Regiospecific synthesis of gem-dinitro derivatives of 2-halogenocycloalka[b]pyridine-3,4-dicarbonitriles

Article abstract of DOI:10.1016/j.tet.2015.06.031

Abstract A simple method for the synthesis of inaccessible gem-dinitro derivatives of pyridine is described. A wide range of 2-halogencycloalka[b]pyridine-3,4-dicarbonitriles are produced by the three-component reaction (ketone, TCNE, hydrohalic acid), si

Full text of DOI:10.1016/j.tet.2015.06.031

Accepted Manuscript
Regiospecific synthesis of gem-dinitro derivatives of 2-
halogenocycloalka[b]pyridine-3,4-dicarbonitriles
Oleg V. Ershov, Veronika N. Maksimova, Konstanin V. Lipin, Mikhail Yu. Belikov,
Mikhail Yu. Ievlev, Victor A. Tafeenko, Oleg. E. Nasakin
PII:
S0040-4020(15)00900-X
10.1016/j.tet.2015.06.031
TET 26866
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 23 May 2015
Revised Date: 4 June 2015
Accepted Date: 9 June 2015
Please cite this article as: Ershov OV, Maksimova VN, Lipin KV, Belikov MY, Ievlev MY, Tafeenko VA,
Nasakin OE, Regiospecific synthesis of gem-dinitro derivatives of 2-halogenocycloalka[b]pyridine-3,4-
dicarbonitriles, Tetrahedron (2015), doi: 10.1016/j.tet.2015.06.031.
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to
our customers we are providing this early version of the manuscript. The manuscript will undergo
copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please
note that during the production process errors may be discovered which could affect the content, and all
legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT
Graphical Abstract
Regiospecific synthesis of gem-dinitro
derivatives of 2-halogenocycloalka[b]pyridine-
3,4-dicarbonitriles
Leave this area blank for abstract info.
Oleg V. Ershov a,*, Veronika N. Maksimovaa, Konstanin V. Lipina, Mikhail Yu. Belikova,
Mikhail Yu. Ievleva, Victor A. Tafeenkob, Oleg. E. Nasakina
a Ulyanov Chuvash State University, Moskovsky pr., 15, Cheboksary, Russia
b Lomonosov Moscow State University, Leninskie gory, 1, Moscow, Russia
CN
N
CN
CN
CN
X
CN
X
HNO3
5 min.
HX
CN
+
NC
n
n
n
O
CN
N
O2N
NO2
n=1-4
X=Cl, Br, I

1
ACCEPTED MANUSCRIPT
Tetrahedron
journal homepage: www.elsevier.com
Regiospecific synthesis of gem-dinitro derivatives of
2-halogenocycloalka[b]pyridine-3,4-dicarbonitriles
Oleg V. Ershov,a,* Veronika N. Maksimova,a Konstanin V. Lipin,a Mikhail Yu. Belikov,a
Mikhail Yu. Ievlev,a Victor A. Tafeenkob and Oleg. E. Nasakina
aUlyanov Chuvash State University, Moskovsky pr., 15, Cheboksary 428015, Russia
bLomonosov Moscow State University, Leninskie gory, 1, Moscow 119991, Russia
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A simple method for the synthesis of the inaccessible gem-dinitro derivatives of pyridine is
described. A wide range of 2-halogencycloalka[b]pyridine-3,4-dicarbonitriles are produced by
the three-component reaction (ketone, TCNE, hydrohalic acid), side-chain nitration of latter
with 60% nitric acid in a solvent-free conditions leads to the formation of gem-dinitro
derivatives with high selectivity and without disturbing of other reaction centers.
Available online
2015 Elsevier Ltd. All rights reserved
.
Keywords:
side-chain nitration
gem-dinitro derivatives
pyridine
tetracyanoethylene
2-alkylpyridines
nitric acid
1. Introduction
was the low yields of the resulting products. The nitration of 2,5-
dimethylpyridine with nitric acid in trifluoroacetic anhydride led
to the formation of 5-methyl-2-(trinitromethyl)pyridine in 10%
yield.4a Nitrogen dioxide reacted with 2-ethylpyridine in the
presence of ozone in dichloromethane at room temperature with
formation of only 8% of 2-(1,1-dinitroethyl)pyridine.7a The
treatment of 6-methylpyrazino[2,3-c]isoquinoline by potassium
nitrate in concentrated sulfuric acid gave 10-nitro-6-
(trinitromethyl)pyrazino[2,3-c]isoquinoline in 31% yield.7b Using
the described methods for the direct insertion of nitro group in
the alkyl substituent of pyridine, only three gem-di- or tri-nitro
compounds were obtained only. 4a,7a,b
Moreover, there are two methods for the indirect nitration of
2-alkylpyridines thorough the gem-trinitromethyl fragment
insertion into the pyridinium salts by nitroform7c,d and using the
Ponzio reaction variations, under the action of nitrate or nitrogen
oxides, to 2-pyridinecarbonyl oximes.7e-g
Many of these methods have one or more disadvantages such
as long reaction times, low yields, formation of byproducts,
tedious workup, and the use of explosive reagents leading to
theserious environmental and safety problems. Therefore, the
development of safe and simple methods for inserting of the nitro
group into the α-alkyl substituent of the pyridine ring is a
significant problem.
Pyridine derivatives, highly developed by great contributions
by Alan Roy Katritzky1, have received a great attention, because
this moiety is presented in a great number of drugs and
biologically active molecules, naturally occurred and synthetic
compounds.2 Furthermore nitro compounds are among the
important groups of chemicals have been proven to be useful
building blocks and widely used in biological, pharmaceutical
and advanced materials science.3 The side-chain nitration of
alkylpyridines usually gives the products of electrophilic
substitution, nitropyridines,4 which are widely used in organic
synthesis as precursors for pharmaceutical and agrochemical
compounds.4a,5 Moreover, the molecules with so-called
“explosophorics” groups stimulates the practical interest for the
preparation of energetic materials by selective nitration of
systems with pyridine fragments.6
gem-Dinitroalkyl pyridine derivatives are an unusual class of
compounds. There are only a few methods for their preparation.
