Synthesis and intramolecular conversion of substituted 2-methyl-11-nitro-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5] oxadiazocin-4(3H)-ones in different solvents

Article abstract of DOI:10.1007/s11172-014-0606-7

A Biginelli reaction of 5-R-salicylic aldehydes (R = H, Me, Br) with nitroacetone and urea in each case leads to a predominant formation of 2R,6S,11Sdiastereomers of 8-R-2-methyl-11-nitro-5,6-dihydro-2H-2,6-methanobenzo[g][1,3,5]oxadiazocin-4(3H)-one. In solutions in DMF and DMSO, these diastereomers undergo the oxadiazocine ring opening with setting a three-component equilibrium between predominant 4-(2-hydroxy-5-R-phenyl)-6-methyl5-nitro-3,4-dihydropyrimidin-2(1H)-ones and 2R,6S,11Sand 2R,6S,11Rdiastereomers of methanobenzoxadiazocine as two minor components.

Full text of DOI:10.1007/s11172-014-0606-7

Russian Chemical Bulletin, International Edition, Vol. 63, No. 6, pp. 1378—1385, June, 2014
1378
Synthesis and intramolecular conversion of substituted
2ꢀmethylꢀ11ꢀnitroꢀ5,6ꢀdihydroꢀ2Hꢀ2,6ꢀmethanobenzo[g][1,3,5]
oxadiazocinꢀ4(3H)ꢀones in different solvents*
V. F. Sedova, V. P. Krivopalov, Yu. V. Gatilov, and O. P. Shkurko
N. N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences,
9 prosp. Akad. Lavrent´eva, 630090 Novosibirsk, Russian Federation.
Fax: +7 (383) 234 4752. Eꢀmail: oshk@nioch.nsc.ru
A Biginelli reaction of 5ꢀRꢀsalicylic aldehydes (R = H, Me, Br) with nitroacetone and urea
in each case leads to a predominant formation of 2R*,6S*,11S* diastereomers of 8ꢀRꢀ2ꢀmethꢀ
ylꢀ11ꢀnitroꢀ5,6ꢀdihydroꢀ2Hꢀ2,6ꢀmethanobenzo[g][1,3,5]oxadiazocinꢀ4(3H)ꢀone. In solutions
in DMF and DMSO, these diastereomers undergo the oxadiazocine ring opening with setting
a threeꢀcomponent equilibrium between predominant 4ꢀ(2ꢀhydroxyꢀ5ꢀRꢀphenyl)ꢀ6ꢀmethylꢀ
5ꢀnitroꢀ3,4ꢀdihydropyrimidinꢀ2(1H)ꢀones and 2R*,6S*,11S* and 2R*,6S*,11R* diastereomers
of methanobenzoxadiazocine as two minor components.
Key words: salicylic aldehydes, Biginelli reaction, nitrodihydroꢀ2,6ꢀmethanobenzoꢀ
[1,3,5]oxadiazocinꢀ4(3H)ꢀones, intramolecular transformations.
At the present time, a threeꢀcomponent Biginelli reacꢀ
In continuation of our studies on the use of nitro carbꢀ
onyl compounds in the Biginelli reaction,16,17 we carried
out the condensation of nitroacetone, salicylic aldehyde,
and urea with the isolation of 5,6ꢀdihydroꢀ2Hꢀ2,6ꢀmethꢀ
anobenzo[g][1,3,5]oxadiazocinꢀ4(3H)ꢀone (3a) with the
nitro group at the methylene bridge as the only reaction
product, the structure of which was confirmed 1H and
13C NMR spectra. Xꢀray diffraction analysis showed that
compound 3a is a diastereomer with the framework conꢀ
figuration 2R*,6S*,11S* (see Ref. 18).
Compound 3a is stable upon storage in the solid
state and in solution in ethanol. However, in solutions
in highly polar aprotic solvents such as DMF and DMSO
compound 3a undergoes oxadiazocine ring opening
with setting a threeꢀcomponent equilibrium between
4ꢀ(2ꢀhydroxyphenyl)ꢀ6ꢀmethylꢀ5ꢀnitroꢀ3,4ꢀdihydropyrꢀ
imidinꢀ2(1H)ꢀone (4) and two diastereomers of benzꢀ
oxadiazocine 3a (2R*,6S*,11S* configuration) and 3b
(2R*,6S*,11R* configuration). Such an equilibrium
for substituted 2,6ꢀmethanobenzo[g][1,3,5]oxadiazocines
was for the first time described in our short communiꢀ
cation.18
tion involving a ꢀdicarbonyl compound, aromatic aldeꢀ
hyde, and urea constitutes a simple and available method
for the preparation of various 4ꢀarylꢀ3,4ꢀdihydropyrimiꢀ
dinꢀ2(1H)ꢀones 1 (see Refs 1—4), which possess a wide
range of biological activity.5—8 It is known that for salicylic
aldehydes this reaction in most cases proceeds with the
transformation of the structure of the intermediately
formed pyrimidinones 1 to the corresponding 11ꢀcarbonyl
derivatives of 5,6ꢀdihydroꢀ2Hꢀ2,6ꢀmethanobenzo[g]ꢀ
[1,3,5]oxadiazocinꢀ4(3H)ꢀones 2 as a single stable diasteꢀ
reomer.9—15 It is believed that the formation of benzoxaꢀ
diazocines 2 results from a tandem Biginelli reaction and
intramolecular oxaꢀMichael reaction, an addition of
the hydroxy group at the double bond of the dihydroꢀ
pyrimidine ring.
