Unexpected reduction of the nitro group in (3-nitrophenyl)-1,2,4-triazines during their aza-Diels-Alder reaction with 1-morpholinocyclopentene

Article abstract of DOI:10.1016/j.mencom.2013.07.010

Unexpected reduction of the nitro group to the amino one during aza-Diels-Alder reaction between (3-nitrophenyl)-1,2,4-triazines and 1-morpholinocyclopentene (neat, 200 C, argon) occurred to furnish 4-(3-aminophenyl)-6,7-dihydro-5H-cyclopenta[c]pyridines.

Full text of DOI:10.1016/j.mencom.2013.07.010

Mendeleev
Communications
Mendeleev Commun., 2013, 23, 209–211
Unexpected reduction of the nitro group in (3-nitrophenyl)-1,2,4-triazines
during their aza-Diels–Alder reaction with 1-morpholinocyclopentene
Dmitry S. Kopchuk,*a,b Albert F. Khasanov,a Igor S. Kovalev,a
Grigory V. Zyryanov,a,b Vladimir L. Rusinova,b and Oleg N. Chupakhina,b
a Department of Organic Chemistry, Ural Federal University, 620002 Ekaterinburg, Russian Federation
b I. Ya. Postovsky Institute of Organic Synthesis, Ural Branch of the Russian Academy of Sciences,
620990 Ekaterinburg, Russian Federation. Fax: +7 343 374 1189; e-mail: dkopchuk@mail.ru
DOI: 10.1016/j.mencom.2013.07.010
Unexpected reduction of the nitro group to the amino one during aza-Diels–Alder reaction between (3-nitrophenyl)-1,2,4-triazines and
1-morpholinocyclopentene (neat, 200°C, argon) occurred to furnish 4-(3-aminophenyl)-6,7-dihydro-5H-cyclopenta[c]pyridines.
NO2
O2N
Aminophenyl-containing pyridines are of interest for their further
functionalization leading to new heterocyclic systems.1 Moreover,
they possess biological activity.2
H2N
O
NH
Ar
+
+
N
N
On the other hand, 2-(het)arylpyridines are common ligands for
various metal cations, some of them having found use as phos-
phorescent labels for bioimaging.3 Aminoaryl-substituted deriva-
tives of 2-(het)arylpyridines are good substrates for this purpose,
as they can be readily converted into isothiocyanate ones by treat-
ment with thiophosgene just before the bioconjugation.4 For the
effective bioimaging these functional groups are usually separated
from the metal chelating site, e.g., by aromatic substituent(s).
A number of methods for the synthesis of aminophenyl-
pyridines are described in literature.5,6 However, only one example
based on 1,2,4-triazine methodology for the synthesis of amino-
phenyl-containing pyridine7 is described, although this approach
has been recognized as a prospective tool to access various
pyridines.8 The key advantage of this methodology is the possi-
bility for one-step derivatization of C3 and/or C4 positions in
newly formed pyridine ring simply by varying the dienophile
and/or the the substitution pattern in the starting 1,2,4-triazines.
Herein, we describe an application of this methodology to access
aminophenyl-containing pyridines.
O
O
NH2
NOH
2a Ar = Ph
2b Ar = 4-MeOC6H4
2c Ar = 2-thienyl
Br
3a 3-NO2
3b 4-NO2
4
1
i
ii
38–45%
68–72%
O2N
N
N
N
Ar
5a 3-NO2, Ar = Ph
5b 3-NO2, Ar = 4-MeOC6H4
5c 3-NO2, Ar = 2-thienyl
5d 3-NO2, Ar = 2-pyridyl
5e 4-NO2, Ar = 2-pyridyl
Scheme 1 Reagents and conditions: i, AcONa, EtOH–AcOH (3:1), 105°C,
12 h; ii, ethanol, 20°C, 10 h, then AcOH, 118°C, 5 min.
2-(Het)arylpyridines bearing aminophenyl substituent at C5
position were the targets of our study since cyclometalled com-
plexes of similar ligands possess an intriguing photophysical
properties,9 therefore these complexes can be promising chromo-
phores for the photoluminescent imaging of biomolecules. In
addition, the phosphorescent label based on platinum complex of
similar ligand containing carboxylic group for further conjuga-
tion with biomolecule was reported.10
The target cyclopenteno[c]pyridines 6 were prepared as de-
scribed12 by heating 1,2,4-triazines 5a–d with an excess of enamine
at 200°C without solvent under argon atmosphere. Unexpectedly,
the processing not only led to the complete formation of the cyclo-
pentenopyridine system, but also caused the reduction of nitro
group into the amino one (Scheme 2).† It should be noted that
for the full conversion of 5, longer reaction time compared to the
original procedure was required.
For the synthesis of parent 1,2,4-triazines two previously
described methods were used.11 Interaction of 2-bromo-3'-nitro-
acetophenone 1 with two equivalents of carboxhydrazides 2
or condensation of isonitrosoacetophenone hydrazones 3 with
pyridine-2-carboxaldehyde 4 afforded triazines 5a–e (Scheme 1,
for details, see Online Supplementary Materials).