Some examples for insertion of nitro groups in alkyl substitute of
pyridines are already known,4a,7 but the methods are given only
for just a few number of substrates and have not been systemized.
We were able to find only three publications with the description
of direct side-chain nitration of 2-alkylpyridines into gem-di- and
tri-nitro derivatives.4a,7a,b A significant disadvantage of these
reactions
———
* Corresponding author. Tel.: +7 9022883144; fax: +7 8352450279.
E-mail address: oleg.ershov@mail.ru (O.V. Ershov)

2
Tetrahedron
ACCEPTED MANUSCRIPT
2. Results/Discussion
coloration) an excess of hydrogen iodide was added and the
reaction mixture was stirred and heated at 50-60 °C for 1-2 hours.
The reaction likely proceeds through the intermediate formation
of 4-oxoalkane-1,1,2,2-tetracarbonitriles 4, based on the
involvement of compounds 4 in similar transformations.9 During
this investigation, tetracyanosubstituted derivatives of
cycloheptanone 4c (n = 3) and cyclooctanone 4d (n = 4) were
obtained and described at first time. They were yielded by
pouring excess of water in the reaction mixture before the
addition of hydrogen iodide.
We suggested that alkylpyridines with electron-withdrawing
groups should be easier to nitrate on the alkyl substituent in the
second position of the pyridine ring. This assumption is based on
the known fact that electron-withdrawing substituents increase
the mobility of hydrogen atoms in the alkyl groups by pulling the
electron density and make the compound ready for reactions.
Therefore, as the starting compounds readily available
pyridines with two cyano groups were chosen, namely 2-
halogenocycloalka[b]pyridine-3,4-dicarbonitriles
1-3.
This
Scheme 1. One-pot synthesis of 2-iodocycloalka[b]pyridine-
3,4-dicarbonitriles 3
choice is influenced by the fact that these compounds contain an
important pyridinecarboxylic acid structural moiety – specifically
nicotinic (nicotinonitrile) and isonicotinic (isonicotinonitrile)
acids. Moreover, readily replaceable halogen atom (X)
commonly used for the directed synthesis are found in the
products. 8a,b
For the synthesis of starting compounds a multi-component
coupling reactions strategy (MCRs) was used. 2-
Halogenocycloalka[b]pyridine-3,4-dicarbonitriles
NC CN
CN
CN
HCl (cat)
dioxane
HI
CN
+
NC
n
n
CN
O
CN
O
4
NC CN
CN
N
NC CN
CN
CN
I
CN
I
1-3
were
I
n
-H2O
- HCN
n
n
prepared according to the earlier described method8c via three-
component reaction: cycloalkanone – tetracyanoethylene (TCNE)
– hydrogen halide. The reaction was carried at 60 °C in 1,4-
dioxane using equimolar amounts of cycloalkanone and TCNE
and an excess of hydrogen halide. During this investigation seven
previously unknown halopyridines 1c, 2a-d, 3c, 3d were
obtained to expand the range of examples for developed side-
chain nitration method and to prove the universality (Table 1).
H2N
O
N
HO
H
3
A
B
Pyridine 3 formation proceeds through the hyrogen halide
addition to the terminal cyano group of compounds 4, ring
closure and aromatization by dehydration and dehydrocyanation.
Pyridine structures 1-3 were confirmed by IR-, 1H NMR-
spectroscopy and mass-spectrometry.
Studies have shown that for side-chain nitration of prepared
nicotinonitriles 1-3 concentrated nitric acid can be used without
any additional enhancing nitrating reagents. It was also found,
that the reaction proceeds rapidly with heating for 4-5 min with
good yields and leads to the regiospecific formation of gem-
Table 1.
Three-component synthesis of 2-halogencycloalka[b]pyridine-
3,4-dicarbonitriles 1-3
dinitro
derivatives
of
α-alkyl
substituents
in
2-
halogenocycloalka[b]pyridine-3,4-dicarbonitriles 5-7.
Table 2.
Side-chain nitration of 2-halogencycloalka[b]pyridine-3,4-
dicarbonitriles 5-7.
Yielda
(%)
Yielda (%)
Scheme 1
Entry
n
X
Product
1
2
1
2
3
4
1
2
3
4
1
2
3
4
Cl
Cl
Cl
Cl
Br
Br
Br
Br
I
1a
1b
1c
1d
2a
2b
2c
2d
3a
3b
3c
3d
80
97
93
94
82
77
67
66
7
-
-
3
-
4
-
Entry
n
X
Product
Yielda (%)
5
-
1
1
Cl
Cl
Cl
Cl
Br
Br
Br
Br
I
5a
5b
5c
5d
6a
6b
6c
6d
7a
7b
7c
7d
74
77
73
78
77
68
63
61
83
86
84
82
6
-
2
3
2
3
4
1
2
3
4
1
2
3
4
7
-
8
-
4
9
84
81
79
76
5
10
11
12
I
12
5
6
I
7
I
2
8
a Isolated yield.
9
10
11
12
I
It is important to note that this approach works well when HCl
and HBr were used (table 1, entries 1–8). However, the synthesis
of iodine derivatives 3 did not proceed well under these
conditions (table 1, entries 9–12). Probably, it is related with the
reducing properties of hydrogen iodide, which is capable of
I
I
a Isolated yield.
It was found, that the applying of nitric acid in mixture with
sulfuric acid (nitrating mixture) is complicated by the formation
of cyano group hydrolysis byproducts. Among the compounds
mixture, the product of α-alkylpyridine gem-dinitration was
indicated by TLC. A similar is observed for other options
mixtures used for nitration. Thus, when acetic acid or acetic
anhydride were used as a co-solvent the decomposition products
of 5-7 were found in the reaction mass, similar to the described
for dinitrobarbituric acid.10 It was found, that the best method is
converting
TCNE
Correspondingly
into
ethane-1,1,2,2-tetracarbonitrile.
two-step one-pot synthesis of 2-
a
iodocycloalka[b]pyridine-3,4-dicarbonitriles 3 was developed to
improve the yield by excluding the interaction of TCNE and HI.
