Synthesis of 3-substituted 1,5-dinitro-3-azabicyclo-[3.3.1]nonanes containing a pyrazole fragment

Article abstract of DOI:10.1016/j.mencom.2008.07.016

3-R-1,5-Dinitro-3-azabicyclo[3.3.1]nonanes fused with a pyrazole ring were synthesised based on isomeric 4,6-dinitro-1- and 2-phenylindazoles.

Full text of DOI:10.1016/j.mencom.2008.07.016

Mendeleev
Communications
Mendeleev Commun., 2008, 18, 213–214
Synthesis of 3-substituted 1,5-dinitro-3-azabicyclo-
[3.3.1]nonanes containing a pyrazole fragment
Ekaterina M. Asadulina, Maxim A. Bastrakov, Vadim V. Kachala,
Aleksei M. Starosotnikov and Svyatoslav A. Shevelev*
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 119991 Moscow, Russian Federation.
Fax: +7 499 135 5328; e-mail: shevelev@ioc.ac.ru
DOI: 10.1016/j.mencom.2008.07.016
3-R-1,5-Dinitro-3-azabicyclo[3.3.1]nonanes fused with a pyrazole ring were synthesised based on isomeric 4,6-dinitro-1- and
2-phenylindazoles.
Heteroanalogues of bicyclo[3.3.1]nonanes are contained in
terpene alkaloids and used as biologically active compounds.1
Recently, an efficient antiarrhythmic activity was found in
1,5-dinitro-3-azabicyclo[3.3.1]nonenes.2 Many of them were
synthesised earlier2–5 on the basis of substituted 1,3-dinitro-
benzenes (Scheme 1). This synthesis involves the reduction of
carbon–carbon bonds of the benzene ring activated by meta-
arranged nitro groups under the action of NaBH4 or KBH4
and further double Mannich reaction with formaldehyde and
primary amines. There are a few examples of the synthesis of
such compounds containing heteroaromatic fragments.5,6 However,
there is no information on the synthesis of 3-azabicyclo[3.3.1]-
nonanes fused with five-membered heterocycles.
Here, we report the synthesis of 3-R-1,5-dinitro-3-azabicyclo-
[3.3.1]nonanes fused with a pyrazole ring. Starting materials in the
synthesis of the above compounds are isomeric 4,6-dinitro-1-
and 2-phenylindazoles 1 and 2, which can be prepared from
2,4,6-trinitrotoluene (TNT).7,8
Thus, the interaction of dinitroindazoles 1 and 2 with NaBH4
gave rise to hydride adducts 3 and 4,9 on treatment of which
with formaldehyde solution and primary amine tricyclic deriva-
tives are formed – 1,5-dinitro-3-azabicyclo[3.3.1]nonanes 5a–f
and 6a–g, annulated with a pyrazole ring at the C(7)–C(8)
bond (Scheme 2). Alkylamines and amino acids were used as
primary amines.
The structures of compounds 5 and 6 were supported by
NMR and IR spectroscopy and elemental analysis.†
NO2
O2N
The steric structures of 1,5-dinitro-3-azabicyclo[3.3.1]nonane
derivatives 5 and 6 were studied using compound 5a as an
R'
i, NaBH4, THF–EtOH–HCONH2
ii, HCO, R' NH2, AcOH
N
R
R
†
Compounds synthesised were characterised by 1H NMR spectroscopy
and elemental analysis. 1H NMR spectra (in [2H6]DMSO) were recorded
on a Bruker AM-300 spectrometer.
NO2
R = OH, Alk, Hal, OAlk, COOH
Scheme 1
NO2
R' = Alk, (CH2)nCOOH
General procedure for the preparation of compounds 5, 6 and 8. To a
solution of 0.48 g (1.7 mmol) of compound 1 or 2 in a mixture of 2 ml of
THF, 6 ml of EtOH and 4 ml of formamide 0.36 g (9.5 mmol) of NaBH4
were added portionwise over 20 min at a temperature below 10 °C. After
30 min, 7 ml of water was added followed by an addition of the mixture
of 2 ml of 30% aqueous solution of RNH2, 2 ml of water and 2 ml of
30% aqueous solution of formaldehyde, and then 2 ml of glacial AcOH.
After stirring for 30 min at room temperature, the reaction mixture was
poured into 150 ml of water, the precipitate was collected by filtration
and dried in air.
We found 4,6-dinitrobenzoannelated five-membered aromatic
heterocycles to be suitable precursors for the synthesis of
3-R-1,5-dinitro-3-azabicyclo[3.3.1]nonanes containing a hetero-
aromatic fragment.