Comparative studies of photophysical properties of platinum
complexes of 5-aryl-2-(2-thienyl)pyridines and the corresponding
cyclopenteno[c]pyridines demonstrated that the latter exhibit
higher values for both the luminescence lifetime and quantum
yield,9(a) therefore they are more preferable for application as
phosphorescent labels for bioimaging. To obtain cyclopenteno-
[c]pyridines from 1,2,4-triazines 5, 1-morpholinocyclopentene
should be used as the dienophile in the aza-Diels–Alder reac-
tion.
†
Synthesis of 6,7-dihydro-5H-cyclopenteno[c]pyridines 6, 9 and 10 (typical
procedure). Mixture of corresponding triazine 5, 7 or 8 (2 mmol) and
1-morpholinocyclopentene (1.6 ml, 10 mmol) was stirred at 200°C under
argon atmosphere for 2 h, after that two more portions of enamine
(2×0.64 ml, 2×4 mmol) were added and the reaction mixture was stirred
at 200°C for 1 h after each portion. The mixture was cooled to room
temperature and placed as is on chromatographic column (SiO2) and
eluted with chloroform. Combined fractions containing product (Rf = 0.2)
were concentrated under reduced pressure to ca. 10 ml. The product was
extracted with 3 n hydrochloric acid (3×20 ml). Sodium hydroxide
pellets were added to hydrochloric acid extract upon cooling to adjust
pH to 12 and the product was extracted with dichloromethane (3×20 ml).
The combined organic extracts were dried with anhydrous sodium sulfate,
filtered and solvent was removed under reduced pressure. Analytical
sample was recrystallized from ethanol.
© 2013 Mendeleev Communications. All rights reserved.
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Mendeleev Commun., 2013, 23, 209–211
NH
NO2
NO2
H2N
N
N
N
O
O2N
H
i,
O
N
N
13
i
N
O
Ar
N
Ar
11
5a–d
NH2
O2N
H2N
N
N
iii
N
N
N
N
N
Ar
6a Ar = Ph, 55%
7
9, 47%
6b Ar = 4-MeOC6H4, 54%
6c Ar = 2-thienyl, 50%
6d Ar = 2-pyridyl, 45%
O
H2N
NO2
Me
N
Scheme 2 Conditions: i, neat, 200°C, argon atmosphere, 4 h.
H
ii,
14
1
Structures of products 6 were proved by H and 13C NMR
data (a significant upfield shift of signals of hydrogen atoms
of phenyl ring was observed). The presence of amino group in
compounds 6 was confirmed by 2D COSY (1H–15N) experiment
carried out for product 6c. Thus, the interaction between nitrogen
atom (54 ppm) and hydrogen atoms (3.78 ppm) was observed in
2D COSY (1H–15N) spectra.
O
Br
12
Me
Me
Interestingly, isomeric 4-nitrophenyl-1,2,4-triazine 5e gave
neither nitro- nor aminophenyl-substituted cyclopenteno[c]pyri-
dine 6e and only a complex mixture of unidentified products was
formed (Scheme 3).
iii
N
N
N
N
O2N
H2N
NO2
NH2
8
10, 52%
N
O
Scheme 4 Reagents and conditions: i, ethanol, 78°C, 2 h; ii, ethanol–AcOH
(3:1), 90°C, argon atmosphere, 10 h; iii, 1-morpholinocyclopentene, neat,
200°C, argon atmosphere, 4 h.
N
N
neat, 200 °C
N
N
N
N
In order to investigate the influence of the position of 3-nitro-
phenyl substituent onto the reaction outcome we tested other
3-nitrophenyl-substituted 1,2,4-triazines11(a),13 7 and 8, which gave
amino pyridines 9 and 10 in satisfactory yields (Scheme 4).†
Presumably enamine acts as a reducing agent in this trans-
formation, with the inert atmosphere being an essential factor.
Mechanism of the reaction is under study. Some literature data14
support our hypothesis, i.e. the reaction of 2,6-bis[6-(4-nitro-
phenyl)-1,2,4-triazin-3-yl]pyridine with excess of enamine in
boiling 1,4-dioxane in air occurred only as a 1,2,4-triazine-to-
pyridine transformation with nitro group remaining untouched.
Refluxing of nitrobenzenes in neat 1-pyrrolidinocyclohexene (more
powerful reducing agent) caused the complete reduction of the
nitro group. Position of the nitro group in the aromatic substituent
in 1,2,4-triazine system is also important. In particular, in case
of 4-nitrophenyl-1,2,4-triazines (e.g., 5e) no 4-aminophenyl-
pyridines were isolated. Such a low reactivity can be explained
by the conjugation between nitro group and 1,2,4-triazine system
as an electron-withdrawing substituent. Apparently, in case of
3-nitrophenyl substituent conjugation between nitro group and
1,2,4-triazine core is weaker.