TCNE was treated at room temperature with equimolar amount
of cycloalkanone in 1,4-dioxane in the presence of catalytic
amount of hydrochloric acid. After the reaction completion
(hydroquinone test – presence of unreacted TCNE gives a blue

3
the use of nitric acid with a concentration in a range of 50-60%.
formation of dinitro- and the difficulty of making mononitro-
derivatives under the same reaction conditions.
ACCEPTED MANUSCRIPT
Moreover, it is the easiest and cheapest way, because this is the
industrially available concentration of acid. It is interesting to
note, that in this case the hydrolysis of cyano groups does not
occur, even in trace amounts, despite the boiling in a medium of
strong acid.
3. Conclusion
A simple and effective method to prepare gem-dinitro
derivatives of 2-halogenocycloalka[b]pyridine-3,4-dicarbonitriles
was investigated. This method includes the selective side-chain
nitration of 2-halogenocycloalka[b]pyridine-3,4-dicarbonitriles
with 60% nitric acid into the α-alkyl substitute of pyridine ring.
The reaction proceeds rapidly (about 5 min) with good yields,
making the method convenient for modification of pyridine
derivatives.
The structure of the pyridine 6c established by the X-ray
diffraction method (Fig. 1).11 Structures of compounds 5-7 are
considered with IR-, 1H NMR-spectroscopy and mass-
spectrometry. The IR spectra of compounds 5-7 characterized
with the intensive absorption bands of valent vibrations of
conjugated С≡N in the area of 2235-2246 cm-1, NO2 in the area
1
of 1536-1592 cm-1. A characteristic distinction of the H NMR
spectra of compounds 5-7 from corresponding starting pyridine
1-3 is the absence of signals of α-methylene protons. For the
mass spectra of compounds 5-7 the presence of the fragment ion
with weight equal to the difference of molecular weight and the
nitro group [М – 46(NO2)]+ is usual. In the mass spectra of some
2-iododerivatives dinitro- compounds 7 the fragment ion with
weight equal to the difference of molecular weight and two nitro
groups [М – 92(2NO2)]+ is presented.
4. Experimental Section
4.1. General information
The progress of reactions and the purity of the products
were monitored by TLC on Sorbfil plates (spots were visualized
under UV light, by treatment with iodine vapor, or by heating).
The IR spectra were recorded on an FSM-1202 spectrometer with
Fourier transform from samples dispersed in mineral oil. The
NMR spectra were measured in DMSO-d6 on a Bruker DRX-500
spectrometer using tetramethylsilane as an internal reference. The
elemental compositions were determined on a CHN-analyzer
vario Micro cube. The mass spectra (electron impact, 70 eV)
were obtained on a Finnigan MAT INCOS-50 spectrometer.
XRD study of a single crystal of compound 6c was carried out on
a diffractometer Cad-4 (Cu Kα emission, λ 1.54087Å, ω-scan).
Correction for absorption was not used. The structure was solved
and refined with SHELX12a program. The non-hydrogen atoms
were refined by using the anisotropic full matrix least-square
procedure. The hydrogen atoms were located from a difference
Fourier map and refined freely. Molecular geometry calculations
were performed with the SHELX program, and the molecular
graphics were prepared by using DIAMOND12b software.
N4
O5
C12
C11
C4
C10
C3
C5
N5
N2
C13
O4
C6
C9
C2
C7
N3
C8
N1
Br
O2
O3
Figure 1. The molecular structure of 2-bromo-9,9-dinitro-6,7,8,9-
tetrahydro-5H-cyclohepta[b]pyridine-3,4-dicarbonitrile (6c) with the atom-
numbering scheme. Displacement ellipsoids are drawn at the 50% probability
level and H atoms are drawn as small spheres of arbitrary radii.
For
the
side-chain
nitration
of
2-
4.2. General procedure for the preparation of 2-
halogenocycloalka[b]pyridine-3,4-dicarbonitriles (1-2)
To the solution of 0.006 mol appropriate ketone in 10 mL
of 1,4-dioxane 0.64 g (0.005 mol) of TCNE and 3 mL of
hydrohalic acid were added. Reaction mixture stirred at 60-70 °C
for 1-2 h (indicated by TLC). Then mixture diluted with water,
precipitated crystals filtered, washed with water and propan-2-ol.
Recrystallized from propan-2-ol.
halogenocycloalka[b]pyridine-3,4-dicarbonitriles 1-3 by nitric
acid with concentration in the range of 50-60%, either a radical
or an electrophilic mechanism can be proposed. The fact that
only one product is formed and the absence of regioisomeric
byproducts of the reaction, partially indicates the electrophilic
nature of substitution.
The analytical properties of compounds 1b,d were identical
to the previously reported literature data.8c
4.2.1. 2-Chloro-6,7-dihydro-5H-cyclopenta[b]pyridine-3,4-
dicarbonitrile (1a). Yield: 0.81 g (80%); mp 77-79 °C.9b IR
1
(KBr): 2233 cm-1. H NMR (500.13 MHz, DMSO-d6): δ = 2.18
(q, J = 7.7 Hz, 2H, CH2), 3.14-3.21 (m, 4H, 2CH2). MS m/z (%):
203 ([M+], 68), 204 ([M+], 6), 205 ([M+], 21). Anal. Calcd for
C10H6ClN3: C, 58.98; H, 2.97; N, 20.64. Found: C, 59.10; H,
2.98; N, 20.59.
