, 112.7, 111.6, 100.9, 55.1, 48.5; HRMS (ESI): m/z calcd for
C H N O [M+H]: 317.0880 ; found: 317.0881.
1
14
12
4
5
General procedure for the synthesis of compounds 10a-g, 11a-g. An appropriate methylketone (1
mmol) was added to a solution of 3,5-dinitropyridine (0.169 g, 1 mmol) in DMF (5 mL) followed by
DBU (0.300 mL, 2 mmol). The reaction mixture was stirred at room temperature for 1-3 hours until
the starting compound was completely consumed (TLC), then poured into diluted hydrochloric acid.
An oily precipitate was dissolved in ethyl acetate and water phase was additionally extracted several
times with ethyl acetate. Combined extracts were washed with brine, dried over anhydrous Na SO and
2
4
evaporated. The residue was purified by flash-chromatography on silica gel with ethyl
acetate/chloroform 1:1 as eluent.
1-(3,5-Dinitro-1,4-dihydropyridin-4-yl)propan-2-one (10a)
o
1
Brownish-yellow solid; yield 50%; m.p. 176-178 C; H NMR (300 MHz, DMSO-d6): δ= 10.39
13
(
bs, 1H), 8.04 (s, 2H), 4.77 (t, J = 4.2 Hz, 1H), 2.75 (d, J = 4.2 Hz, 2H), 2.05 (s, 3H); C NMR (125
MHz, DMSO-d6): δ= 205.6, 135.5, 130.5, 45.4, 30.9, 29.9; HRMS (ESI): m/z calcd for C H N O
5
8
9
3
[
M+K]: 266.0174; found: 266.0178.
1-(3,5-Dinitro-1,2-dihydropyridin-2-yl)propan-2-one (11a)
1
Not isolated in pure form; H NMR (300 MHz, DMSO-d6): δ= 10.39 (bs, 1H), 8.40 (s, 1H),
.11 (s, 1H), 5.43 (dd, J = 8.9 Hz, J = 2.2 Hz, 1H), 3.15 (dd, J = 17.7 Hz, J = 9 Hz, 1H), 2.81 (d, J
8
1
2
1
2
=
11.6 Hz, 1H), 2.12 (s, 3H).
1-Cyclopropyl-2-(3,5-dinitro-1,4-dihydropyridin-4-yl)ethan-1-one (10b)
1
Yellow crystals; yield 69%; m.p. 145-146 °С; H NMR (300 MHz, DMSO-d6): δ= 10.38 (bs,
1
4
H), 8.03 (s, 2H), 4.83 (t, J = 4.2 Hz, 1H), 2.85 (d, J = 4.2 Hz, 2H), 1.98-1.90 (m, 1H), 0.87-0.73 (m,
1
3
H); C NMR (150 MHz, DMSO-d6): δ= 207.8, 135.6, 130.3, 44.3, 31.4, 20.7, 10.7.= HRMS (ESI):
m/z calcd for C H N O [M+K]: 292.0330; found: 292.0336.
1
0
11
3
5
1-Cyclopropyl-2-(3,5-dinitro-1,2-dihydropyridin-2-yl)ethan-1-one (11b)
1
Red oil; yield 12%; H NMR (300 MHz, DMSO-d6): δ= 10.36 (bs, 1H), 8.41 (s, 1H), 8.11 (s,
1
1
1
1
H), 5.46 (dd, J = 8.5 Hz, J = 2.5 Hz, 1H), 3.25 (dd, J = 17.9 Hz, J = 8.7 Hz, 1H), 2.89 (dd, J =
1
2
1
2
1
13
7.7 Hz, J = 2.6 Hz, 1H), 2.01 (m, 1H), 0.91-0.83 (m, 4H); C NMR (150 MHz, DMSO-d6): δ 207.3,
2
49.7, 128.8, 126.3, 120.0, 48.4, 46.5, 20.8, 10.8, 10.7.