NO2
NO2Na
5a: yield 48%, mp 152–154 °C (EtOH). 1H NMR, d: 2.34 (s, 3H, NMe),
2.55 (d, 1H, J 10.2 Hz), 2.60 (d, 1H, J 10.9 Hz), 2.80 (d, 1H, J 11.8 Hz),
3.09 (d, 1H, J 11.8 Hz), 3.27 (d, 1H, J 10.2 Hz), 3.31 (d, 1H, J 10.9 Hz),
3.41 (d, 1H, J 16.6 Hz), 3.47 (d, 1H, J 16.7 Hz), 7.43 (m, 1H, Ph), 7.49–
7.51 (m, 4H, Ph), 7.69 (s, 1H, Pz).
i
ii
N
N
N
Ph
N
Ph
O2N
NaO2N
R
1, 2
3, 4
NO2
NO2
5b: yield 70%, mp 154–155 °C. 1H NMR, d: 2.92 (d, 1H, J 12.8 Hz),
3.08 (d, 1H, J 12.9 Hz), 3.23–3.57 (m, 7H), 3.74 (d, 1H, J 16.2 Hz), 7.44
(t, 1H, p-Ph, J 8.1 Hz), 7.52–7.65 (m, 5H, Pz, Ph).
R
N
N
N
or
N Ph
5c: yield 80%, mp 208–210 °C. 1H NMR, d: 2.24 (t, 2H, CH2, J 5.1 Hz),
2.60–3.53 (m, 9H), 3.72 (d, 1H, J 16.2 Hz), 7.41–7.64 (m, 6H, Pz, Ph).
N
N
O2N
O2N
Ph
1
5d: yield 68%, mp 193–194 °C. H NMR, d: 0.89, 1.04 [2d, 3H, Me
5a–f
6a–g
(mixture of diastereomers), J 7.6 Hz], 2.92–3.53 (m, 8H), 3.73 (d, 1H,
J 16.1 Hz), 7.43–7.62 (m, 6H, Pz, Ph).
1, 3 1-Ph
2, 4 2-Ph
5, 6 a R = Me
e
f
R = Pri
R = (CH2)3COOH
b R = CH2COOH
c R = (CH2)2COOH
d R = CH(Me)COOH
5e: yield 72%, mp 96–98 °C. 1H NMR, d: 0.88 (d, 3H, Me, J 8.6 Hz),
1.06 (d, 3H, Me, J 8.6 Hz), 2.91–3.67 (m, 9H), 7.38–7.63 (m, 6H, Pz, Ph).
5f: yield 75%, mp 79–81 °C. 1H NMR, d: 1.46 (m, 2H, CH2), 1.78
(m, 2H, CH2), 2.41 (m, 2H, CH2), 2.68 (d, 1H, J 10.7 Hz), 2.75 (d, 1H,
J 10.7 Hz), 2.94 (d, 1H, J 10.7 Hz), 3.10 (t, 2H, J 12.9 Hz), 3.32 (d, 2H,
J 17.5 Hz), 3.79 (d, 1H, J 17.5 Hz), 7.42–7.63 (m, 6H, Pz, Ph).
g R = (CH2)2Cl
Scheme 2 Reagents and conditions: i, NaBH4 (5.6 equiv.), THF–EtOH–
HCONH2, 10 °C, 1 h; ii, HCHO (30% aqueous solution) (12 equiv.), RNH2
(12 equiv.), AcOH–H2O.
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Mendeleev Commun., 2008, 18, 213–214
Me
NO2
NO2
N
CN
N
CN
N
HOOC
N
i, ii
N
N
N
N
O2N
O2N
O2N NO2
Figure 1 Steric structure of 5a.
NO2
NO2
example. The data of NMR experiments (1H, 13C, COSY,
2D-NOESY, HSQC and HMBC) showed that the piperidine ring
in the molecule of 5a has the ‘chair’ conformation, although the
cyclohexene ring is approximately planar (Figure 1).
7
8
Scheme 3 Reagents and conditions: i, NaBH4 (5.6 equiv.), THF–EtOH–
HCONH2, 10 °C, 1 h; ii, HCHO (30% aqueous solution) (12 equiv.),
H2NCH2COOH (12 equiv.), AcOH–H2O.
These data are analogous to published data10,11 obtained for
7-polyfluoroalkoxy-1,5-dinitro-3-azabicyclo[3.3.1]non-6-enes.
On interaction of 3-cyano-4,6-dinitro-1-(4-nitrophenyl)indazole
7 prepared by the nitration of a corresponding N-phenyl deri-
vative12 with NaBH4 the reduction proceeds selectively (only at
the dinitrophenyl fragment) and further double Mannich reaction
with formaldehyde and glycine gives tricyclic derivative 8† in a
good yield (Scheme 3).