Scheme 2. Proposed mechanism side-chain nitration
4.2.2. 2-Chloro-6,7-dihydro-5H-cyclohepta[b]pyridine-3,4-
dicarbonitrile (1c). Yield: 1.15 g (93%); mp 90-92 °C. IR (KBr):
1
2235 cm-1. H NMR (500.13 MHz, DMSO-d6): δ = 1.62-1.71
Probably, acid-catalyzed tautomerization of the α-
alkylpyridine fragment occurs at first. Further, nitronium cation
undergoes the electrophilic addition to the double bond and
proton eliminates then. Substitution of the second hydrogen
occurs in a similar way, even being much easier, because the
acidity of the proton increases. This hypothesis explains the
(m, 4H, 2CH2), 1.83-1.88 (m, 2H, CH2), 3.04-3.07 (m, 2H, CH2),
3.10-3.13 (m, 2H, CH2). MS m/z (%): 231 ([M+], 64), 232 ([M+],
5), 233 ([M+], 22). Anal. Calcd for C12H10ClN3: C, 62.21; H,
4.35; N, 18.14. Found: C, 62.35; H, 4.37; N, 18.10.

4
Tetrahedron
4.2.3. 2-Bromo-6,7-dihydro-5H-cyclopenta[b]pyridine-
Anal. Calcd for C12H10IN3: C, 44.60; H, 3.12; N, 13.00. Found:
ACCEPTED MANUSCRIPT
3,4-dicarbonitrile (2a). Yield: 1.02 g (82%); mp 91-93 °C. IR
C, 44.69; H, 3.13; N, 12.98.
(KBr): 2233 cm-1. H NMR (500.13 MHz, DMSO-d6): δ = 2.19
1
(q, J = 7.7 Hz, 2H, CH2), 3.07-3.14 (m, 4H, 2CH2). MS m/z (%):
247 ([M+], 28), 249 ([M+], 25),. Anal. Calcd for C10H6BrN3: C,
48.42; H, 2.44; N, 16.94. Found: C, 48.47; H, 2.46; N, 16.90.
4.3.4. 2-Iodo-5,6,7,8,9,10-hexahydrocycloocta[b]pyridine-
3,4-dicarbonitrile (3d). Yield: 1.28 g (76%); mp 96-98 °C. IR
1
(KBr): 2232 cm-1. H NMR (500.13 MHz, DMSO-d6): δ = 1.30-
1.38 (m, 4H, 2CH2), 1.81-1.86 (m, 2H, CH2), 2.95-2.98 (m, 2H,
CH2), 3.00-3.03 (m, 4H, 2CH2). MS m/z (%): 337 ([M+], 88).
Anal. Calcd for C13H12IN3: C, 46.31; H, 3.59; N, 12.46. Found:
C, 46.37; H, 3.61; N, 12.42.
4.2.4.
2-Bromo-5,6,7,8-tetrahydroquinoline-3,4-
dicarbonitrile (2b). Yield: 1.01 g (77%); mp 99-101 °C. IR
(KBr): 2231 cm-1. 1H NMR (500.13 MHz, DMSO-d6): δ = 1.79-
1.85 (m, 4H, 2CH2), 2.87-2.90 (m, 2H, CH2), 2.94-2.97 (m, 2H,
CH2). MS m/z (%): 261 ([M+], 47), 263 ([M+], 45). Anal. Calcd
for C11H8BrN3: C, 50.41; H, 3.08; N, 16.03. Found: C, 50.48; H,
3.09; N, 15.99.
4.4. General procedure for the preparation of 4-
oxoalcane-1,1,2,2-tetracarbonitriles (4)
1.28 g (0.01 mol) of TCNE was dissolved in a minimal
amount of 1,4-dioxane (10 mL), then 0.015 mol of the
appropriate ketone was added and mixture stirred until the
complete dissolution then 1-2 drop of concentrated hydrochloric
acid was added (d = 1.17-1.19). After the disappearance of
TCNE (hydroquinone test) the mixture was poured into 100 mL
of ice-cold water. The obtained oil crystallized with intensive
stirring. The precipitated crystals were filtered, washed with
water and ice-cold propan-2-ol. If it was needed, recrystallized
from propan-2-ol.
4.2.5.
2-Bromo-6,7,8,9-tetrahydro-5H-
cyclohepta[b]pyridine-3,4-dicarbonitrile (2c). Yield: 0.92 g
(67%); mp 112-114 °C. IR (KBr): 2234 cm-1. H NMR (500.13
1
MHz, DMSO-d6): δ = 1.63-1.70 (m, 4H, 2CH2), 1.82-1.87 (m,
2H, CH2), 3.01-3.04 (m, 2H, CH2), 3.10-3.13 (m, 2H, CH2). MS
m/z (%): 275 ([M+], 73), 277 ([M+], 70). Anal. Calcd for
C12H10BrN3: C, 52.20; H, 3.65; N, 15.22. Found: C, 52.26; H,
3.66; N, 15.19.
4.2.6.
2-Bromo-5,6,7,8,9,10-
hexahydrocycloocta[b]pyridine-3,4-dicarbonitrile (2d). Yield:
4.4.1. 1-(2-Oxocycloheptyl)ethane-1,1,2,2-tetracarbonitrile
(4c).Yield: 2.23 g (93%); mp 104-106 °C. IR (KBr): 2259, 1701
cm-1. 1H NMR (500.13 MHz, acetone-d6): δ = 1.47-1.55 (m, 1H,
CH2), 1.75-2.07 (m, 5H, (CH2)3), 2.35-2.40 (m, 1H, CH2), 2.59-
2.66 (m, 1H, CH2), 2.81-2.87 (m, 1H, COCH2), 3.16-3.21 (m,
1H, CH2CO), 3.98-4.02 (m, 1H, CHCO), 5.93 (s, 1H, CHCN).
MS m/z (%): 240 ([M+], 8). Anal. Calcd for C13H12N4O: C,
64.99; H, 5.03; N, 23.32. Found: C, 64.89; H, 5.05; N, 23.36.
1
0.96 g (66%); mp 84-86 °C. IR (KBr): 2232 cm-1. H NMR
(500.13 MHz, DMSO-d6): δ = 1.31-1.38 (m, 4H, 2CH2), 1.69-
1.77 (m, 4H, 2CH2), 2.98-3.01 (m, 2H, CH2), 3.02-3.05 (m, 2H,
CH2). MS m/z (%): 289 ([M+], 21), 291 ([M+], 20). Anal. Calcd
for C13H12BrN3: C, 53.81; H, 4.17; N, 14.48. Found: C, 53.88; H,
4.19; N, 14.44.
