One-step synthesis of substituted 3,5-dinitropiperidines and 1,5-dinitro-3,7-diazabicyclo[3.3.1]nonanes from 1,3-dinitropropanes

Article abstract of DOI:10.1007/s11172-005-0265-9

1,5-Dinitro-3,7-diazabicyclo[3.3.1]nonane derivatives were synthesized in up to 83%yields by the Mannich reaction of 1,3-dinitropropanes with excess formaldehyde and primary amines. In some cases, for instance, when 2,2-dimethyl-1,3-dinitropropane and benzylamine or monoethanolamine are used, the reaction occurs with low yields or stops at the step of formation of 3,5-dinitropiperidines. The influence of the structure of the starting compounds and reaction conditions on the yields of 1,5-dinitro-3,7-diazabicyclo[3.3.1] nonanes and 3,5-dinitropiperidines was studied.

Full text of DOI:10.1007/s11172-005-0265-9

4
14
Russian Chemical Bulletin, International Edition, Vol. 54, No. 2, pp. 414—420, February, 2005
Oneꢀstep synthesis of substituted 3,5ꢀdinitropiperidines
and 1,5ꢀdinitroꢀ3,7ꢀdiazabicyclo[3.3.1]nonanes from 1,3ꢀdinitropropanes
a
a
aꢀ
a
N. N. Yarmukhamedov, N. Z. Baibulatova, V. A. Dokichev, T. V. Khakimova,
a
b
a
L. V. Spirikhin, Yu. V. Tomilov, and M. S. Yunusov
aInstitute of Organic Chemistry, Ufa Research Center of the Russian Academy of Sciences,
1 prosp. Oktyabrya, 450054 Ufa, Russian Federation.
7
Fax: +7 (347 2) 35 6066. Eꢀmail: dokichev@anrb.ru
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences,
b
4
7 Leninsky prosp., 119992 Moscow, Russian Federation.
Fax: +7 (095) 135 6390. Eꢀmail: tom@ioc.ac.ru
1
,5ꢀDinitroꢀ3,7ꢀdiazabicyclo[3.3.1]nonane derivatives were synthesized in up to 83% yields
by the Mannich reaction of 1,3ꢀdinitropropanes with excess formaldehyde and primary amines.
In some cases, for instance, when 2,2ꢀdimethylꢀ1,3ꢀdinitropropane and benzylamine or
monoethanolamine are used, the reaction occurs with low yields or stops at the step of formaꢀ
tion of 3,5ꢀdinitropiperidines. The influence of the structure of the starting compounds
and reaction conditions on the yields of 1,5ꢀdinitroꢀ3,7ꢀdiazabicyclo[3.3.1]nonanes and
3
,5ꢀdinitropiperidines was studied.
Key words: 1,3ꢀdinitropropanes, formaldehyde, primary amines, Mannich reaction,
3
,5ꢀdinitropiperidines, 1,5ꢀdinitroꢀ3,7ꢀdiazabicyclo[3.3.1]nonanes.
1
2
High biological activity (antitumor, antiarrhythmic,
Experiments were carried out for 4 h at 20 °С with the
molar ratio 1,3ꢀdinitropropane : formaldehyde : amine =
1 : 10 : 5. Using the condensation of 1,3ꢀdinitroꢀ2ꢀ
phenylpropane (1b) with methylamine (2a) and formalꢀ
dehyde as an example, we found that chloroform is the
best solvent in which the yield of the corresponding
1,5ꢀdinitroꢀ3,7ꢀdiazabicyclo[3.3.1]nonane 3d reaches
83% (Scheme 1). The use of more polar solvents deꢀ
creases considerably the yield of compound 3d (Table 1).
3
and insecticide ) of compounds containing the 3,7ꢀdiꢀ
azabicyclo[3.3.1]nonane fragment stimulates the develꢀ
opment of new methods for their syntheses, as well as the
synthesis of unknown compounds of this type by the
Mannich reaction of aliphatic CH acids4—6 with primary
amines and formaldehydes. Oneꢀpot methods for straightꢀ
forward syntheses of these heterocycles by multiple conꢀ
densation without isolation of intermediate products are
7
of special interest. In the previous report, we described a
new convenient method for the oneꢀstep synthesis of
Scheme 1
1
,5ꢀdinitroꢀ3,7ꢀdiazabicyclo[3.3.1]nonanes by the fourꢀ
fold condensation of 1,3ꢀdinitroꢀ2ꢀphenylpropane with
formaldehyde and methylamine or monoethanolamine
under the Mannich reaction conditions. In this work, we
studied the syntheses of a wide scope of 1,5ꢀdinitroꢀ3,7ꢀ
diazabicyclo[3.3.1]nonanes and the influence of the strucꢀ
ture of the starting reagents and reaction conditions on
the yield and composition of the products formed by the
reactions of 1,3ꢀdinitropropanes with primary amines and
formaldehyde.
We used 1,3ꢀdinitropropane (1а), 1,3ꢀdinitroꢀ2ꢀpheꢀ
nylꢀ (1b), 2ꢀ(4ꢀbromophenyl)ꢀ1,3ꢀdinitroꢀ (1c), 1,3ꢀdiꢀ
nitroꢀ2ꢀ(2,4ꢀdichlorophenyl)ꢀ (1d), and 2,2ꢀdimethylꢀ
1
,3ꢀdinitropropanes (1e) as dinitro compounds and
methylꢀ (2a), benzylꢀ (2b), monoethanolꢀ (2c), and
cyclopropylamines (2d) as amines.
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 2, pp. 405—411, February, 2005.
066ꢀ5285/05/5402ꢀ0414 © 2005 Springer Science+Business Media, Inc.