Thus, based on isomeric 4,6-dinitro-1- and 2-phenylindazoles,
a general method was developed for the synthesis of 3-R-1,5-di-
nitro-3-azabicyclo[3.3.1]nonanes fused with a pyrazole ring, a
new type of 1,5-dinitro-3-azabicyclo[3.3.1]nonanes.
This work was supported by the Russian Foundation for
Basic Research (grant no. 07-03-00414).
References
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6a: yield 29%, mp 127–129 °C (EtOH). 1H NMR, d: 2.26 (s, 3H, NMe),
2.52, 2.60, 2.72 (3d, 1H, J 10.1 Hz), 2.92, 3.05 (2d, 1H, J 11.1 Hz), 3.17
(d, 1H, J 8.9 Hz), 3.35–3.54 (m, 2H), 7.31 (t, 1H, p-Ph, J 8.1 Hz), 7.48
(t, 2H, m-Ph, J 8.1 Hz), 7.85 (d, 2H, o-Ph, J 8.0 Hz), 8.42 (s, 1H, Pz).
6b: yield 82%, mp 88–90 °C. 1H NMR, d: 2.92 (d, 1H, J 13.3 Hz),
3.02–3.54 (m, 9H), 7.28 (t, 1H, p-Ph, J 8.2 Hz), 7.45 (t, 2H, m-Ph,
J 8.2 Hz), 7.80 (d, 2H, o-Ph, J 8.3 Hz), 8.43 (s, 1H, Pz).
6
7
8
9
I. E. Yakunina, I. V. Shakhkel’dyan, Yu. M. Atroshchenko, A. S. Rybakova,
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37, 504].
6c: yield 76%, mp 92–94 °C. 1H NMR, d: 2.25 (t, 2H, CH2, J 6.6 Hz),
2.65–3.62 (m, 10H), 7.28 (t, 1H, p-Ph, J 8.0 Hz), 7.46 (t, 2H, m-Ph,
J 8.1 Hz), 7.82 (d, 2H, o-Ph, J 8.1 Hz), 8.38 (s, 1H, Pz).
1
6d: yield 76%, mp 188–190 °C. H NMR, d: 0.88, 1.08 [2d, 3H, Me
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(mixture of diastereomers), J 8.6 Hz], 2.95–3.58 (m, 9H), 7.29 (t, 1H,
p-Ph, J 8.5 Hz), 7.47 (t, 2H, m-Ph, J 8.6 Hz), 7.83 (d, 2H, o-Ph, J 8.6 Hz),
8.41 (s, 1H, Pz).
10 E. G. Nikiforova, M. A. Korolev, I. V. Shakhkel’dyan, M. D. Dutov,
Yu. D. Grudytsin, Yu. M. Atroshchenko, S. A. Shevelev and V. A.
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Chem. Bull., Int. Ed., 2003, 52, 1782).
6e: yield 83%, mp 139–141 °C. 1H NMR, d: 0.81 (d, 3H, Me, J 8.6 Hz),
0.90 (d, 3H, Me, J 8.6 Hz), 2.80–3.52 (m, 9H), 7.28 (t, 1H, p-Ph, J 8.1 Hz),
7.47 (t, 2H, m-Ph, J 8.1 Hz), 7.83 (d, 2H, o-Ph, J 8.0 Hz), 8.37 (s, 1H, Pz).
1
6f: yield 75%, mp 75 °C. H NMR, d: 1.48 (m, 2H, CH2), 1.86 (m,
2H, CH2), 2.48 (m, 2H, CH2), 2.73–3.30 (m, 5H), 3.34–3.62 (m, 3H),
7.29 (t, 1H, p-Ph, J 8.5 Hz), 7.48 (t, 2H, m-Ph, J 8.4 Hz), 7.80 (d, 2H,
o-Ph, J 8.6 Hz), 8.35 (s, 1H, Pz).
1
6g: yield 16%, mp 65–67 °C. H NMR, d: 2.71–3.10 (m, 6H), 3.23–
3.58 (m, 6H), 7.30 (t, 1H, p-Ph, J 8.1 Hz), 7.47 (t, 2H, m-Ph, J 8.1 Hz),
7.82 (d, 2H, o-Ph, J 8.2 Hz), 8.42 (s, 1H, Pz).
1
8: yield 75%, mp 178–180 °C. H NMR, d: 2.95–3.45 (m, 8H), 3.60
(d, 1H, J 18.6 Hz), 3.93 (d, 1H, J 18.6 Hz), 8.00 (d, 2H, 4-NO2C6H4,
J 9.4 Hz), 8.43 (d, 2H, 4-NO2C6H4, J 9.4 Hz).
Received: 14th March 2008; Com. 08/3102
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