4.3. General procedure for the preparation of 2-
iodocycloalka[b]pyridine-3,4-dicarbonitriles (3)
4.4.2. 1-(2-Oxocyclooctyl)ethane-1,1,2,2-tetracarbonitrile
(4d). Yield: 2.41 g (95%); mp 134-136 °C. IR (KBr): 2258, 1703
cm-1. 1H NMR (500.13 MHz, acetone-d6): δ = 1.12-1.20 (m, 1H,
CH2), 1.57-2.21 (m, 8H, (CH2)4), 2.48-2.54 (m, 1H, CH2), 2.76-
2.83 (m, 1H, CH2СО), 2.89-2.99 (m, 1H, CH2СО), 3.92-3.99 (m,
1H, CHCO), 5.88 (s, 1H, CHCN). MS m/z (%): 254 ([M+], 3).
Anal. Calcd for C14H14N4O: C, 66.13; H, 5.55; N, 22.03. Found:
C, 66.11; H, 5.54; N, 22.05.
To the solution of 0.006 mol of the appropriate ketone in 10
mL of 1,4-dioxane 0.64 g (0.005 mol) of TCNE and 0.1 mL of
hydrochloric acid were added. The reaction mixture stirred at
room temperature and after the disappearance of TCNE
(hydroquinone test) 3 mL of concentrated hydriodic acid was
added. Mixture heated to 60-70 °C and continued stirring for 1-2
h (indicated by TLC). Precipitated crystals filtered, washed with
water and propan-2-ol. Recrystallized from propan-2-ol
4.5. General procedure for the preparation of gem-
dinitro
derivatives
2-halogenocycloalka[b]pyridine-3,4-
4.3.1. 2-Iodo-6,7-dihydro-5H-cyclopenta[b]pyridine-3,4-
dicarbonitrile (3a). Yield: 1.24 g (84%); mp 102-103 °C.9c IR
dicarbonitriles
1
(KBr): 2235 cm-1. H NMR (500.13 MHz, DMSO-d6): δ = 2.15
To the 0.005 mol of 2-halogenocycloalka[b]pyridine-3,4-
dicarbonitriles (1-3) 5 mL of 60% nitric acid was added. Mixture
refluxed for 4-5 min then allowed to cool and diluted with water.
Precipitated crystals were filtered and then washed with water.
(quin, J = 7.7 Hz, 2H, CH2), 3.06 (t, J = 7.7 Hz, 2H, CH2), 3.10
(t, J = 7.7 Hz, 2H, CH2). MS m/z (%): 295 ([M+], 21). Anal.
Calcd for C10H6IN3: C, 40.70; H, 2.05; N, 14.24. Found: C,
40.78; H, 2.06; N, 14.21.
4.5.1.
2-Chloro-7,7-dinitro-6,7-dihydro-5H-
4.3.2. 2-Iodo-5,6,7,8-tetrahydroquinoline-3,4-dicarbonitrile
(3b). Yield: 1.25 g (81%); mp 103-104 °C.9c IR (KBr): 2225 cm-
cyclopenta[b]pyridine-3,4-dicarbonitrile (5a). Yield: 1.08 g
1
(74%); mp 104-105 °C. IR (KBr): 2243, 1575 cm-1. H NMR
1
1. H NMR (500.13 MHz, DMSO-d6): δ = 1.77-1.84 (m, 4H,
(500.13 MHz, DMSO-d6): δ = 3.46-3.49 (m, 2H, CH2), 3.60-3.63
(m, 2H, CH2). MS m/z (%): 247 ([M-46]+, 10), 249 ([M-46]+, 3).
Anal. Calcd for C10H4ClN5O4: C, 40.91; H, 1.37; N, 23.85.
Found: C, 41.00; H, 1.37; N, 23.81.
2CH2), 2.84-2.87 (m, 2H, CH2), 2.92-2.95 (m, 2H, CH2). MS m/z
(%): 309 ([M+], 12). Anal. Calcd for C11H8IN3: C, 42.74; H, 2.61;
N, 13.59. Found: C, 42.80; H, 2.61; N, 13.56.
4.3.3. 2-Iodo-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridine-
3,4-dicarbonitrile (3c). Yield: 1.28 g (79%); mp 124-126 °C. IR
(KBr): 2231 cm-1. 1H NMR (500.13 MHz, DMSO-d6): δ = 1.62-
1.69 (m, 4H, 2CH2), 1.81-1.86 (m, 2H, CH2), 2.97-3.00 (m, 2H,
CH2), 3.08-3.11 (m, 4H, 2CH2). MS m/z (%): 323 ([M+], 97).
4.5.2.
2-Chloro-8,8-dinitro-5,6,7,8-tetrahydroquinoline-
3,4-dicarbonitrile (5b). Yield: 1.18 g (77%); mp 148-150 °C. IR
(KBr): 2245, 1561 cm-1. 1H NMR (500.13 MHz, DMSO-d6): δ =
1.96-2.01 (m, 2H, CH2), 3.19 (t, J = 6.4 Hz, 2H, CH2), 3.23-3.26
(m, 2H, CH2). MS m/z (%): 261 ([M-46]+, 13), 263 ([M-46]+, 4).

5
Anal. Calcd for C11H6ClN5O4: C, 42.95; H, 1.97; N, 22.76.
Found: C, 43.05; H, 1.98; N, 22.71.
1.92-1.97 (m, 2H, CH2), 3.10 (t, J = 6.4 Hz, 2H, CH2), 3.20-
ACCEPTED MANUSCRIPT
3.23 (m, 2H, CH2). MS m/z (%): 307 ([M-92]+, 11). Anal. Calcd
for C11H6IN5O4: C, 33.10; H, 1.52; N, 17.55. Found: C, 33.17; H,
1.53; N, 17.51.
4.5.3.