The purpose of the present work is the confirmation of
generality of the Biginelli reaction course leading to the
formation of 11ꢀnitromethanobenzoxadiazocines in the
condensation of nitroacetone, substituted salicylic aldeꢀ
hydes (5ꢀmethylꢀ and 5ꢀbromo substituted), and urea, as
well as the evaluation of influence of structural modificaꢀ
tions on the character of intramolecular conversions of
methanobenzoxadiazocine nitro derivatives and a threeꢀ
R = Alk, OAlk
* Dedicated to Academician of the Russian Academy of Sciences
O. N. Chupakhin on the occasion of his 80th birthday.
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 6, pp. 1378—1385, June, 2014.
1066ꢀ5285/14/6306ꢀ1378 © 2014 Springer Science+Business Media, Inc.

Nitroꢀ2,6ꢀmethanobenzo[1,3,5]oxadiazocinones
Russ.Chem.Bull., Int.Ed., Vol. 63, No. 6, June, 2014
1379
component equilibrium discovered by us in the media of
different nature.
C(H)(NO2)), respectively (for compound 5a Fig. 1, a
and 2, a ).18,19
The steric structure of compound 5 established by Xꢀray
diffraction analysis (Fig. 3) confirms the presence of
a bridged framework with three stereogenic C atoms with
configuration 2R*,6S*,11S* (diastereomer 5a) similarly
to the structure of compound 3a described earlier.18 Beꢀ
cause of the pseudoaxial position of the benzene ring, it is
oriented approximately perpendicular (89.01(8)) to the
hexahydropyrimidine ring. Dihydropyran and tetrhydroꢀ
pyrimidine rings are each in the halfꢀchair conformation
with the deviation of atoms C(2), C(11) by –0.367(4),
0.515(4) Å and atoms C(6), C(11) by –0.417(4), 0.424(5) Å
from the planes of the corresponding rings formed by
the rest of the atoms. In crystal, the hydrogen bonds
Results and Discussion
Heating a mixture of nitroacetone, the corresponding
substituted salicylic aldehyde, and urea taken in the molar
ratios 1 : 1.05 : 2 was carried out in refluxing ethanol in
the presence of a catalytic amount of HCl (conc.). The
reaction products 5 and 6 were isolated as snowꢀwhite
solid compounds (like compound 3a18). The IR spectra of
these compounds exhibited absorption bands of stretching
vibrations of the N—H, C=O, NO2, and C—O—C groups,
while no stretching vibrations band for the O—H group
(in KBr and mineral oil) was observed. These data indiꢀ
cate the formation of Oꢀcyclic compounds, namely, the
corresponding 8ꢀsubstituted 2ꢀmethylꢀ11ꢀnitroꢀ5,6ꢀdiꢀ
hydroꢀ2Hꢀ2,6ꢀmethanobenzo[g][1,3,5]oxadiazocinꢀ4(3H)ꢀ
ones (5 and 6) (Scheme 1).
Approximately 10—15 min after dissolution, the 1H
and 13C NMR spectra (DMSOꢀd6) of compounds 5 and 6
exhibit signals of only one diastereomer: for atoms H(6)
and H(11) in the region  4.50—5.75 with the spinꢀspin
coupling constants characteristic of 11ꢀnitroꢀsubstitꢀ
uted 2,6ꢀmethanobenzoxadiazocines,18 as well as for
sp3ꢀhybridized atoms C(2) (82.32 and 82.91, C(N)O),
C(6) (49.32 and 48.74), and C(11) (79.30 and 78.63,
...
...
...
N(3)—H O(2) (H O 2.05(4) Å, N—H O 170(3)) and
...
N(5)—H O(2) (1.96(4) Å, 171(3)) combine the moleꢀ
cules in the zigzagꢀlike centrosymmetric chains oriented
along the axis a. Similar chains were also observed in comꢀ
pound 3a (see Ref. 18).
Steric configuration of compound 6 (R = Br) cannot
be found by Xꢀray diffraction analysis because of the forꢀ
mation of twin crystals during its crystallization from
ethanol. However, based on the similarities of the 1H and
13C NMR spectral characteristics of this compound and
diastereomers 3a and 5a (Table 1), the 2R*,6S*,11S* conꢀ
figuration was also assigned to its steric structure (diasteꢀ
Scheme 1
R = H (3, 4), Me (5, 7), Br (6, 8)

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Sedova et al.
5a (H(11))
a
5a (H(6))
5b (H(11))
7 (H(4))
5b (H(6))
b
5b
5a
5a
5b
c
5b
5a
5a 5b
7
7 (H(4))
d
5a
5a
5b
5b
5.7
5.6
5.5
5.4
5.3
5.2
5.1
5.0
4.9
4.8
4.7

1
Fig. 1. Characteristic signals in the H NMR spectra of compounds 5a, 5b, and 7 in DMSOꢀd6: (a) immediately after dissolution of
diastereomer 5a; (b) the same solution 9 days later (an equilibrium mixture of compounds 5a + 5b + 7 with the ratio 7 : 6 : 87);
(c) a solution of the precipitate formed from DMSO + H2O (1 : 10) (a mixture of 5a + 5b + 7 with the ratio 48 : 50 : 2); (d) the same
solution 15 days later for the mixture 5a + 5b + 7 with the ratio 37 : 19 : 44).