-(3,5-Dinitro-1,4-dihydropyridin-4-yl)-3,3-dimethylbutan-2-one (10c)
1
Brown powder; yield 52%; m.p. 190°С; H NMR (300 MHz, DMSO-d6): δ= 10.39 (bs, 1H),
1
3
8
.03 (s, 2H), 4.80 (t, J = 3.9 Hz ,1H), 2.87 (d, J = 3.9 Hz, 2H), 0.97 (s, 12H); C NMR (150 MHz,
1
5

DMSO-d6): δ= 213.6, 136.8, 131.7, 45.4, 38.7, 32.3, 26.7; HRMS (ESI): m/z calcd for C H N O
5
1
1
15
3
[
M+K]: 308.0643; found: 308.0643.
1-(3,5-Dinitro-1,2-dihydropyridin-2-yl)-3,3-dimethylbutan-2-one (11c)
1
Not isolated in pure form; H NMR (300 MHz, DMSO-d6): δ= 10.39 (bs, 1H), 8.38 (s, 1H),
.11 (s, 1H), 5.44 (d, J = 8.6 Hz, 1H), 3.11 (s, 1H), 2.83 (s, 1H), 1.06 (s, 12H).
-(3,5-Dinitro-1,4-dihydropyridin-4-yl)-1-phenylethan-1-one (10d)
8
2
1
Orange crystals; yield 67%; m.p. 187-188 °С; H NMR (300 MHz, DMSO-d6): δ= 10.42 (bs,
1H), 8.04 (s, 2H), 7.88 (d, J = 7.5 Hz, 2H), 7.63 (t, J = 7.2 Hz , 1H), 7.51 (t, J = 7.5 Hz ,2H), 4.99 (t, J
1
3
=
4.5 Hz ,1H), 3.29 (d, J = 4.5 Hz, 2H); C NMR (125 MHz, DMSO-d6): δ= 197.4, 136.6, 135.6,
1
33.3, 130.2, 128.8, 127.9, 40.7, 31.9; HRMS (ESI): m/z calcd for C H N O [M+H]: 290.0771 ;
13 11 3 5
found: 290.0772.
2-(3,5-Dinitro-1,2-dihydropyridin-2-yl)-1-phenylethan-1-one (11d)
1
Red oil; yield 17%; H NMR (300 MHz, DMSO-d6): δ= 10.45 (bs, 1H), 8.42 (s, 1H), 8.16 (s,
1
H), 7.99 (d, J = 8 Hz, 2H), 7.67 (m, 1H), 7.54 (m, 2H), 5.67 (d, J = 7.8 Hz, 1H), 3.80 (dd, J = 17.8
1
Hz, J = 8.7 Hz, 1H), 3.32 (s, 1H).
2
2-(3,5-Dinitro-1,4-dihydropyridin-4-yl)-1-(4-methoxyphenyl)ethan-1-one (10e)
1
Orange crystals; yield 52%; m.p. 174 °С; H NMR (300 MHz, DMSO-d6): δ= 10.38 (bs, 1H),
8.02 (s, 2H), 7.84 (d, J = 8.7 Hz, 2H), 7.01 (d, J = 8.7 Hz), 4.96 (t, J = 4.8 Hz, 1H), 3.83 (s, 3H), 3.21
1
3
(
d, J = 4.5 Hz, 2H); C NMR (125 MHz, DMSO-d6): δ= 195.8, 163.3, 135.6, 130.3, 130.2, 129.7,
1
14.0, 55.6, 40.0, 32.1; HRMS (ESI): m/z calcd for C H N O [M+H]: 320.0877 ; found: 320.0869.