2-Chloro-9,9-dinitro-6,7,8,9-tetrahydro-5H-
cyclohepta[b]pyridine-3,4-dicarbonitrile (5c). Yield: 1.17 g
1
(73%); mp 185-187 °C. IR (KBr): 2235, 1554 cm-1. H NMR
4.5.11.
2-Iodo-9,9-dinitro-6,7,8,9-tetrahydro-5H-
(500.13 MHz, DMSO-d6): δ = 1.78-1.82 (m, 2H, CH2), 1.89-1.94
(m, 2H, CH2), 2.97-3.00 (m, 2H, CH2), 3.08-3.11 (m, 2H, CH2).
MS m/z (%): 275 ([M-46]+, 11), 277 ([M-46]+, 3). Anal. Calcd
for C12H8ClN5O4: C, 44.81; H, 2.51; N, 21.77. Found: C, 44.91;
H, 2.52; N, 21.72.
cyclohepta[b]pyridine-3,4-dicarbonitrile (7c). Yield: 1.73 g
1
(84%); mp 194-196 °C. IR (KBr): 2239, 1592 cm-1. H NMR
(500.13 MHz, DMSO-d6): δ = 1.76-1.80 (m, 2H, CH2), 1.87-1.92
(m, 2H, CH2), 2.88-2.91 (m, 2H, CH2), 3.05-3.08 (m, 2H, CH2).
MS m/z (%): 321 ([M-92]+, 14). Anal. Calcd for C12H8IN5O4: C,
34.89; H, 1.95; N, 16.95. Found: C, 35.06; H, 1.95; N, 16.90.
4.5.4.
2-Chloro-10,10-dinitro-5,6,7,8,9,10-
hexahydrocycloocta[b]pyridine-3,4-dicarbonitrile (5d). Yield:
4.5.12.
2-Iodo-10,10-dinitro-5,6,7,8,9,10-
1
1.30 g (78%); mp 197-199 °C. IR (KBr): 2237, 1556 cm-1. H
hexahydrocycloocta[b]pyridine-3,4-dicarbonitrile (7d). Yield:
1
NMR (500.13 MHz, DMSO-d6): δ = 1.34-1.38 (m, 2H, CH2),
1.81-1.85 (m, 4H, 2CH2), 2.98 (t, J = 6.6 Hz, 2H, CH2), 3.26-3.28
(m, 2H, CH2). MS m/z (%): 289 ([M-46]+, 5). Anal. Calcd for
C13H10ClN5O4: C, 46.51; H, 3.00; N, 20.86. Found: C, 46.63; H,
3.01; N, 20.81.
1.74 g (82%); mp 180-182 °C. IR (KBr): 2235, 1569 cm-1. H
NMR (500.13 MHz, DMSO-d6): δ = 1.38-1.40 (m, 2H, CH2),
1.79-1.85 (m, 4H, 2CH2), 2.92 (t, J = 6.5 Hz, 2H, CH2), 3.25-3.28
(m, 2H, CH2). MS m/z (%): 381 ([M-46]+, 39). Anal. Calcd for
C13H10IN5O4: C, 36.55; H, 2.36; N, 16.40. Found: C, 36.62; H,
2.37; N, 16.36.
4.5.5.
2-Bromo-7,7-dinitro-6,7-dihydro-5H-
cyclopenta[b]pyridine-3,4-dicarbonitrile (6a). Yield: 1.29 g
Acknowledgements
This work was supported by Russian Fund for Basic
Research, Grant No. 15-33-21087.
The XRD study was carried out using the equipment
purchased from the funds of the Program of development of
Moscow University and within the framework of the Agreement
on collaboration between the Chemical Department of the
Lomonsov Moscow State University and the Chemical-
Pharmaceutical Department of the I.N. Ulyanov Chuvash State
University.
1
(77%); mp 135-137 °C. IR (KBr): 2246, 1589 cm-1. H NMR
(500.13 MHz, DMSO-d6): δ = 3.42-3.45 (m, 2H, CH2), 3.59-3.62
(m, 2H, CH2). MS m/z (%): 291 ([M-46]+, 29), 293 ([M-46]+,
30). Anal. Calcd for C10H4BrN5O4: C, 35.53; H, 1.19; N, 20.72.
Found: C, 35.61; H, 1.20; N, 20.67.
4.5.6. 2-Bromo-8,8-dinitro-5,6,7,8-tetrahydroquinoline-3,4-
dicarbonitrile (6b). Yield: 1.19 g (68%); mp 153-155 °C. IR
(KBr): 2239, 1569 cm-1. 1H NMR (500.13 MHz, DMSO-d6): δ =
1.95-2.00 (m, 2H, CH2), 3.15 (t, J = 6.4 Hz, 2H, CH2), 3.23-3.25
(m, 2H, CH2). MS m/z (%): 305 ([M-46]+, 21), 307 ([M-46]+,
20). Anal. Calcd for C11H6BrN5O4: C, 37.52; H, 1.72; N, 19.89.
Found: C, 37.61; H, 1.73; N, 19.84.
Supplementary data
Supplementary data (Copies of 1H NMR spectra for
compounds 1-7) associated with this article can be found in the
online version, at http://
4.5.7.
2-Bromo-9,9-dinitro-6,7,8,9-tetrahydro-5H-
cyclohepta[b]pyridine-3,4-dicarbonitrile (6c). Yield: 1.15 g
References and notes
1
(63%); mp 172-174 °C. IR (KBr): 2241, 1564 cm-1. H NMR
1.
(a) Marquet, J.; Moreno-Mañas, M.; Pacheco, P.; Prat, M.;
Katritzky, A. R.; Brycki, B. Tetrahedron, 1990, 46, 5333-5346; (b)
Katritzky, A. R.; Ostercamp, D. L.; Yousaf, T. I. Tetrahedron, 1987,
43, 5171-5186; (c) Katritzky, A. R.; Ostercamp, D. L.; Yousaf, T. I.