1
Table 1. Chemical shifts of characteristic signals of diastereomers of compounds 3, 5, and 6 in the H and 13C NMR
spectra in DMSOꢀd6 (, J/Hz)
Comꢀ
pound
Н(6)
Н(11)
NH(3)
NH(5)
C(2)
C(6)
C(11)
3а
3b
5a
5b
6a
6b
4.86 (dd,
J = 3.3, J = 4.6)
4.76 (dd,
J = 2.7, J = 5.2)
4.77 (dd,
J = 3.3, J = 4.5)
4.70 (dd,
J = 2.4, J = 4.7)
4.93 (dd,
5.67 (d,
J = 3.3)
5.58 (d,
J = 2.7)
5.53 (d,
J = 3.3)
5.55 (d,
J = 2.4)
5.70 (d,
J = 2.7)
5.63 (d,
J = 2.5)
8.00 (br.s)
7.54 (d,
J = 4.6)
7.68 (dd,
82.48
81.83
82.32
81.75
83.96*
83.88*
49.27
46.32
49.32
46.36
50.21*
50.12*
79.13
80.01
79.30
80.07
79.77*
79.94*
7.91 (d,
J = 2.1)
7.96 (br.s)
J = 2.1, J = 5.2)
7.50 (d,
J = 4.5)
7.63 (dd,
J = 2.1, J = 4.7)
7.54 (d,
J = 3.7)
7.63 (dd,
J = 2.2, J = 5.0)
7.87 (d,
J = 2.1)
8.11 (br.s)
J = 2.7, J = 3.7)
4.82 (dd,
J = 2.5, J = 5.0)
8.0 (d,
J = 2.2)
* The data extracted from the spectra of a mixture of diastereomers in DMFꢀd7.

Nitroꢀ2,6ꢀmethanobenzo[1,3,5]oxadiazocinones
Russ.Chem.Bull., Int.Ed., Vol. 63, No. 6, June, 2014
1381
a
5a (C(2))
5a (C(10a))
5a (C(4))
5a (C(8))
5a (C(6a))
5a (C(7))
5a (C(9))
5a (C(10))
5a (C(11))
5a (C(6))
7
b
7
7
7
7
7
5a
5a
5a
5a
5b
5a, 5b
5b
5b
5b
5a
5a
5a
5a
5a
7
7
7
7
c
7 (C(8))
7 (C(2))
7 (C(6))
7 (C(7), C(11))
7 (C(5))
7 (C(12)) 7 (C(10))
7 (C(9))
7 (C(4))
B
5a
d
5a, 5b
7 7
5a
5a
5a
7
7
5b
5b
5b
5b
7
7 (C(7),
C(11))
7
A
B
5b
5b
5a
7
7
7
5b
5a
5b
129.5 129.0
5a
128 125
5a
5a, 5b
A
155 150 145 140 135 130 125 120 115
85 80 75 55 50

Fig. 2. The fragments the13C NMR spectra (JMOD) of compounds 5a, 5b, and 7 in DMSOꢀd6: (a) 30 min after dissolution of
diastereomer 5a; (b) the same solution 2 days later (a mixture 5a + 5b + 7 with the ratio ~ 32 : 4 : 64); (c) the same solution 9 days later
(a mixture 5a + 5b + 7 with the ratio 7 : 6 : 87); (d) a solution of the precipitate formed from DMSO + H2O (1 : 10), for the mixture
5a + 5b + 7 with the ratio 40 : 25 : 35 (d).

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Sedova et al.
O(3)
Scheme 2
С(13)
С(7)
N(5)
С(6)
N(1)
С(8)
С(6A)
С(11)
O(4)
С(4)
O(2)
С(10A)
N(3)
С(9)
С(2)
С(10)
O(1)
С(12)
Fig. 3. Spatial structure of compounds 5a (the ORTEP view).
reomer 6a). Note that the steric structure of compounds 5a
and 6a completely correspond to the described structures
of 11ꢀethoxycarbonyl analogs of methanobenzoxadiazoꢀ
cine 2 obtained by the Biginelli reaction and isolated as
individual diastereomers.10,12,14
R = H (3, 4), Me (5, 7), Br (6, 8)
Diastereomers 5a and 6a are stable on recrystallization
from ethanol, as well as upon storage in the solid state and
as alcoholic solutions and solutions in CF3COOH. Only
one diastereomer is present in the last mentioned solvent,
which remains unchanged for several days.
Upon recording NMR spectra of solutions of the niꢀ
troꢀsubstituted methanobenzoxadiazocines 5a and 6a in
DMSOꢀd6, a conversion of the starting individual diaꢀ
stereomers to the threeꢀcomponent mixtures of isomeric
compounds was observed like it was described earlier for
compound 3a (see Ref. 18).
stereomers 5a and 6a in DMSOꢀd6 are the corresponding
4ꢀ(5ꢀRꢀ2ꢀhydroxyphenyl)ꢀ6ꢀmethylꢀ5ꢀnitroꢀ3,4ꢀdihydroꢀ
pyrimidinꢀ2(1H)ꢀones 7 (R = Me) and 8 (R = Br), whose
structural identification is obvious enough and confirmed
by plenty of literature examples.18
With time, solutions of the individual diastereomers in
DMSO form an equilibrium mixture, consisting of the
corresponding two diastereomers and dihydropyrimidinone.
The ratios of isomers in the mixtures formed remain unꢀ
changed upon standing for a month and longer (Table 2).
Some time later after dissolution of individual diasteꢀ
reomers 5a and 6a, the NMR spectra began to exhibit
signals of two another compounds, whose intensities gradꢀ
ually grew at different rates, with simultaneous decrease in
the intensities of the signals for the starting diastereomers
until an equilibrium is set (see Fig. 1, a, b and 2, a, b, c).
Some of the growing signals appear next to the signals of
the starting diastereomers, whereas some signals completeꢀ
ly collapse to one multiplet signals. Thus, for compound 5
(R = Me) the difference in chemical shifts of 1H sigꢀ
nals for diastereomer 5a and a forming compound is
0.01—0.09 ppm (see Table 1), and only for the signal
NH(5) it reaches 0.13 ppm. The differences in chemical
shifts of 13C signals for these compounds does not exceed
1 ppm, except for the signal of C(6) (~3 ppm) (see Table 1).