14 13 3 6
2-(3,5-Dinitro-1,2-dihydropyridin-2-yl)-1-(4-methoxyphenyl)ethan-1-one (11e)
1
Red oil; yield 13%; H NMR (300 MHz, CDCl ): δ= 8.38 (s, 1H), 8.36 (d, J = 7.9 Hz, 1H),
3
7.93 (d, J = 8.9 Hz, 2H), 7.91 (s, 1H), 6.95 (d, J = 8.9 Hz, 2H), 5.77 (s, 1H), 3.89 (s, 3H), 3.53 (d, J = 2
Hz, 1H), 3.50 (s, 1H).
2-(3,5-Dinitro-1,4-dihydropyridin-4-yl)-1-(p-tolyl)ethan-1-one (10f)
1
Orange crystals; yield 62%; m.p. 153-154 °С; H NMR (300 MHz, DMSO-d6): δ= 10.40 (bs,
1H), 8.02 (s, 2H), 7.76 (d, J = 7.8 Hz, 2H), 7.30 (d, J = 7.8 Hz, 2H), 4.96 (t, J = 4.5 Hz, 1H), 3.24 (d, J
1
3
=
4.8 Hz, 2H), 2.36 (s, 3H); C NMR (125 MHz, DMSO-d6): δ= 196.9, 143.7, 135.6, 134.2, 130.2,
1
3
2
29.3, 128.1, 40.4, 32.0, 21.2; HRMS (ESI): m/z calcd for C H N O [M+H]: 304.0928 ; found:
14 13 3 5
04.0928.
-(3,5-Dinitro-1,2-dihydropyridin-2-yl)-1-(p-tolyl)ethan-1-one (11f)
1
Red oil; yield 17%; H NMR (300 MHz, CDCl ): δ= 8.36 (s, 1H), 8.31 (d, J = 7.3 Hz, 1H),
3
7
2
1
.77 (d, J = 6.4 Hz, 2H), 7.75 (s, 1H), 7.25 (d, J = 6.5 Hz, 2H), 5.74 (s, 1H), 3.52 (d, J = 5.2 Hz, 2H),
.40 (s, 3H).
-(2-Chlorophenyl)-2-(3,5-dinitro-1,4-dihydropyridin-4-yl)ethan-1-one (10g)
1
6

1
Orange crystals; yield 47%; m.p. 164-165 °С; H NMR (300 MHz, DMSO-d6): δ= 10.43 (bs,
1
3
1
H), 8.03 (s, 2H), 7.57-7.38 (m, 4H), 4.94 (t, J = 3.9 Hz, 1H), 3.32 (d, J = 3.9 Hz, 2H); C NMR (150
MHz, DMSO-d6): δ= 201.0, 139.4, 136.9, 133.6, 131.6, 131.3, 130.8, 130.6, 128.5, 44.9, 32.7; HRMS
(
ESI): m/z calcd for C H ClN O [M+NH ]: 341.0647 ; found: 341.0647.
13 10 3 5 4
1-(2-Chlorophenyl)-2-(3,5-dinitro-1,2-dihydropyridin-2-yl)ethan-1-one (11g)
1
Red oil; yield 21%; H NMR (300 MHz, DMSO-d6): δ= 10.52 (bs, 1H), 8.47 (s, 1H), 8.12 (s,
1
H), 7.75 (d, J = 7.6 Hz, 1H), 7.56 (s, 1H), 7.55 (s, 1H), 7.46 (m, 1H), 5.65 (dd, J = 8.2 Hz, J = 2.5
1
2
Hz, 1H), 3.71 (dd, J = 17.9 Hz, J = 8.2 Hz, 1H), 3.28 (dd, J = 17.9 Hz, J = 2.7 Hz, 1H).
1
2
1
2
References
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Reactions of 3-R-5-nitropyridines with nucleophiles were investigated
Anionic nucleophiles substitute non-activated nitro group
Interaction with ambident nucleophiles leads to dearomatization of pyridine
ring
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A number of novel or hardly accessible pyridine derivatives were synthesized
Methods for the synthesis of polyfunctionalized pyridines were developed