5e
6e
Scheme 3
4-(3-Aminophenyl)-1-phenyl-6,7-dihydro-5H-cyclopenteno[c]pyridine
6a. Yield 315 mg (1.1 mmol, 55%), mp 144–146°C. H NMR (CDCl3)
1
d: 2.08 (m, 2H, 6-CH2), 3.06 (t, 2H, 7-CH2, 3J 7.2 Hz), 3.17 (t, 2H,
5-CH2, 3J 7.2 Hz), 3.78 (br.s, 2H, NH2), 6.73 [m, 1H, H-4 (3-NH2Ph)],
6.80 [dd, 1H, H-2 (3-NH2Ph), J 1.8 Hz], 6.89 [m, 1H, H-6 (3-NH2Ph)],
7.26 [dd, 1H, H-5 (3-NH2Ph), J 8.0 Hz], 7.41 (m, 1H, Ph), 7.48 (m, 2H,
Ph), 7.79 (m, 2H, Ph), 8.54 (s, 1H, H-3). 13C NMR (CDCl3) d: 25.9,
33.0, 33.1, 114.4, 115.1, 119.0, 128.2, 128.3, 128.5, 129.5, 132.8, 137.4,
139.0, 140.1, 146.7, 147.1, 152.5, 152.8. ESI-MS, m/z: 287.16 (M+H)+
(required 287.15). Found (%): C, 83.60; H, 6.27; N, 9.69. Calc. for
C20H18N2 (%): C, 83.88; H, 6.34; N, 9.78.
3-(3-Aminophenyl)-1-(2-pyridyl)-6,7-dihydro-5H-cyclopenteno[c]-
pyridine 9. Yield 270 mg (0.94 mmol, 47%), mp 108–110°C. H NMR
1
(CDCl3) d: 2.13 (m, 2H, 6-CH2), 3.00 (t, 2H, 7-CH2, J 7.6 Hz), 3.45 (t,
2H, 5-CH2, J 7.2 Hz), 3.75 (br.s, 2H, NH2), 6.73 [m, 1H, H-4 (3-NH2Ph)],
7.26 [m, 2H, H-5 (3-NH2Ph), H-5 (Py)], 7.45 [m, 1H, H-6 (3-NH2Ph)],
7.51 [dd, 1H, H-2 (3-NH2Ph), J 2.0 Hz], 7.63 (s, 1H, H-4), 7.81 [ddd, 1H,
H-4 (Py), J 7.8, 7.8 and 2.0 Hz], 8.43 [dd, 1H, H-3 (Py), J 7.8 and 1.0 Hz],
8.69 [dd, 1H, H-6 (Py), J 4.8 and 2.0 Hz]. 13C NMR (CDCl3) d: 25.1,
32.8, 33.0, 113.8, 115.4, 116.6, 117.3, 122.7, 123.2, 129.5, 136.3, 138.0,
141.0, 146.8, 148.4, 151.2, 154.6, 156.7, 158.8. ESI-MS, m/z: 288.15
(M+H)+ (required 288.15). Found (%): C, 79.22; H, 5.80; N, 14.72. Calc.
for C19H17N3 (%): C, 79.41; H, 5.96; N, 14.62.
In conclusion, we have suggested a good method for the
conversion of 3-nitrophenyl-substituted 1,2,4-triazines into aryl-
6,7-dihydro-5H-cyclopenteno[c]pyridines 6a–d, 9, 10 bearing
3-aminophenyl moiety, which seems promising for their further
conjugation with biomolecules. This method is advantageous
in view of the little number of steps and simplicity of the pro-
cessing.
For synthesis of compounds 5, 7 and 8 and characteristics of compounds
6b–d, 7, 8 and 10, see Online Supplementary Materials.
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Mendeleev Commun., 2013, 23, 209–211
6 A. K. Nedeltchev, H. Han and P. K. Bhowmik, J. Polym. Sci., Part A:
This work was supported by the Russian Ministry of Education
and Science (state contract nos. 14.740.11.1020 and 14.A18.21.0817),
Russian Foundation for Basic Research (grant no. 12-03-31726)
and the Council for grants of the President of Russian Federation
(grant no. MK-1511.2013.3).
Polym. Chem., 2010, 48, 4408.
7 A. M. Prokhorov,V. N. Kozhevnikov, D. S. Kopchuk, H. Bernard, N. Le Bris,
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8 (a) D. L. Boger, Tetrahedron, 1983, 39, 2869; (b) G. R. Pabst, O. C. Pfüller
and J. Sauer, Tetrahedron, 1999, 55, 8045; (c)A. Rykowski, D. Branowska
and J. Kielak, Tetrahedron Lett., 2000, 41, 3657; (d) D. N. Kozhevnikov,
O.V. Shabunina, D. S. Kopchuk, P.A. Slepukhin andV. N. Kozhevnikov,
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Online Supplementary Materials
Supplementary data associated with this article can be found
in the online version at doi:10.1016/j.mencom.2013.07.010.
9 (a) D. N. Kozhevnikov, V. N. Kozhevnikov, M. M. Ustinova, A. Santoro,
D. W. Bruce, B. Köenig, R. Czerwieniec, T. Fischer, M. Zabel and H.Yersin
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Received: 8th April 2013; Com. 13/4100
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