The data obtained allow us to assign to the emerged comꢀ
pound 5b the structure of 2R*,6S*,11R* diastereomer (see
Schemes 1 and 2). Similar picture with the appearance of
diastereomer 6b is observed for the solution of diastereoꢀ
mer 6a in DMSOꢀd6.
Table 2. Isomerization of individual diastereomers 3a, 5a, and
6a
Comꢀ
pound
Solvent
Isomers
t*
Ratio
of isomers (%)**
3а
3а
5а
DMFꢀd7
3а : 3b : 4
10 min
24 h
99 : <1 : <118
16 : 10 : 7418
26 : 3 : 71
5 : 4 : 91
DMSOꢀd6 3а : 3b : 4
DMSOꢀd6 5а : 5b : 7
10 min
30 min
12 min
2 days
5 days
9 days
10 min
1 h
96 : 1 : 3
32 : 4 : 64
10 : 6: 84
7 : 6 : 87
94 : 4 : 2
7 : 2 : 91
6а
DMSOꢀd6 6а : 6b : 8
3 h
2 : 2 : 96
* Time after dissolution.
** Ratio of isomers in the mixture was calculated based on the
1H NMR spectra from relative intensities of the signals for atoms
H(6)/H(11) of diastereomers 3, 5, 6 and the signals for atoms
H(4) of compounds 4, 7, 8, respectively.
The NMR spectra show that yet another compounds
formed upon standing of solutions of the individual diaꢀ

Nitroꢀ2,6ꢀmethanobenzo[1,3,5]oxadiazocinones
Russ.Chem.Bull., Int.Ed., Vol. 63, No. 6, June, 2014
1383
Table 3. Ratio of isomeric products of the Biginelli reaction and
The rate of isomerization of compounds decreases in the
order 3a > 6a > 5a, that allows us to draw a conclusion
on a sequential decrease in the effect of substituents R
(H > Br > Me) (see Table 2).
the products precipitated with water from the equilibrium mixꢀ
a
tures in solutions in DMSOꢀd6
Mixture of
isomers
Ratio of isomers
It is seen from the data in Table 2 that during the
process of isomerization of individual diastereomers 3a,
5a, and 6a in aprotic dipolar solvents and setting the equiꢀ
librium, the amount of the starting diastereomers in the
mixture decreases to 2—7%, whereas the amount of formꢀ
ing diastereomers 3b, 5b, and 6b does not exceed 6% (in
DMSOꢀd6). Dihydropyrimidinones 4, 7, and 8 become
the major components of the mixtures (up to 70—96%).
The data obtained confirm the earlier observation18 that in
highly polar aprotic media the C(2)—O bond of the oxadiꢀ
azocine ring in 11ꢀnitroꢀ2,6ꢀmethanobenzoxadiazocines
is easily cleaved, whereas 4ꢀ(2ꢀhydroxyaryl)dihydroꢀ
pyrimidinones formed in this case are stabilized due to the
solvation of the aromatic hydroxy group by the dipolar
molecules of solvents.
In the reaction Upon standing Upon precipitation
productsb
in DMSOꢀd6
with waterb
c
3а : 3b : 4 99 : <1 : <1d
16 : 10 : 74d
7 : 6 : 87
2 : 2 : 96
71 : 20 : 9
48 : 50 : 2
51 : 25 : 24
5a : 5b : 7
6a : 6b : 8
96 : 1 : 3
94 : 4 : 2
a Ratios of isomers were calculated from the integral intensities
of the signals for atoms H(6) or H(11) of diastereomers 3, 5, and
6 and the signals for atom H(4) of compounds 4, 7, and 8 in the
1H NMR spectra.
b
The spectra were recorded immediately after dissolution
(10—12 min).
c For the time of standing, see Table 2.
d According to the 1H NMR spectrum in DMFꢀd7 (see Ref. 18).
Attempted isolation of dihydropyrimidinones 4, 7, and
8 from the equilibrium mixtures by dilution of the soluꢀ
tions with water failed. After the yellow solutions of
dihydropyrimidinones in DMSO were poured into a tenꢀ
fold amount of water, the color of the solutions gradually
became paler, which was accompanied by a slow formaꢀ
tion of a white precipitate. According to the NMR specꢀ
tra, this precipitate was a threeꢀcomponent mixture of the
same isomers, but with another ratio. Since benzoxadiꢀ
azocines and dihydropyrimidinones differ little in the solꢀ
ubility, it can be suggested that the composition of these
precipitates characterizes the changes taking place in diꢀ
lute aqueous DMSO solutions. For each mixture, the equiꢀ
librium was shifted to the side of Oꢀcyclic compounds:
91% for 3a + 3b, 98% for 5a + 5b, 76% for 6a + 6b, with
predominance in the mixtures of diastereomers 3a and 6a
over diastereomers 3b and 6b and virtually equal amounts
of diastereomers 5a and 5b (Table 3; see Fig. 1, c, d; 2, d).
The DMSO molecules in aqueous media possess lower
solvation affinity to the aromatic hydroxy group, that faꢀ
cilitates the oxaꢀMichaelꢀtype addition of the latter to the
activated double bond of dihydropyrimidine framework.