Tetrahedron, 1986, 42, 5729-5738; (d) Katritzky, A. R.;
Chermprapai, A.; Bravo, S.; Patel, R. C. Tetrahedron, 1981, 37,
3603-3607; (e) Katritzky, A. R.; . Langthorne, R. T.; Patel, R. C. ;
Lhommet G. Tetrahedron, 1981, 37, 2383-2390; (f) Katritzky, A. R.;
Ville, G.; Patel, R. C. Tetrahedron, 1981, 37, 25-30; (g)
Katritzky, A. R.; Suwinski J. W. Tetrahedron, 1975, 31, 1549-1556;
(h) Epsztajn, J.; Lunt, E.; Katritzky, A. R. Tetrahedron, 1970, 26,
1665-1673; (i) Katritzky, A. R.; Lunt, E. Tetrahedron, 1969, 25,
4291-4305; (j) Eisenthal, R.; Katritzky, A. R.; Lunt, E. Tetrahedron,
1967, 23, 2775-2788; (k) Eisenthal, R.; Katritzky, A. R.
Tetrahedron, 1965, 21, 2205-2213; Johnson, C. D.; Katritzky, A. R.;
Ridgewell, B. J.; Shakir, N.; White, A. M. Tetrahedron, 1965, 21,
1055-1059.
(500.13 MHz, DMSO-d6): δ = 1.77-1.81 (m, 2H, CH2), 1.88-1.93
(m, 2H, CH2), 2.96-2.99 (m, 2H, CH2), 3.07-3.10 (m, 2H, CH2).
MS m/z (%): 319 ([M-46]+, 18), 321 ([M-46]+, 17). Anal. Calcd
for C12H8BrN5O4: C, 39.37; H, 2.20; N, 19.13. Found: C, 39.46;
H, 2.21; N, 19.08.
4.5.8.
2-Bromo-10,10-dinitro-5,6,7,8,9,10-
hexahydrocycloocta[b]pyridine-3,4-dicarbonitrile (6d). Yield:
1
1.16 g (61%); mp 187-188 °C. IR (KBr): 2238, 1567 cm-1. H
NMR (500.13 MHz, DMSO-d6): δ = 1.36-1.40 (m, 2H, CH2),
1.81-1.86 (m, 4H, 2CH2), 2.98 (t, J = 6.5 Hz, 2H, CH2), 3.27-3.29
(m, 2H, CH2). MS m/z (%): 333 ([M-46]+, 24), 335 ([M-46]+,
24). Anal. Calcd for C13H10BrN5O4: C, 41.07; H, 2.65; N, 18.42.
Found: C, 41.16; H, 2.67; N, 18.37.
4.5.9.
2-Iodo-7,7-dinitro-6,7-dihydro-5H-
2.
(a) Kiuru, P.; Yli-Kauhaluoma, J. Pyridine and Its
cyclopenta[b]pyridine-3,4-dicarbonitrile (7a). Yield: 1.59 g
Derivatives. In Heterocycles in Natural Product Synthesis;
Majumdar, K.; Chattopadhyay, S. K., Eds.; Wiley-VCH Verlag
GmbH & Co. KGaA: Weinheim, Germany, 2011; pp 267-297;
(b) Baumann, M.; Baxendale, I. R. Beilstein J. Org. Chem. 2013,
9, 2265-2319; (c) Perdigão, G.; Deraeve, C.; Mori, G.; Pasca,
M. R.; Pratviel, G.; Bernardes-Génisson, V. Tetrahedron, 2015,
71, 1555-1559; (d) Henry, G. D. Tetrahedron, 2004, 60, 6043-
6061; (e) Allais, C.; Grassot, J. M.; Rodriguez, J.; Constantieux,
T. Chem. Rev. 2014, 114, 10829–10868; (f) ) Spitzner, D.
1
(83%); mp 197-198 °C. IR (KBr): 2241, 1589 cm-1. H NMR
(500.13 MHz, DMSO-d6): δ = 3.37-3.40 (m, 2H, CH2), 3.55-3.58
(m, 2H, CH2). MS m/z (%): 339 ([M-46]+, 23). Anal. Calcd for
C10H4IN5O4: C, 31.19; H, 1.05; N, 18.19. Found: C, 31.27; H,
1.06; N, 18.14.
4.5.10. 2-Iodo-8,8-dinitro-5,6,7,8-tetrahydroquinoline-3,4-
dicarbonitrile (7b). Yield: 1.71 g (86%); mp 207-210 °C. IR
(KBr): 2239, 1588 cm-1. 1H NMR (500.13 MHz, DMSO-d6): δ =

6
Tetrahedron
ACCEPTED MANUSCRIPT
Product Class 1: Pyridines. In Science of Synthesis; Black, D.
obtained free of charge via www.ccdc.cam.ac.uk/data_
StC., Ed.; Thieme Verlag: Stuttgart, 2005; Vol. 15, pp 11-284.
3. (a) Dabrowska-Urbańska, H.; Katritzky, A. R.;
request/cif, by emailing data_request@ccdc.cam.ac.uk, or by
contacting the Cambridge Crystallographic Data Centre, 12,
Union Road, Cambridge CB2 1EZ, UK; fax: þ44 1223 336033.
12. (a) Sheldrick, G. M. Acta Crystallogr. 2008, A64, 112-
122; (b) Brandenburg, K. DIAMOND, Release 2.1d; Crystal
Impact GbR: Bonn, Germany, 2000.
Urbanski, T. Tetrahedron, 1969, 25, 1617-1628; (b) Winkler, R.;
Hertweck, R. C. ChemBioChem. 2007, 8, 973-977; (c) Patterson,
S.; Wyllie, S. Trends Parasitol. 2014, 30, 289-298; (d) Truong,
D.D. Clin. Interv. Aging, 2009, 4, 109-113; (e) Raether, W.;
Hänel, H. Parasitol. Res. 2003, 90, S19–S39; Wilkinson, S.R.
Curr. Top. Med. Chem. 2011, 11, 2072-2084; (f) Hemphill, A.
Expert Opin. Pharmacother., 2006, 7, 953-964; (g) Straus, M.J.