1

1
,5ꢀDinitroꢀ3,7ꢀdiazabicyclo[3.3.1]nonanes
Russ.Chem.Bull., Int.Ed., Vol. 54, No. 2, February, 2005
415
Table 1. Influence of the solvent nature on the composition
and yield of the reaction products of 1,3ꢀdinitropropane 1b
with formaldehyde and methylamine (molar ratio
In this case, the yield of piperidines 4 achieves ~40% after
h of the reaction and decreases to ~3% at the end
after 4 h. The results obtained indicate that a molecule of
diazabicyclononanes is formed through the step of formaꢀ
tion of substituted piperidines.
The study of the influence of the nature of the starting
reagents on the reaction course revealed that the strucꢀ
ture of the amine component is a substantial factor. For
example, similarly to 2ꢀphenyldinitropropane 1b, the conꢀ
densation of 1,3ꢀdinitropropanes 1а,с,d with formaldeꢀ
hyde and methylamine under the chosen conditions
2
1
b : CH O : MeNH = 1 : 10 : 5, 4 h, 20 °C)
2 2
Solvent
Yield* (%)
3
d
4
5
СHCl3
83
82
42
20
18
9
3
4
34
13
16
56
5
4
4
41
41
4
СHCl —EtOH (5 : 1)
3
СHCl —AcOH (1 : 1)
3
EtOH
DMSO
THF—H О (1 : 1)
(
ratio 1 : 10 : 5, CHCl ) affords the corresponding
3
1,5ꢀdinitroꢀ3,7ꢀdiazabicyclo[3.3.1]nonanes 3a,h,i in
rather high yields (64—77%) (Scheme 2). However, on
going from methylamine (2a) to monoethanolamine (2c)
or benzylamine (2b), their yield decreases remarkably or
the reaction ceases at the step of piperidine formation. In
2
*
Calculated to the isolated product.
In this reaction, monocyclic heterocycles, viz., stereoꢀ
isomeric 1ꢀmethylꢀ3,5ꢀdinitroꢀ4ꢀphenylpiperidines 4,
´, and 4″ and 1,3,5ꢀtrimethylhexahydrotriazine (5),
are formed along with bicyclic compound 3d. When a
the reactions of dinitropropanes 1а,b with CH O and
2
4
benzylamine (2b) and in the reaction of compound 1a
with CH O and monoethanolamine (2c), the yields of
2
THF—H О (1 : 1) mixture is used as a solvent, the overall
2
the corresponding diazabicyclononanes 3b,c,f are only
yield of piperidines 4, 4´, and 4″ is 56% and their ratio is
10—16% (see Scheme 2).
~
3 : 1.3 : 1, respectively. It should be mentioned that the
reaction medium contains predominantly isomer 4″ after
Scheme 2
2
h of reaction in CHCl3.
The change in the molar ratio of reagents
1
b : СН О : МеNH from 1 : 10 : 5 to 1 : 2 : 1 decreases
2
2
: R1 = H (a), Ph (b), 4ꢀBrC H4 (c), 2,4ꢀCl C H (d)
1
2
6
2 6 3
the yield of diazabicyclononane 3d with a simultaneous
increase in the overall yield of 3,5ꢀdinitropiperidines 4
2
: R = Me (a), PhCH (b), CH CH OH (c), cycloꢀC H (d)
2
2
2
3 5
3
R1
R2
Me
PhCH2
CH CH OH
Yield (%)
(
Table 2).
When the reaction time increases from 1 to 4 h, the
a
b
c
d
e
f
g
h
i
H
H
H
Ph
Ph
Ph
Ph
64
10
16
83
60
16
75
77
75
yield of diazabicyclononane 3d increases from 54 to 83%.
2
2
Me
cycloꢀC H5
3
Table 2. Influence of the ratio of the starting reagents on the
composition and yields of the reaction products of 1,3ꢀdiꢀ
nitropropane 1b with formaldehyde and methylamine (CHCl3,
PhCH2
CH CH OH
2 2
4ꢀBrC H4
2,4ꢀCl C H
Me
Me
6
4
h, 20 °C)
2
6 3
Ratio
Yield (%)
The structures of all synthesized compounds were conꢀ
1
b : CH O : MeNH
1
13
2
2
firmed by the H and С NMR spectra. The structures of
diazabicyclo[3.3.1]nonanes were interpreted and signals
of the H and C atoms of the methylene fragments were
assigned, in some cases, using the {C,H} correlation proꢀ
cedure and NOEDIFF experiments. The С(1), C(5), and
С(9) atoms are unambiguously determined from the mulꢀ
3
d
4
5
1
1
1
1
1
: 2 : 1
: 4 : 2
: 8 : 4
: 10 : 5
: 20 : 10
12
42
78
83
83
55
33
16
3
—*
—*
—*
05
3
10
13
tiplicity and chemical shifts of signals in the С NMR
spectra. The С(2), C(4), С(6), and C(8) atoms of unꢀ
*
Traces.

4
16
Russ.Chem.Bull., Int.Ed., Vol. 54, No. 2, February, 2005
Yarmukhamedov et al.
substituted bicyclononanes 3a—c are chemically equivaꢀ
lent and appear in a region of δC 58—61, and the same
C atoms of their substituted analogs are pairwise nonꢀ
equivalent due to the effect of the aryl substituent and
the same side with the aryl substituent being the most
screened (Table 3). A similar regularity was observed earꢀ
13
lier for the same C atoms in the С NMR spectrum of
3,7ꢀdibenzylꢀ9ꢀhydroxyꢀ1,5ꢀbis(methoxycarbonyl)ꢀ3,7ꢀ
8
appear as signals at δ 52—55 and 63—65, the C atoms at
diazabicyclo[3.3.1]nonane (δ 53.4 and 59.6).
С
С
Table 3. Н and 13C NMR spectra of 1,5ꢀdinitroꢀ3,7ꢀdiazabicyclo[3.3.1]nonanes 3a—i (CDCl3)
1
Comꢀ
poꢀ
und
δH (J/Hz)
H (2), H (2), H (6), H (6), H(9)
δC
Other
H atoms
C(1), C(2), C(6), C(9)
C(5) C(4) C(8)
Other
C atoms
ax
eq
ax
eq
H (4) H (4) H (8) H (8) (s)
ax
eq
ax
eq
(
d)
(d)
(d)
(d)
3
3
a a
b
2.48
12.0)
3.00
2.28
(12.0)
2.86
2.48
(12.0)
3.00
2.28 2.18
(12.0)
2.86 2.77
(11.3)
1.90 (s, 2 Ме)
84.8 60.9 60.9 34.9
84.6 58.5 58.5 35.5
44.1 (2 Ме)
(
(
3.70 (s, 2 CH );
60.6 (2 CH ); 127.7
2
2
11.3)
(11.3)
(11.3)
7.25—7.39 (2 Ph)
(pꢀCPh); 128.7, 128.9
(
(
oꢀCPh, mꢀCPh); 136.2
iꢀCPh
)
3
3
3
c
d
e
3.45
11.2)
2.88
(11.2)
3.45
(11.2)
2.88 2.68
(11.2)
2.67 (t, NCH2,
J = 5.2); 3.65 (t,
83.9 58.1 58.1 38.5
88.1 54.7 64.6 51.1
87.4 52.7 62.3 50.8
58.3 (NCH );
58.5 (OCH2)
2
(
(
(
OCH , J = 5.2);
2
4
.15 (br.s, 2 ОН)
3.45
12.0)
2.87
(12.0)
3.10
(12.0)
2.87 4.44
(12.0)
2.34, 2.49 (both s,
2 Ме); 7.05—7.36
44.1, 44.8 (2 Ме);
128.5, 128.8, 130.6,
131.6 (oꢀCPh, mꢀCPh,
(
m, Ph)
iꢀCPh, pꢀCPh
)
3.77
12.1)
3.05
(12.1)
3.40
(11.3)
2.98 4.51
(11.3)
0.44—0.66 (m,
2 CH CH ); 1.86
7.1, 7.3 (CH CH );
2
2
35.6, 36.0 (2 CH);
2
2
(
7
m, 2 CH);
.18—7.40 (m, Ph)
128.3 (pꢀCPh); 128.6
(oꢀCPh); 131.3 (mꢀCPh);
31.6 (iꢀCPh
1
)
3
3
f
3.54
11.1)
2.88
(11.1)
3.18
(12.0)
2.93 4.60
(12.0)
3.70, 3.82 (both s,
2 CH ); 7.05—7.36
88.2 52.6 62.2 51.6
87.0 51.5 63.7 54.3
88.1 54.7 64.8 51.3
60.6, 61.6 (2 CH );
128.7, 128.8, 128.9,
129.3 (oꢀCPh, mꢀCPh,
2
(
2
(
m, 3 Ph)
oꢀCBn, mꢀCBn, pꢀCBn);
31.5 (pꢀCPh); 131.6
iꢀCPh); 136.3, 136.4
iꢀCBn
1
(
(
)
g
3.74 b
12.2,
.3)
3.47
(12.2)
3.44 b
(10.8,
2.3)
3.54 4.33 c 2.76 (t, N(3)CH2,
(10.8)
58.0 (N(3)CH ); 58.1
2
(
J = 5.2); 3.02 (t,
N(7)CH , J = 5.4);
(N(7)CH ); 58.3, 58.7
2
2
(2 OCH ); 128.9 (oꢀCPh);
2
2
3
.68 (t, OCH2,
J = 5.2); 3.84 (t,
OCH , J = 5.4);
129.2 (mꢀCPh); 130.8
(iꢀCPh); 131.0 (pꢀCPh
)
2
7
.10—7.34 (m, Ph)
3
3
h
i
3.58
12.1)
2.96
(12.1)
3.18
(10.9)
2.98 4.45
(10.9)
2.45, 2.58 (both s,
2 Ме); 7.23—7.42
44.2, 44.7 (2 Ме);
123.4, 130.8, 131.8,
(
(
(
m, H arom.)
133.3 (pꢀCPh, iꢀCPh
oꢀCPh, mꢀCPh
,
)
3.65
12.3)
2.95
(12.3)
3.14
(10.8)
3.05 5.12
(10.8)
2.50, 2.57 (both s, 2 88.1 55.2 65.6 46.9
Ме); 7.16 (dd, H(5´),
J = 8.7, J = 2.3);
44.0, 44.5 (2 Ме);
127.1 С(5´); 128.9
С(2´); 130.4 С(3´);
132.5 С(6´); 134.9
С(1´); 139.0 С(4´)
7
.40 (d, Н(3´),
J = 2.3); 7.98 (d,
Н(6´), J = 8.7)
a
b
c
The H and 13С NMR spectra correspond to published data.5
Dd.
Br.s.
1

1
,5ꢀDinitroꢀ3,7ꢀdiazabicyclo[3.3.1]nonanes
Russ.Chem.Bull., Int.Ed., Vol. 54, No. 2, February, 2005
417
It seems more difficult to assign signals of nonꢀ
diequatorially arranged nitro groups (δH 4.79 and 4.96)
and different cisꢀ or transꢀarrangements of the phenyl
substituent. In this case, signals of the protons at the C(4)
atom appear as triplets at δ 4.34 and 3.88 with the SSC
equivalent methylenic protons of the heterocycles, whose
1
positions in the H NMR spectra can be affected by a
conformational equilibrium in solutions of the correꢀ
sponding diazabicyclo[3.3.1]nonanes (chair—chair or
chair—boat). In particular, the 1D NOEDIFF experiꢀ
ments for compound 3f showed that the protons with
δ 3.54 are localized at the side of the phenyl substituent,
and irradiation at the resonance frequency H—C(9) inꢀ
creases the intensity of signals of the downfield protons
with δ 3.18 at the С(6) and С(8) atoms. In both cases, this
indicates that the axial protons at both the С(2), С(4) and
С(6), С(8) atoms appear in a low field compared to the
equatorial protons. Similar changes in chemical shifts of
the protons and C atoms were observed for compound 3d
with the methyl substituents at the N atoms.
3
3
constants J = 7.5 Hz and J = 11.2 Hz. Taking into
1
0
account published data for piperidineꢀ2,3,4,5ꢀtetraꢀ
carboxylates, we can assign them to isomers 4 and 4´,
respectively. In isomer 4″, the H(3) and H(5) protons at
the nitro groups also appear as one signal, whose downfield
shift (δH 6.10) indicates their transꢀarrangement and,
13
probably, fast ring inversion. In the С NMR spectra of
isomers 4 and 4´, signals of the C atoms containing the
nitro groups are observed at δ ~86, while in isomer 4″ they
appear at δ 81.2.
The condensation of formaldehyde and monoethanolꢀ
amine (2c) with 2ꢀarylꢀ1,3ꢀdinitropropanes 1c,d proceeds
poorly and ceases at the step of formation of 3,5ꢀdinitroꢀ
piperidines. In the case of dinitropropane 1с, only
4
ꢀ(4ꢀbromophenyl)ꢀ1ꢀ(2ꢀhydroxyethyl)ꢀ3,5ꢀdinitropiꢀ
peridine (6) was isolated in 13% yield. The chemical shifts
and SSC constants of signals from the protons of the
1
heterocycle in the H NMR spectrum of this compound
are very close to similar signals of compounds 4´ and
correspond to the isomer with diequatorial arrangement
of both nitro groups. The repeated introduction of dinitroꢀ
piperidine 6 into the reaction with formaldehyde and meꢀ
thylamine does not furnish the expected unsymmetrically
substituted diazabicyclo[3.3.1]nonane, and the starting
piperidine 6 returns unchanged.
It should be noted that these results are only in part
similar to the data for 3,7ꢀdibenzylꢀ9ꢀhydroxyꢀ1,5ꢀ
bis(methoxycarbonyl)ꢀ3,7ꢀdiazabicyclo[3.3.1]nonane. In
8
fact, the axial protons from the side of the substituent
have a downfield shift compared to the equatorial proꢀ
tons, whereas an opposite tendency is observed for the
protons at the С(6) and С(8) atoms (δHeq – δHax < 0 for
3
d,f and δHeq – δHax = 0.14 for the corresponding hydroxy
derivative). Among 3,7ꢀdiazabicyclo[3.3.1]nonanes synꢀ
thesized here, only Nꢀhydroxyethyl substituted compound
Unlike dinitropropane 1с, the use in this reaction of
2ꢀ(2,4ꢀdichlorophenyl)ꢀ1,3ꢀdinitropropane (1d) containꢀ
ing the Cl atom in the orthoꢀposition of the benzene ring
leads to 3,5ꢀdinitropiperidine 7 in 49% yield. This comꢀ
pound has the equatorial/axial nitro groups. In the
1
3
g exhibits a similar regularity in the H NMR spectrum
(
see Table 3). The 1D NOEDIFF experiment for this
compound exhibited an interaction between the proton at
the C(9) atom and the proton giving a signal at δ 3.44. In
addition, this is the case of compound 3g when the
1
H NMR spectrum of compound 7, all protons of the
1
H NMR spectrum contains the farꢀrange spinꢀspin couꢀ
heterocycle are nonequivalent and have equal integral
intensities, whereas the signals of the C(2), C(6) and C(3),
pling (SSC) constant between the H(2), H(8) and H(4),
H(6) axial protons, respectively (J = 2.3 Hz), which is
likely related to their specific W arrangement. It should be
mentioned that the structure of compound 3g was also
confirmed by the encounter synthesis from 2,4ꢀdinitroꢀ
13
C(4) atoms in the C NMR spectrum are also pairwise
nonequivalent. The spinꢀspin proton decoupling at the
3
3
С(4) atom ( J
= 3.0 Hz, J
= 11.4 Hz) and
,5
ax ax
3
,4
eq ax
4
chemical shifts of the methinic protons at the С(5) (δ 6.00)
and С(3) (δ 5.20) atoms indicate their axial and equatoꢀ
rial arrangement. These data along with the absence of
doubled signals of the hydroxyethyl substituent indicate
that heterocycle 7 in solution has a retarded chairꢀlike
conformation with equatorial arrangement of the aryl subꢀ
stituent.
9
phenol using a known method ; however, its yield was
only ~1%.
The chemical shift and SSC constant values were also
used for the assignment of signals of protons of isomeric
piperidines 4. For isomers 4 and 4´, the most probable is a
chairꢀlike conformation of the heterocycle with the

4
18
Russ.Chem.Bull., Int.Ed., Vol. 54, No. 2, February, 2005
Yarmukhamedov et al.
The reaction of 2,2ꢀdimethylꢀ1,3ꢀdinitropropane (1e)
Thus, we have developed the oneꢀstep methods for
the synthesis of substituted 1,5ꢀdinitroꢀ3,7ꢀdiazabiꢀ
cyclo[3.3.1]nonanes and the corresponding 3,5ꢀdinitroꢀ
piperidines by the reaction of 1,3ꢀdinitropropanes with
formaldehyde and primary amines. The reaction direcꢀ
tion depends on the structure of the starting reagents and
reaction conditions.
with formaldehyde and methylamine (2a) or monoꢀ
ethylamine (2c) also ceases at the step of formation of
the corresponding 3,5ꢀdinitropiperidines 8 and 9
(
Scheme 3), and the repeated introduction of the latter
into condensation with methylamine and formaldehyde
does not provide the expected unsymmetrical 3,7ꢀdiazabiꢀ
cyclo[3.3.1]nonane. In this case, 1,4,4ꢀtrimethylꢀ3,5ꢀ
dinitropiperidine (8) is synthesized as a mixture of
transꢀ and cisꢀisomers (~1 : 1.5) with an overall yield
of 51%, while 1ꢀ(2ꢀhydroxyethyl)ꢀ4,4ꢀdimethylꢀ3,5ꢀ
dinitropiperidine (9) was isolated as the single transꢀisoꢀ
mer (~20% yield).
Experimental
1H and 13С NMR spectra were recorded on a Bruker AMꢀ300
spectrometer (300.13 and 75.47 MHz, respectively) in CDCl3
using Me Si as the internal standard. IR spectra were obtained
4
on a Specord Mꢀ80 instrument in thin layer or Nujol. Mass
spectra were recorded on an MXꢀ1300 spectrometer with a temꢀ
perature of the supply cylinder of 100 °C and an ionizing voltage
of 12 and 70 eV. GLC analysis was carried out on a Chromꢀ5
chromatograph with a flameꢀionization detector (column
Scheme 3
1
200×5 mm with 5% SEꢀ30 on Inerton NꢀAW DMCS
(
0.125—0.160 mm), helium as carrier gas). TLC analysis was
carried out on Silufol chromatographic plates (Merck), and preꢀ
parative separation was performed by column chromatography
on silica gel.
1
1
1
,3ꢀDinitropropane (1a) and arylꢀsubstituted 1,3ꢀdinitroꢀ
1
2
13
propanes 1b—d and 2,2ꢀdimethylꢀ1,3ꢀdinitropropane (1e)
were synthesized according to described procedures. The physiꢀ
5
cochemical constants of compounds 3a (eluent petroleum
7
i
7
ether—CHCl , 1 : 3), 3d (eluent CНCl —Pr OH, 7 : 3), 3g
3
3
i
14
i
(
eluent CНCl —Pr OH, 9 : 1), and 5 (eluent CНCl —Pr OH,
3
3
1
: 9) coincided with published data.
Reaction of 1,3ꢀdinitropropanes 1a—d with formaldehyde and
amines (general procedure). A mixture of 26% aqueous formalꢀ
dehyde (2.58 g, 22 mmol) and the corresponding primary amine
2
1
a—d (11 mmol) were added to a solution of 1,3ꢀdinitropropane
a—d (2.2 mmol) in СНCl3 (15 mL) at 0—10 °С, and the
In the spectrum of isomer cisꢀ8, the signal assigned to
the protons at the С(3) and С(5) atoms is a doublet of
resulting mixture was kept for 4 h at 20 °C. The reaction mixture
was washed with water (3×5 mL) and dried with Na SO . After
the solvent was removed under reduced pressure, the residue
3
doublets with the SSC constants J
= 11.4 Hz and
ax,ax
2
4
3
Jax,eq = 4.0 Hz. The methyl substituents at the C(4)
atoms are chemically nonequivalent and appear as signals
at δ 1.08 and 1.37. Therefore, in this compound both
nitro groups are equatorial, and the conformational equiꢀ
librium is strongly shifted toward the predomination of
was chromatographed on a column packed with SiO . To study
2
the influence of the reaction conditions on the yields of
1,5ꢀdinitroꢀ3,7ꢀdiazabicyclo[3.3.1]nonanes and 3,5ꢀdinitroꢀ
piperidines, we changed the solvent nature and ratio of the startꢀ
ing reagents (see Tables 1 and 2). The H and С NMR spectra
of dinitrodiazabicyclononanes 3a—i are presented in Table 3.
1
13
1
the chairꢀlike isomer. In the H NMR spectrum of isomer
transꢀ8, protons at the С(3) and С(5) atoms appear as a
3
,7ꢀDibenzylꢀ1,5ꢀdinitroꢀ3,7ꢀdiazabicyclo[3.3.1]nonane (3b).
3
triplet with J = 5.4 Hz, and the methyl substituents at the
Dinitropropane 1a (0.29 g), amine 2с (1.20 g), and formaldeꢀ
hyde (22 mmol) gave 0.09 g (10%) of compound 3b as an oily
liquid, R 0.67 (eluent CHCl —MeOH, 7 : 3). Found (%):
C, 63.75; H, 6.05; N, 14.17. C H N O . Calculated (%):
C, 63.62; H, 6.10; N, 14.14. MS, m/z: 396 [M] . IR, ν/cm :
С(4) atom are equivalent and have a chemical shift at
δ 1.23, indicating (in the case of transꢀarranged nitro
groups as in piperidine 4″) an averaged conformational
f
3
2
1
24
4
4
+
–1
state in a CDCl solution at room temperature. Signals of
3
1
the protons in the H NMR spectrum of piperidine 9,
704, 816, 1364 (Ph); 1376, 1544 (NO2).
3
,7ꢀDi(2ꢀhydroxyethyl)ꢀ1,5ꢀdinitroꢀ3,7ꢀdiazabiꢀ
cyclo[3.3.1]nonane (3c). Dinitropropane 1a (0.29 g), amine 2c
0.67 g), and formaldehyde (22 mmol) gave 0.09 g (16%) of
compound 3c as an oily liquid, R 0.65 (eluent CHCl —MeOH,
which also has the transꢀconfiguration of two nitro groups,
appear similarly and, moreover, they are broadened due
to the conformational mobility of the heterocycle.
It should be noted that 1,3ꢀdinitroꢀ2ꢀphenylpropane
1b) does not react with formaldehyde and 2ꢀaminoꢀ2ꢀ
hydroxymethyl)ꢀ1,3ꢀpropanediol or aminotrimethoxyꢀ
(
f
3
7
: 3). Found (%): C, 48.55; H, 7.46; N, 20.67. C H N O .
1
1
20
–1
4
4
(
(
Calculated (%): C, 48.53; H, 7.39; N, 20.59. IR, ν/cm : 1376,
+
1
544 (NO ); 3400 (ОН). MS, m/z: 304 [M ].
2
methane (unlike monoethanolamine) and returns unꢀ
changed from the reaction mixture.
3,7ꢀDicyclopropylꢀ1,5ꢀdinitroꢀ9ꢀphenylꢀ3,7ꢀdiazabiꢀ
cyclo[3.3.1]nonane (3e). Dinitropropane 1b (0.29 g), amine 2d

1
,5ꢀDinitroꢀ3,7ꢀdiazabicyclo[3.3.1]nonanes
Russ.Chem.Bull., Int.Ed., Vol. 54, No. 2, February, 2005
419
2
3
3
(
0.63 g), and formaldehyde (22 mmol) gave 0.49 g (60%) of
H (6), J = 11.5 Hz, J
= 4.5 Hz); 5.05 (t, 1 H, H(4), J =
eq
ax,eq
3
3
compound 3e as colorless crystals, m.p. 164—166 °С (from hexꢀ
ane), R 0.66 (eluent CHCl ). Found (%): C, 60.86; H, 6.51;
10.1 Hz); 6.10 (ddd, 2 H, H(3), H(5), J = 4.5 Hz, J = 10.1 Hz,
J = 11.5 Hz). С NMR, δ: 45.3 (МеN); 45.9 (С(4)); 58.2
3
13
f
3
N, 14.92. C H N O . Calculated (%): C, 61.29; H, 6.48;
(С(2), C(6)); 81.2 (С(3), C(5)).
1
9
24
4
4
+
–1
N, 15.05. MS, m/z: 372 [M] . IR, ν/cm : 840, 3020, 3080,
100 (Ar); 1360, 1555 (NO ).
4tꢀ(4ꢀBromophenyl)ꢀ1ꢀ(2ꢀhydroxyethyl)ꢀ3r,5cꢀdinitroꢀ
piperidine (6). Dinitropropane 1c (0.64 g), amine 2b (0.67 g),
and formaldehyde (22 mmol) gave 0.11 g (13%) of compound 6
3
2
3
,7ꢀDibenzylꢀ1,5ꢀdinitroꢀ9ꢀphenylꢀ3,7ꢀdiazabiꢀ
cyclo[3.3.1]nonane (3f). Dinitropropane 1b (0.46 g), amine 2b
1.20 g), and formaldehyde (22 mmol) gave 0.16 g (16%) of
compound 3f as colorless crystals, m.p. 179—180 °C, R 0.75
as colorless crystals, m.p. 139—140 °C (from hexane), R 0.50
f
i
(
(eluent CHCl —Pr OH, 7 : 3). Found (%): C, 41.85; H, 4.28;
3
Br, 21.45; N, 11.29. C H BrN O . Calculated (%): C, 41.73;
f
13 16
3
5
+
–1
(
eluent CHCl —MeOH, 7 : 3). Found (%): C, 68.75; H, 6.05;
H, 4.31; Br, 21.35; N, 11.23. MS, m/z: 374 [M] . IR, ν/cm :
680, 816, 1348, 1376, 1544, 3600. H NMR, δ: 2.81 (t, 2 H,
3
1
N, 11.97. C H N O . Calculated (%): C, 68.64; H, 5.97;
2
7
28
4
4
+
–1
3
2
N, 11.86. MS, m/z: 472 [M] . IR, ν/cm : 704, 816, 1364 (Ph);
376, 1544 (NO ).
СH N, J = 4.4 Hz); 2.86 (dd, 2 H, H (2), H (6), J = 11.1 Hz,
2
ax
ax
3
2
1
Jax,ax = 11.5 Hz); 3.58 (dd, 2 H, H (2), H (6), J = 11.1 Hz,
2
eq
eq
3J
= 4.2 Hz); 3.75 (t, 2 H, СH О, J = 4.4 Hz); 3.90 (t, 1 H,
2
3
9
ꢀ(4ꢀBromophenyl)ꢀ3,7ꢀdimethylꢀ1,5ꢀdinitroꢀ3,7ꢀdiazabiꢀ
cyclo[3.3.1]nonane (3h). Dinitropropane 1c (0.64 g), amine 2a
1.40 g), and formaldehyde (22 mmol) gave 0.56 g (64%) of
compound 3h as colorless crystals, m.p. 196—197 °C, R 0.80
ax,eq
3
3
H(4), J
= 11.5 Hz); 4.91 (td, 2 H, H(3), H(5), J
=
ax,ax
ax,ax
(
11.5 Hz, 3Jax,ax = 11.1 Hz, 3Jax,eq = 4.2 Hz); 7.13 (d, 2 H,
оꢀH arom., J = 8.4 Hz); 7.50 (d, 2 H, mꢀH arom., J = 8.4 Hz).
f
13
(
eluent CHCl —MeOH, 7 : 3). Found (%): C, 45.50; H, 4.55;
С NMR, δ: 48.7 (С(4)); 56.2 (С(2), C(6)); 58.7 (СH N);
3
2
Br, 20.25; N, 13.94. C H BrN O . Calculated (%): C, 45.13;
58.9 (СH O); 85.6 (C(3), C(5)); 123.5 (pꢀC arom.); 130.9
(oꢀC arom.); 132.4 (iꢀC arom.); 132.7 (mꢀC arom.).
1ꢀ(2ꢀHydroxyethyl)ꢀ3r,5tꢀdinitroꢀ4сꢀ(2,4ꢀdichlorophenyl)piꢀ
peridine (7). Dinitropropane 1d (0.80 g), amine 2b (0.67 g), and
formaldehyde (22 mmol) gave 0.49 g (49%) of compound 7 as
15
19
4
4
2
+
–1
H, 4.80; Br, 20.01; N, 14.03. MS, m/z: 380 [M] . IR, ν/cm
80 (Br); 704, 816, 1364 (Ar); 1376, 1544 (NO ).
:
6
2
3
,7ꢀDimethylꢀ9ꢀ(2,4ꢀdichlorophenyl)ꢀ1,5ꢀdinitroꢀ3,7ꢀdiazaꢀ
bicyclo[3.3.1]nonane (3i). Dinitropropane 1d (0.80 g), amine 2a
1.40 g), and formaldehyde (22 mmol) gave 0.85 g (77%) of
compound 3i as colorless crystals, m.p. 151—152 °C, R 0.77
(
colorless crystals, m.p. 108—109 °C (from hexane), R 0.51 (eluꢀ
f
i
ent CНCl —Pr OH, 7 : 3). Found (%): C, 42.69; H, 4.10;
f
3
(
eluent CHCl —MeOH, 7 : 3). Found (%): C, 46.65; H, 4.65;
Cl, 19.55; N, 11.59. C H Cl N O . Calculated (%): C, 42.87;
3
13 15
2
3
5
+
–1
Cl, 18.10; N, 14.57. C H Cl N O . Calculated (%): C, 46.27;
H, 4.15; Cl, 19.47; N, 11.54. MS, m/z: 364 [M] . IR, ν/cm :
15
18
2
4
4
+
–1
1
H, 4.66; Cl, 18.22; N, 14.40. MS, m/z: 389 [M] . IR, ν/cm
16, 1348, 3056 (Ar); 1376, 1544 (NO ).
:
816, 1348, 3056, 1376, 1544, 3600. H NMR, δ: 2.75 (t, 2 H,
3
2
3
8
H СN, J = 5.8 Hz); 2.82 (t, 1 H, H (6), J = J
= 11.4 Hz);
2
2
ax
3
ax,ax
2
1
ꢀMethylꢀ3r,5cꢀdinitroꢀ4cꢀphenylꢀ (4), 1ꢀmethylꢀ3r,5cꢀ
3.00 (dd, 1 H, H (2), J = 11.5 Hz, J
= 2.7 Hz); 3.62 (dd,
ax
ax,eq
2
3
dinitroꢀ4tꢀphenylꢀ (4´), and 1ꢀmethylꢀ3r,5tꢀdinitroꢀ4cꢀphenylꢀ
piperidines (4″). According to the general procedure, a yellowish
viscous liquid, being a mixture of isomeric compounds 4, 4´,
and 4″ in a ratio of 3 : 1.3 : 1, was obtained from dinitropropane
1
(
1 H, H (6), J = 11.4 Hz, J
= 3.9 Hz); 3.65 (t, 2 H, H СO,
eq
ax,eq
2
3
3
3
J = 5.8 Hz); 3.75 (dd, 1 H, H (4), J
3.0 Hz); 4.18 (dd, 1 H, H (2), J = 11.5 Hz, J
5.20 (ddd, 1 H, H (3), J
3.0 Hz); 6.00 (td, 1 H, H (5), Jax,ax = 11.4 Hz, Jax,eq
= 11.4 Hz, J
3
=
ax,eq
ax
2
ax,ax
= 3.9 Hz);
eq
eq,eq
3
3
3
= 3.9 Hz, J
= 2.7 Hz, J
=
=
eq
eq,eq
ax,eq
ax,eq
3
3
b (0.46 g, 2.2 mmol), a 25% solution of methylamine (2a)
1.36 g, 11 mmol), and 26% aqueous formaldehyde (2.58 g,
2 mmol) in a THF—H O (1 : 1) mixture. Found (%): C, 54.55;
ax
13
3.9 Hz); 7.27—7.30, 7.39—7.45 (m, 3 H, H arom.). С NMR,
2
δ: 42.7 (С(4)); 56.2 (С(6)); 56.9 (С(2)); 58.3 (СH N); 58.8
2
2
H, 5.46; N, 15.97. C H N O . Calculated (%): C, 54.33;
(СH OH); 80.7 (C(5)); 83.3 (C(3)); 128.1 (C arom.); 129.5
1
2
15
3
4
2
H, 5.70; N, 15.84. The isomers were characterized in mixture by
NMR spectroscopy, and their quantitative composition was deꢀ
termined from the ratio of surface areas of signals from the
methinic protons at the C(4) atom. For all isomers, signals of
(C arom.); 130.3 (C arom.); 129.9 (C arom.); 134.8 (C arom.);
135.5 (C arom.).
1,4,4ꢀTrimethylꢀtransꢀ and 1,4,4ꢀtrimethylꢀcisꢀ3,5ꢀdinitroꢀ
piperidines (8). Dinitropropane 1e (0.36 g), amine 2a (1.40 g),
and formaldehyde (22 mmol) gave 0.24 g (51%) of isomeric
piperidines 8 (trans : cis ≈ 1 : 1.5) as colorless crystals, m.p.
55—56 °C (from hexane), R 0.68 (eluent CНCl ). Found (%):
1
the protons of the phenyl substituent in the H NMR spectrum
appear at δ 7.21—7.56. In the 13С NMR spectrum, signals of
protonꢀcontaining C atoms are observed at δ 127.4—130.0, while
the signals of quaternary C atoms lie at δ 133.1, 133.3, and 134.0.
f
3
C, 44.38; H, 7.00; N, 19.24. C H N O . Calculated (%):
8
15
3
4
1
+
–1
Isomer 4. H NMR, δ: 2.42 (s, 3 H, MeN); 2.56 (t, 2 H,
C, 44.23; H, 6.96; N, 19.34. MS, m/z: 217 [M] . IR, ν/cm :
2
3
1
H (2), H (6), J = J
= 10.4 Hz); 3.60 (dd, 2 H, H (2),
1184, 1200 (Me); 1376, 1552 (NO ). Isomer cisꢀ8. H NMR, δ:
ax
ax
ax,ax
eq
3
2
2
3
H (6), J = 10.4 Hz, J
.5 Hz); 4.79 (ddd, 2 H, H(3), H(5), J
0.4 Hz, 3Jax,eq = 3.1 Hz). С NMR, δ: 45.3 (МеN); 45.9
= 3.1 Hz); 4.34 (t, 1 H, H(4), J =
1.08, 1.37 (s, 6 H, 2 Me); 2.42 (s, 3 H, MeN); 2.84 (t, 2 H,
eq
ax,eq
3
3
2
3
7
1
= 7.5 Hz, J
=
H (2), H (6), J = J
= 11.4 Hz); 3.30 (dd, 2 H, H (2),
ax,eq
ax,ax
ax
ax
ax,ax
eq
13
2
3
H (6), J = 11.4 Hz, J
= 4.0 Hz); 4.50 (dd, 2 H, H (3),
eq
ax,eq
ax
3
= 11.4 Hz, 3J
13
(
С(4)); 58.0 (С(2), C(6)); 86.4 (С(3), C(5)).
H (5), J
= 4.0 Hz). С NMR, δ: 14.5,
ax,eq
ax
ax,ax
1
Isomer 4´. H NMR, δ: 2.50 (s, 3 H, MeN); 2.72 (t, 2 H,
25.4 (Me С(4)); 35.0 (С(4)); 45.4 (MeN); 53.0 (С(2), C(6));
2
2
3
1
H (2), H (6), J = J
H (6), J = 10.8 Hz, J
H(5), J
(
(
= 10.8 Hz); 3.45 (dd, 2 H, H (2),
88.7 (С(3), C(5)). Isomer transꢀ8. H NMR, δ: 1.23 (s, 6 H,
ax
ax
ax,ax
eq
2
3
= 4.1 Hz); 4.96 (ddd, 2 H, H(3),
Me C(4)); 2.36 (s, 3 H, MeN); 2.95 (d, 4 H, H C(2), H C(6),
eq
ax,eq
2
2
2
3
3
3
3
3
13
= 11.2 Hz, J
= 10.8 Hz, J
= 4.1 Hz); 3.88
J = 5.0 Hz); 4.99 (t, 2 H, H(3), H(5), J = 5.0 Hz). С NMR,
ax,ax
ax,ax
ax,eq
3
13
t, 1 H, H(4), J = 11.2 Hz). С NMR, δ: 45.3 (МеN); 48.8
δ: 22.4 (Me С(4)); 35.1 (С(4)); 45.4 (MeN); 53.5 (С(2), C(6));
2
C(4)); 58.8 (С(2), C(6)); 85.8 (С(3), C(5)).
87.6 (C(3), C(5)).
1ꢀ(2ꢀHydroxyethyl)ꢀ4,4ꢀdimethylꢀtransꢀ3,5ꢀdinitropiperidine
(9). Dinitropropane 1e (0.36 g), amine 2b (0.67 g), and formalꢀ
1
Isomer 4″. H NMR, δ: 2.47 (s, 3 H, MeN); 2.79 (dd, 2 H,
2
3
H (2), H (6), J = J
= 11.5 Hz); 3.70 (dd, 2 H, H (2),
ax
ax
ax,ax
eq

420
Russ.Chem.Bull., Int.Ed., Vol. 54, No. 2, February, 2005
Yarmukhamedov et al.
dehyde (22 mmol) gave compound 9 (0.11 g, 20%) as colorꢀ
2. Pat. US 5468858; RZh Khim. [Russian J. Chem. Abstracts],
1997, 18О70P (in Russian).
less crystals, m.p. 81—82 °C (from hexane), R 0.47 (eluent
f
i
CНCl —Pr OH, 7 : 3). Found (%): C, 43.85; H, 6.99; N, 17.37.
3. K. Y. Blackhall, D. Hendry, R. Y. Pryce, and S. M. Roberts,
J. Chem. Soc., Perkin Trans. 1, 1995, 21, 2767.
4. R. Jejaraman and S. Avila, Chem. Rev., 1981, 81, 1526.
5. N. S. Zefirov, V. A. Palyulin, G. A. Efimov, O. A. Subbotin,
O. I. Levina, K. A. Potekhin, and Yu. T. Struchkov, Dokl.
Akad. Nauk SSSR, 1991, 320, 1392 [Dokl. Chem., 1991 (Engl.
Transl.)].
3
C H N O . Calculated (%): C, 43.72; H, 6.93; N, 17.00. MS,
9
17
3
5
+
–1
m/z: 247 [M] . IR, ν/cm : 1192, 1204, 1376, 1544, 3600.
H NMR, δ: 1.22 (s, 6 H, 2 Me); 2.44 (br.s, 1 H, ОH); 2.65 (m,
H, H СN); 3.08 (d, 4 H, H С(2), H С(6), J = 5.1 Hz); 3.57
1
3
2
(
1
2
2
2
3
br.s, 2 H, H СО); 4.94 (t, 2 H, H(3), H(5), J = 5.1 Hz).
2
3
С NMR, δ: 22.2 (2 Me); 36.2 (С(4)); 51.1 (СH N); 58.1
2
(
С(2), C(6)); 58.2 (СH O); 88.2 (C(3), C(5)).
6. D. A. Cichra and H. G. Adolph, J. Org. Chem., 1982,
2
4
7, 2474.
This work was financially supported by the Foundaꢀ
7. N. N. Yarmukhamedov, N. Z. Baibulatova, V. A. Dokichev,
Yu. V. Tomilov, and M. S. Yunusov, Izv. Akad. Nauk, Ser.
Khim., 2001, 721 [Russ. Chem. Bull., Int. Ed., 2001, 50, 753].
tion of the President of the Russian Federation (Program
of Support for Leading Scientific Schools, Grant
NShꢀ139.2003.03) and the Presidium of the Russian Acadꢀ
emy of Sciences (Program of Fundamental Research "Diꢀ
rected Synthesis of Organic Substances with Specified
Properties and Creation of Related Functional Mateꢀ
rials").
8
. A. Gogoll, H. Grennberg, and A. Axén, Magn. Reson. Chem.,
977, 35, 13.
. R. T. Wall, Tetrahedron, 1970, 26, 2107.
1
9
1
0. Y. Arakawa, T. Murakami, F. Ozawa, Y. Arakawa, and
S. Yoshifuji, Tetrahedron, 2003, 59, 7555.
1. K. Meyer, Ber., 1892, 25, 1710.
2. M. D. Alkantara, F. C. Escribano, D. Estrada, A. Lopesꢀ
Castro, and S. PerezꢀGarrido, Synthesis, 1996, 1, 64.
3. A. Lambert and A. Lowe, J. Chem. Soc., 1947, 1517.
4. Beilsteins Handbuch der organischen Chemie, 3 und 4
Erganzungswerk, 1982, 26(1), 3.
1
1
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(
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in revised form October 26, 2004