In this case, the ratio of diastereomers a and b considerꢀ
ably changes as compared to the products isolated from
the Biginelli reaction formed during the acidꢀcatalyzed
cyclocondensation of salicylic aldehydes, nitroacetone,
and urea.
oxadiazocines 3, 5, and 6 predominantly as single diaꢀ
stereomers. Such an assumption on the step of the formaꢀ
tion of the Oꢀbridged structure as a single diastereomer of
compound 2 (R = Me) was suggested earlier in the
works.9,10
It can be supposed that the selective formation of one
diastereomer of nitromethanobenzoxadiazocinone occurs
directly through the intermediate carbocation B and is
kinetically controlled. The formation of the intermediate
carbocation C on the way to the nitromethanobenzoxadiꢀ
azocinone molecules can be also considered as a minor
pathway (see Scheme 1).
In conclusion, the Biginelli condensation of substitutꢀ
ed salicylic aldehydes, nitroacetone, and urea is of general
character and leads to the formation of 8ꢀsubstituted
2ꢀmethylꢀ11ꢀnitroꢀ5,6ꢀdihydroꢀ2Hꢀmethanobenzo[g]ꢀ
[1,3,5]oxadiazocinꢀ4(3H)ꢀones predominantly as a single
diastereomer with configuration 2R*,6S*,11S*.
The nitro group at the methylene bridge of methaꢀ
nobenzoxadiazocines promotes the formation of the equiꢀ
librium threeꢀcomponent mixtures in the aprotic dipoꢀ
lar solvents, viz., two diastereomers (2R*,6S*,11S* and
2R*,6S*,11R*) of compounds 3, 5, and 6 and substituted
dihydropyrimidinones 4, 7, and 8, respectively with conꢀ
siderable predominance of the last mentioned compounds.
The products isolated from the dilute aqueous DMSO
(DMF) solution predominantly contain diastereomers of
Oꢀcyclic compounds 3, 5, and 6.
The facts given above on the whole do not agree with
the opinion suggested in the literature that the classic Bigꢀ
inelli reaction conditions involving substituted salicylic
aldehydes lead to the initial formation of dihydropyrimidꢀ
inone 4ꢀ(2ꢀhydroxyaryl) derivatives with subsequent proꢀ
ceeding the oxaꢀMichael reaction.10,11 At least, when
nitroacetone is used in the reaction, the major products of
the conversion of the intermediate carbocation B (see
Scheme 1) are the corresponding dihydromethanobenzꢀ
Experimental
IR spectra were obtained on a Bruker Vector 22 spectroꢀ
photometer for samples in KBr and in perfluorinated mineral oil
1
in the region 4000—2600 cm–1. H and 13C NMR spectra were
recorded on a Bruker AMꢀ400 spectrometer (400.13 (1H) and

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Sedova et al.
100.61 (13C) MHz) in DMSOꢀd6 and DMFꢀd7, using residual
(C(11)), 121.91 (C(5)), 127.51 (C(7)), 128.33 (C(10)), 128.99
(C(12)), 150.59 (C(6)), 151.06 (C(2)), 155.21 (C(8)).
signals of DMSO ( 2.50,  39.50) and DMF ( 2.74,
H
C
H

C 30.10) as references. High resolution mass spectra were meaꢀ
2,8ꢀDimethylꢀ11ꢀnitroꢀ5,6ꢀdihydroꢀ2Hꢀ2,6ꢀmethanobenzoꢀ
[g][1,3,5]oxadiazocinꢀ4(3H)ꢀone (5). The yield was 71%, m.p.
241—243 C (EtOH). IR (KBr), /cm–1: 3334, 3232 (NH), 1697
(C=O), 1555, 1371 (NO2), 1249 (C—O—C). MS, m/z (Irel. (%)):
263 [M+] (89), 246 [M+ – OH] (64), 217 [M+ – NO2] (55), 216
[M+ – HNO2] (61), 203 (38), 174 (73), 162 (78), 156 (19),
147 (84), 133 (100), 111 (51), 105 (41). Found (%): C, 54.76;
H, 4.91; N, 15.86. C12H13N3O4. Calculated (%): C, 54.75; H, 4.98;
N, 15.96. HRMS. Found: m/z 263.0903. C12H13N3O4. Calcuꢀ
lated: M = 263.0901.
(2R*,6S*,11S*)ꢀDiastereomer 5a. 1H NMR (DMSOꢀd6),
 (10 min after dissolution, 100%): 1.76 (s, 3 H, Me(2)); 2.23
(s, 3 H, Me(8)); 4.77 (dd, 1 H, H(6), JH(6),H(11) = 3.3 Hz,
JH(6),H(5) = 4.5 Hz); 5.53 (d, 1 H, H(11), JH(11),H(6) = 3.3 Hz);
6.74 (d, 1H, H(10), JH(10),H(9) = 8.0 Hz); 6.98—7.04 (br.s, 1 H,
H(7)); 7.06 (dd, 1 H, H(9), JH(9),H(10) = 8.0 Hz, JH(9),H(7) = 1.9 Hz);
7.50 (d, 1 H, NH(5), JH(5),H(6) = 4.5 Hz), 7.96 (s, 1 H, NH(3)).
13C NMR (DMSOꢀd6), : 20.08 (Me(2)), 22.95 (Me(8)), 49.32
(C(6)), 79.30 (C(11)), 82.32 (C(2)), 116.48 (C(10)), 123.93
(C(6a)), 129.02 (C(9)), 130.22 (C(8)), 130.53 (C(7)), 147.55
(C(4)), 153.79 (C(10a)).
(2R*,6S*,11R*)ꢀDiastereomer 5b. 1H NMR (DMSOꢀd6),
 (the content of the diastereomer in the mixture 50%): 1.77
(s, 3 H, Me(2)); 2.25 (s, 3 H, Me(8)); 4.70 (dd, 1 H, H(6),
JH(6),H(11) = 2.4 Hz, JH(6),H(5) = 4,7 Hz); 5.55 (d, 1 H, H(11),
JH(11),H(6) = 2.4 Hz); 6.71 (d, 1 H, H(10), JH(10),H(9) = 8.1 Hz);
6.98—7.04 (m, 1 H, H(9)); 7.04—7.10 (m, 1 H, H(7)); 7.63 (dd,
1 H, NH(5), JH(5),H(6) = 4.7 Hz, JH(5),H(3) = 2.1 Hz); 7.87 (d, 1 H,
NH(3), JH(3),H(5) = 2.1 Hz). 13C NMR (DMSOꢀd6,), : 20.19
(Me(2)), 22.95 (Me(8)), 46.36 (C(6)), 80.07 (C(11)), 81.75
(C(2)), 116.51 (C(10)), 123.93 (C(6a)), 129.14 (C(9)), 129.67
(C(7)), 130.61 (C(8)), 147.63 (C(4)), 154.61 (C(10a)).
sured on a DFS Thermo Electron Corporation instrument (EI,
70 eV, direct injection of samples in source of ions). Electrospray
ionization technique (ESI) was used for compound 3a in soluꢀ
tion in MeOH on a Bruker Daltonics micro TOFꢀQ instrument.
Xꢀray diffraction analysis of compound 5a was performed on
a Bruker Kappa Apex II CCD Xꢀray diffractometer using MoK
irradiation (0.71073 Å) with graphite monochromator. Single
crystals were prepared by crystallization of compound from ethanol.
Compounds 3b, 4, 5b, 6b, 7, and 8 were not isolated in the
pure form, their identification was inferred from 1H and 13C NMR
spectra for the mixtures of different compositions. Nitroacetone
was obtained according to the known procedures20,21. Descripꢀ
tion of the synthesis, analytical and spectral data for compound 3a
are given in the work.18
Condensation of nitroacetone, 5ꢀRꢀsalicylic aldehydes, and
urea (general procedure). A mixture of nitroacetone (12.5 mmol),
substituted salicylic aldehyde (12 mmol), urea (25 mmol), ethaꢀ
nol (25 mL), and concentrated HCl (1.25 mL) was heated in
a water bath at 95 C. Then, the mixture was cooled , a precipiꢀ
tate formed was filtered off, washed with water, dried, and reꢀ
crystallized from ethanol.
2ꢀMethylꢀ11ꢀnitroꢀ5,6ꢀdihydroꢀ2Hꢀ2,6ꢀmethanobenzo[g]ꢀ
[1,3,5]oxadiazocinꢀ4(3H)ꢀone (3a)18. MS (ESI), m/z: 250.08
[M + H], 272.06 [M + Na]+, 521.14 [2 M + Na]+. C11H11N3O4.
Calculated: 249.07 [M], 250.08 [M + H], 272.06 [M + Na],
521.13 [2 M + Na].
(2R*,6S*,11S*)ꢀDiastereomer 3a. 1H NMR (DMSOꢀd6),
 (the mixture was composed of 3a (71%) + 3b (20%) + 4 (9%)):
1.79 (s, 3 H, CH3, 3a + 3b); 4.86 (dd, 1 H, H(6), JH(6),H(11) = 3.3 Hz,
JH(6),H(5) = 4.6 Hz); 5.67 (d, 1 H, H(11), JH(11),H(6) = 3.3 Hz);
6.85 (d, 1 H, H(10), JH(10),H(9) = 8.1 Hz); 6.99 (t, 1 H, H(8),
JH(8),H(7) = 7.8 Hz; JH(8),H(9) = 7.8 Hz); 7.24—7.28 (m, 2 H,
H(7), H(9), 3a + 3b); 7.56 (d, 1 H, NH(5), JH(5),H(6) = 4.6 Hz);
8.02 (s, 1 H, NH(3)). 13C NMR (DMSOꢀd6), : 22.97 (Me),
49.27 (C(6)), 79.13 (C(11)), 82.48 (C(2)), 116.68 (C(10)), 121.43
(C(8)), 124.23 (C(6a)), 129.00 (C(9)), 130.03 (C(7)), 149.81
(C(4)), 153.78 (C(10a)).
(2R*,6S*,11R*)ꢀDiastereomer 3b. 1H NMR (DMSOꢀd6),
 (the mixture was composed of 3a (71%) + 3b (20%) + 4 (9%)):
1.79 (s, 3 H, Me, 3b + 3a); 4.76 (dd, 1 H, H(6), JH(6),H(11) = 2.7 Hz,
JH(6),H(5) = 5.2 Hz); 5.58 (d, 1 H, H(11), JH(11),H(6) = 2.7 Hz);
6.82 (d, 1 H, H(10), JH(10),H(9) = 8.3 Hz); 7.01 (dt, 1 H, H(8),
JH(8),H(10) = 1.0 Hz, JH(8),H(7) = 7.6 Hz, JH(8),H(9) = 7.6 Hz);
7.18—7.28 (m, 2 H, H(7), H(9), 3b + 3a); 7.68 (dd, 1 H, NH(5),
JH(5),H(6) = 5.2 Hz, JH(5),H(3) = 2.1 Hz); 7.91 (d, 1 H, NH(3),
JH(3),H(5) = 2.1 Hz). 13C NMR (DMSOꢀd6), : 24.06 (Me), 46.32
(C(6)), 80.01 (C(11)), 81.83 (C(2)), 115.75 (C(10)), 118.76
(C(8)), 123.61 (C(6a)), 128.37 (C(9)), 131.33 (C(7)), 147.63
(C(4)), 154.57 (C(10a)).
4ꢀ(2ꢀHydroxyphenyl)ꢀ6ꢀmethylꢀ5ꢀnitroꢀ3,4ꢀdihydropyrimidꢀ
inꢀ2(1H)ꢀone (4). 1H NMR (DMSOꢀd6),  (the content in
the mixture 75%): 2.48 (s, 3 H, Me); 5.71 (d, 1 H, H(4),
JH(4),H(3) 3.0 Hz); 6.74 (dt, 1 H, H (11), JH(11),H(9) = 1.0 Hz,
JH(11),H(10) = = 7.5 Hz, JH(11),H(12) = 7.5 Hz); 6.81(d, 1 H, H(9),
JH(9),H(10) = 7.5 Hz); 7.06 (dd, 1 H, H(12), JH(12),H(10) = 1.5 Hz,
JH(12),H(11) = 7.5 Hz); 7.10 (dt, 1 H, H(10), JH(10),H(12) = 1.5 Hz,
JH(10),H(9) = 7.5 Hz, JH(10),H(11) = 7.5 Hz); 7.84 (br.s, 1 H,
NH(3)); 9.76 (s, 1 H, OH); 9.96 (s, 1 H, NH(1)). 13C NMR
(DMSOꢀd6), : 19.45 (Me), 50.81 (C(4)), 115.77 (C(9)), 118.78
8ꢀBromoꢀ2ꢀmethylꢀ11ꢀnitroꢀ2Hꢀ2,6ꢀmethanobenzo[g]ꢀ
[1,3,5]oxadiazocinꢀ4(3H)ꢀone (6). The reaction time was 2 h,
the yield was 48%, m.p. 244—246 C (EtOH). IR (KBr), /cm–1
:
3419, 3238 (NH); 1699 (C=O); 1556, 1367 (NO2); 1246 (C—O—C).
IR (Nujol), /cm–1: 3334, 3196 (NH); 3072 (CHarom). MS, m/z
(Irel. (%)): 329, 327 [M+] (57, 59); 312, 310 [M+ – OH] (34, 36);
283, 281 [M+ – NO2] (30, 36); 282, 280 [M+ – HNO2] (31, 32);
269, 267 [M+ – 60] (24, 25); 240, 238 [M+ – 89] (47, 47); 228,
226 [M+ – 101] (39, 41); 156 (26); 132 (80); 111 (38); 102 (28);
42 (100). Found (%): C, 39.84; H, 2.69; Br, 24.56; N, 12.76.
C11H10BrN3O4. Calculated (%): C, 40.26; H, 3.07; Br, 24.36;
N, 12.81. HRMS. Found: m/z 326.9855. C11H10BrN3O4. Calcuꢀ
lated: M = 326.9849.
(2R*,6S*,11S*)ꢀDiastereomer 6a. 1H NMR (DMSOꢀd6),
: (the content of the isomer 93%): 1.78 (s, 3 H, Me); 4.93
(dd, 1 H, H(6), JH(6),H(11) = 2.7 Hz, JH(6),H(5) = 3.7 Hz); 5.70
(d, 1 H, H(11), JH(11),H(6) = 2.7 Hz); 6.85 (d, 1 H, H(10),
JH(10),H(9) = 8.6 Hz); 7.38–7.47 (m, 2 H, H(9), H(7)); 7.54 (d, 1 H,
NH(5), JH(5),H(6) = 3.7 Hz); 8.11 (s, 1 H, NH(3)). 13C NMR
(DMSOꢀd6), : 22.87 (Me); 48.74 (C(6)); 78.63 (C(11)); 82.91
(C(2)); 112.51 (C(8)); 119.14 (C(10)); 126.66 (C(6a)); 131.38,
132.63 (C(7), C(9)); 149.27 (C(4)); 153.67 (C(10a)). 13C NMR
(DMFꢀd7),  (the content was 83% in the mixture of three isoꢀ
mers): 23.42 (Me); 50.21 (C(6)); 79.77 (C(11)); 83.96 (C(2));
113.40 (C(8)); 119.87 (C(10)); 127.59 (C(6a)); 132.12, 133.44
(C(7), C(9)); 150.37 (C(4)); 154.46 (C(10a)).
(2R*,6S*,11R*)ꢀDiastereomer 6b. 1H NMR (DMSOꢀd6),
 (the content in the mixture 25%): 1.77 (s, 3 H, Me); 4.82 (dd, 1 H,

Nitroꢀ2,6ꢀmethanobenzo[1,3,5]oxadiazocinones
Russ.Chem.Bull., Int.Ed., Vol. 63, No. 6, June, 2014
1385
H(6), JH(6),H(11) = 2.5 Hz, JH(6),H(5) = 5.0 Hz); 5.63 (d, 1 H,
tion using the fullꢀmatrix least squares method. Amine hydrogen
atoms were localized from the differential syntheses and refined
in isotropic approximation, other hydrogen atoms were refined
using a riding model. All the calculations were performed using
the SHELXTL software. Atomic coordinates and their temperaꢀ
ture parameters were deposited with the Cambridge Structural
Database (CCDC No. 949516).
H(11), JH(11),H(6) = 2.5 Hz); 6.82 (d, 1 H, H(10), JH(10),H(9)
=
= 8.6 Hz); 7.38—7.47 (m, 2 H, H(7), H(9)); 7.63 (dd, 1 H, NH(5),
JH(5),H(6) = 5.0 Hz, JH(5),H(3) = 2.2 Hz); 8.00 (d, 1 H, NH(3),
JH(3),H(5) = 2.2 Hz). 13C NMR (DMFꢀd7),  (the content 7% in the
mixture of three isomers): 23.35 (CH3); 50.12 (C(6)); 79.94 (C(11));
83.88 (C(2)); 113.29 (C(8)); 119.92 (C(10)); 127.25 (C(6a));
132.12, 133.44 (C(7), C(9)); 150.42 (C(4)); 154.39 (C(10a)).
4ꢀ(2ꢀHydroxyꢀ5ꢀmethylphenyl)ꢀ6ꢀmethylꢀ5ꢀnitroꢀ3,4ꢀdihyꢀ
Spectral measurements were carried out in the Multiꢀ
user Chemical Service Center of the Siberian Branch of
the Russian Academy of Sciences.
This work was financially supported by the Siberian
Branch of the Russian Academy of Sciences (Integration
Project No. 93).
1
dropyrimidinꢀ2(1H)ꢀone (7). H NMR (DMSOꢀd6),  (the conꢀ
tent in the mixture 87%): 2.16 (s, 3 H, Me); 2.48 (s, 3 H, Me);
5.65 (d, 1 H, H(4), JH(4),H(3) = 3.0 Hz); 6.69 (d, 1 H, H(9),
JH(9),H(10) = 8.1 Hz); 6.83 (d, 1 H, H(12), JH(12),H(10) = 2.0 Hz);
6.90 (dd, 1 H, H(10), JH(10),H(12) = 2.0 Hz, JH(10),H(9) = 8.1 Hz);
7.81 (s, 1 H, NH(3)); 9.51 (s, 1 H, OH); 9.95 (s, 1 H, NH(1)).
13C NMR (DMSOꢀd6), : 19.52 (Me); 20.18 (Me); 50.91(C(4));
115.67 (C(9)); 121.85 (C(5)); 127.10, 127.23 (C(7), C(11));
128.65 (C(10)); 129.34 (C(12)); 150.51 (C(6)); 150.99 (C(2));
152.94 (C(8)).
References
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4ꢀ(5ꢀBromoꢀ2ꢀhydroxyphenyl)ꢀ6ꢀmethylꢀ5ꢀnitroꢀ3,4ꢀdihyꢀ
dropyrimidinꢀ2(1H)ꢀone (8). 1H NMR (DMSOꢀd6),  (the conꢀ
tent in the mixture 96%): 2.47 (s, 3 H, Me); 5.64 (d, 1 H, H(4),
JH(4),H(3) = 2.7 Hz); 6.77 (d, 1 H, H(9), JH(9),H(10) = 8.6 Hz);
7.19 (d, 1 H, H(12), JH(12),H(10) = 2.0 Hz); 7.27 (dd, 1 H, H(10),
JH(10),H(12) = 2.0 Hz, JH(10),H(9) = 8.6 Hz); 7.93 (d, 1 H, NH(3),
JH(3),H(4) = 2.7 Hz); 10.04 (s, 1 H, OH); 10.14 (s, 1 H, NH(1)).
13C NMR (DMSOꢀd6), : 19.59 (CH3), 51.25(C(4)), 109.72
(C(11)), 118.06 (C(9)), 121.20 (C(5)), 130.04 (C(7)), 131.20
(C(10)), 131.58 (C(12)), 150.38 (C(6)), 151.52 (C(2)), 154.82 (C(8)).
Isomerization of benzoxadiazocines in solutions (general proꢀ
cedure). Method A. A solution of benzoxadiazocine (30 mg) in
DMSOꢀd6 (or DMFꢀd7) (0.5 mL), which was colorless at the
moment of dissolution, upon standing at ~20 C rapidly acquired
yellow color of various intensity depending on compound taken.
Registration of spectra began 10—12 min after dissolution of the
sample. 1H NMR spectra were regularly recorded while changes
were observed in solutions until the spectra of the mixtures
showed a constant ratio of isomers, indicating that an equilibriꢀ
um was reached. Such a solution was poured into water (5 mL).
A precipitate was slowly formed upon standing. Usually, a soluꢀ
tion was allowed to stand for several days to maximize amount of
isolated precipitate. The precipitate was filtered off, washed with
water, and dried. The yield of the product was 80–85% based on
the starting weight. Then, the precipitate was dissolved in
DMSOꢀd6 to record 1H NMR spectrum.
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Method B. A solution of benzoxadiazocine (100 mg) in
DMSO (5 mL) was allowed to stand at ~20 C. The changes of
the solution color and further manipulations with it and precipiꢀ
tate formed upon pouring into water were similar to those deꢀ
scribed in method A.
Crystallographic data for compound 5a: at 150 K, C12H13N3O4,
M = 263.25, monoclinic crystal system, space group P21/n, a =
18. V. F. Sedova, V. P. Krivopalov, Yu. V. Gatilov, O. P. Shkurꢀ
ko, Mendeleev Commun., 2013, 23, 176.
= 7.3919(7), b = 18.4971(17), c = 9.3583(9) Å,  = 108.531(3),
3
V = 1213.2(2) Å , Z = 4, dcalc = 1.441 g cm–3,  = 0.110 mm–1
,
19. H. O. Kalinowski, S. Berger, S. Braun, in Carbonꢀ13 NMR
Spectroscopy, John Wiley, New York, 1988, p. 239, 350, 351.
20. C. D. Hurd, M. E. Nilson, J. Org. Chem., 1955, 20, 927.
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Heterocycl. Compd. (Engl.Transl.), 2005, 41, 739 [Khim.
Geterotsikl. Soedin., 2005, 858].
region of scanning 2 < 55, number of measured reflections
20706, number of independent reflections 2749 (Rint = 0.0562),
number of observed reflections 2126 with I  2(I), number of
refined parameters 178, R1(I  2(I)) = 0.0621, wR2 = 0.1678,
S = 1.164 on all the reflections. Absorption was included using
the SADABS program (Tmin/Tmax = 0.803/0.970). The structure
was solved by direct method. Positional and temperature factors
of nonhydrogen atoms were refined in anisotropic approximaꢀ
Received December 5, 2013;
in revised form May 6, 2014