Ind. Eng. Chem. Prod. Res. Dev., 1979, 18, 158-166; (h) S. Kaap,
I. Quentin, D. Tamiru, M. Shaheen, K. Eger and H. J. Steinfelder,
Biochem. Pharmacol., 2003, 65, 603; (i) M. A. Reddy, N. Jain,
D. Yada, C. Kishore, V. J. Reddy, P. S. Reddy, A. Addlagatta, S.
V. Kalivendi and B. Sreedhar, J. Med. Chem., 2011, 54, 6751.
4.
(a) Katritzky, A. R.; Scriven, E. F; Majumder, S.;
Akhmedova, R. G; Vakulenko, A. V.; Akhmedov, N. G.;
Murugan, R.; Abboud, K. A. Org. Biomol. Chem. 2005, 3, 538–
541; (b) Bakke, J. M. Pure Appl. Chem. 2003, 75, 1403-1415; (c)
Rusinov, V. L.; Petrov, A. Yu.; Chupakhin, O. N. Chem.
Heterocycl. Comp. 1985, 21, 113-131.
5.
(a) Lesher, G. Y.; Opalka, Ch. J. US Patent 4,004,012,
1977; Chem. Abstr. 1977, 86, 189725; (b) Huang, Y.; Bennett, F.;
Girijavallabhan, V.; Alvarez, C.; Chan, T.-M.; Osterman, R.;
Senior, M.; Kwong, C.; Bansal, N.; Njoroge, G. F.; MacCoss,
Malcolm; Tetrahedron Lett., 2010, 51, 2800-2802; (c) McElroy,
W. T.; DeShong, Ph. Tetrahedron, 2006, 62, 6945-6954; (d)
Benjahad, A.; Guillemont, J.; Andries, K.; Nguyen, C. H.;
Grierson, D. S. Bioorg. Med. Chem. Lett., 2003, 13, 4309-4312;
(e) Lindstrom, S.; Ahmad, T.; Grivas, S. Heterocycles, 1994, 38,
529-540; (f) Tite, T.; Lougiakis, N.; Marakos, P.; Pouli, N.
Synlett, 2009, 2927-2930; (g) Chen, J.; Lingand G.; Lu, S.
Tetrahedron, 2003, 59, 8251-8256; (h) Hayakawa, I.; Suzuki, N.;
Suzuki, K.; Tanaka, Y. Chem. Pharm. Bull., 1984, 32, 4914-
4922.
6.
D. Thermochimica Acta, 2002, 384, 187-204.
7. (a) Suzuki, H.; Kozai, I.; Murashima, T. J. Chem. Res.
Pagoria, Ph. F.; Lee, G. S.; Mitchell, A. R.; Schmidt, R.
(S) 1993, 156-157; (b) Deady, L. W.; Quazi, N. H. Aust. J. Chem.
1992, 45, 2083-2087; (c) Gakh, A. A.; Kiselyov, A. S.;
Semenov, V. V. Tetrahedron Lett., 1990 , 31, 7379-7382; (d)
Gakh, A. A.; Khutoretskii, V. M.; Russ. Chem. Bull., 1983, 32,
2386; (e) Novikov, S. S.; Khmel'nitskii, L. I.; Novikova, T. S.;
Lebedev, O. V. Chem. Heterocycl. Comp., 1970, 6, 543; (f) Bark,
T.; Stoeckli-Evans, H.; Von Zelewsky, A. J. Chem. Soc. Perkin
Trans. 1, 2002, 1881-1886; (g) Luk'yanov, O. A.; Zhiguleva, T.
I.; Russ. Chem. Bull., 1982, 31, 1270-1271.
8.
(a) Vachova, L.; Machacek, M; Kucera, R.; Demuth, J.,
Cermak, P.; Kopecky, K.; Miletin, M.; Jedlickova, A.; Simunek,
T.; Novakova, V.; Zimcik P. Org. Biomol. Chem., 2015, 13,
5608-5612; (b) Maksimova, V. N.; Ershov, O. V; Lipin, K. V.;
Eremkin, A. V., Nasakin, O. E. Russ. J. Org. Chem., 2012, 48,
426-429; (c) Lipin, K. V.; Maksimova, V. N.; Ershov, O. V.;
Eremkin, A. V.; Kayukov, Ya. S.; Nasakin, O. E. Russ. J. Org.
Chem., 2010, 46, 617-618.
9.
(a) Belikov, M. Yu; Ievlev, M. Yu; Ershov, O. V.;
Lipin, K. V.; Legotin, S. A.; Nasakin, O. E. Russ. J. Org. Chem.,
2014, 50, 1372-1374; (b) Nasakin, O. E.; Nikolaev, E. G.;
Terent'ev, P. B.; Bulai, A. Kh.; Lavrent'eva, I. V. Chem.
Heterocycl. Comp., 1987, 23, 541-544; (c) Nasakin, O. E.;
Sheverdov, V. P.; Moiseeva, I. V.; Ershov, O. V.; Chernushkin,
A. N.; Tafeenko, V. A. Zh. Obsh. Khim. 1999, 69, 291-300.
10. Langlet, A.; Latypov, N. V.; Wellmar, U.; Goede, P.;
Bergman, J. Tetrahedron Lett., 2000, 41, 2011-2013.
11. CCDC No. 1402024. CCDC 1402024 contains
supplementary crystallographic data for 6c. These data can be

ACCEPTED MANUSCRIPT
Supporting information
Regiospecific synthesis of gem-dinitro derivatives of
2-halogenocycloalka[b]pyridine-3,4-dicarbonitriles
*Oleg V. Ershov,a Veronika N. Maksimova,a Konstanin V. Lipin,a
Mikhail Yu. Belikov,a Mikhail Yu. Ievlev,a Victor A. Tafeenkob
and Oleg. E. Nasakina
a. Ulyanov Chuvash State University, Moskovskiy pr. 15, Cheboksary, Russia.
b.Lomonosov Moscow State University, Leninskie gory 1, Moscow, Russia
*E-mail: oleg.ershov@mail.ru

ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT