Reactions of 5-nitrospiro[benzimidazole-2,1'-cyclohexane] 1,3-dioxide with nucleophiles

Article abstract of DOI:10.1134/S1070428012030116

Reactions of 5-nitrospiro[benzimidazole-2,1'-cyclohexane] 1,3-dioxide with aliphatic amines and sodium hydroxide resulted in removal of one N-oxide oxygen atom and formation of 4-alkylamino- or 4-hydroxy-substituted 5-nitrospiro[benzimidazole-2,1'-cyclohe

Full text of DOI:10.1134/S1070428012030116

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2012, Vol. 48, No. 3, pp. 399–410. © Pleiades Publishing, Ltd., 2012.
Original Russian Text © V.A. Samsonov, Yu.V. Gatilov, V.A. Savel’ev, S.S. Baranova, 2012, published in Zhurnal Organicheskoi Khimii, 2012, Vol. 48, No. 3,
pp. 403–413.
Reactions of 5-Nitrospiro[benzimidazole-2,1′-cyclohexane]
1,3-Dioxide with Nucleophiles
V. A. Samsonov, Yu. V. Gatilov, V. A. Savel’ev, and S. S. Baranova
Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Division, Russian Academy of Sciences,
pr. Akademika Lavrent’eva 9, Novosibirsk, 630090 Russia
e-mail: Samson@nioch.nsc.ru
Received August 11, 2011
Abstract—Reactions of 5-nitrospiro[benzimidazole-2,1′-cyclohexane] 1,3-dioxide with aliphatic amines and
sodium hydroxide resulted in removal of one N-oxide oxygen atom and formation of 4-alkylamino- or
4-hydroxy-substituted 5-nitrospiro[benzimidazole-2,1′-cyclohexane] 1-oxides, respectively. The title compound
reacted with ammonia and methylamine in the presence of MnO2 with conservation of both N-oxide moieties,
and the products were 4-amino- and 4-methylamino-5-nitrospiro[benzimidazole-2,1′-cyclohexane] 1,3-di-
oxides. The reactions with aromatic amines were accompanied by removal of both N-oxide oxygen atoms with
formation of N-aryl-5-nitrospiro[benzimidazole-2,1′-cyclohexane]-4-amines. In the reactions of 5-nitrospiro-
[benzimidazole-2,1′-cyclohexane] 1,3-dioxide with sodium azide and aromatic amine hydrochlorides nucleo-
philic replacement of the 5-nitro group by azido or arylamino occurred, in the first case both N-oxide fragments
being conserved. The reactions with aromatic amine hydrochlorides afforded N-aryl-5-nitrospiro[benzimid-
azole-2,1′-cyclohexan]-4-amine 1-oxides. Treatment of 5-nitrospiro[benzimidazole-2,1′-cyclohexane] 1,3-di-
oxide with sodium cyanide led to the formation of 5-oxo-3,5-dihydrospiro[benzimidazole-2,1′-cyclohexane]-4-
carbonitrile 1-oxide.
DOI: 10.1134/S1070428012030116
2H-Benzimidazoles and their derivatives attract
researchers’ attention as starting compounds for the
synthesis of a number of heterocyclic compounds
[1, 2]. 2H-Benzimidazole 1,3-dioxides have been
studied to a considerably lesser extent despite their
unusual reactivity [3]. Some 2H-benzimidazole 1,3-di-
oxides showed high biological activity against Tripa-
nosoma cruzi and Leishmania spp. According to the
World Health Organization data, these trypanoso-
matids alone are responsible for an infected population
of nearly 30 million and more than 400 million are at
risk [4–6]. Therefore, studies on the properties and
development of methods of synthesis of 2H-benzimid-
azole-1,3-dioxides and preparation of their new deriva-
tives constitute an important problem.
haloalkanes in sulfuric or perchloric acid [7]. The
procedure ensured preparation of a large series of
2H-benzimidazole 1,3-dioxides, including those inac-
cessible by other methods.
The ortho-quinone diimine structure of 2H-benz-
imidazole 1,3-dioxides implies that such compounds
should be capable of reacting with nucleophiles to give
the corresponding addition products, which is typical
of quinoid systems. We previously showed that 4,7-di-
bromo-2,2-dimethyl-2H-benzimidazole 1,3-dioxide
takes up amine molecule with simultaneous removal of
one N-oxide oxygen atom and two hydrogen atoms,
the ortho-quinone diimine system being retained [8].
In continuation of these studies in the present work
we examined reactions of 5-nitrospiro[benzimidazole-
2,1′-cyclohexane] 1,3-dioxide (I) prepared by us previ-
ously [7] with some nucleophilic reagents. Compound
I reacted with ammonia in chloroform to produce
amine IIa (Scheme 1). According to the analytical and
spectral data, nucleophilic replacement in molecule I
was accompanied by elimination of one N-oxide oxy-
gen atom and two hydrogen atoms. With a view to
The main procedure for the synthesis of 2H-benz-
imidazole 1,3-dioxides is based on reaction of benzo-
furoxans with secondary nitroalkanes in the presence
of a base. Nitro derivatives of benzofuroxan failed to
react in such a way [3]. We have developed a proce-
dure for the synthesis of 2H-benzimidazole 1,3-diox-
ides via reaction of benzofuroxans with alcohols or
399

SAMSONOV et al.
Scheme 1.
OH
400
R1
R2
N
OMe
O2N
O2N
O2N
N
N
N
N
N
OH–
CH2N2
N
O–
O–
O–
IIa–IIm
III
IV
OH–
HNR1R2
R
NHR
O–
N
O–
O–
HN
H
O2N
O2N
O2N
N
N
RNH2
MnO2
N
N
N
O–
OH
O–
I
A
Va, Vb
II, R1 = R2 = H (a); R1 = H, R2 = Me (b), HOCH2CH2 (c), Me(CH2)2 (d), Me(CH2)3 (e), t-Bu (f), cyclohexyl (g), 2,2,6,6-tetramethyl-
piperidin-4-yl (h), PhCH2 (i), PhCH2CH2 (j); R1R2N = piperidino (k), morpholino (l), pyrrolidin-1-yl (m); V, R = H (a), Me (b).
elucidate which N-oxide oxygen atom was lost in this
reaction, we obtained a single crystal of IIa, and the
structure of this compound was unambiguously deter-
mined by X-ray analysis (see figure). The benzim-
idazole fragment in molecule IIa is planar within
±0.015 Å. The nitro and amino groups reside in the
benzimidazole ring plane, the corresponding dihedral
angles being equal to 3.19(4) and 1.7(4)°, respectively.
The bond lengths in molecule IIa are similar to those
found for dispiro[benzimidazole-2,1′-cyclohexane-
4′,2″-benzimidazole] 1-oxide and dispiro[benzimid-
azole-2,1′-cyclohexane-4′,2″-benzimidazole] 1,1″-di-
oxide [9]. Intramolecular hydrogen bonds N2–H···O2
[N–H 0.86(2), H···O 2.08(2) Å, ∠NHO 123(2)°] and
N2–H···N3 [0.89(2), 2.40(2) Å, 105(1)°], as well as
intermolecular hydrogen bond N2–H···O1 [0.86(2),
2.23(2) Å, 121(2)°], were detected in the crystalline
structure of compound IIa; the latter bond is respon-
sible for the formation of chains along the c axis. Also,
intermolecular N4–O2···π interactions were found with
the following parameters: O···centroid (Cg) 3.387(1)
(benzo), 3.362(1) Å (imidazole), ∠NOCg 100.81(9),
100.30(9)°.
Treatment of N-oxide IIa in alcohol with aqueous
sodium hydroxide gave compound III which was
assigned the structure of 5-nitrospiro[benzimidazole-
2,1′-cyclohexan]-4-ol 1-oxide on the basis of its spec-
1
tral parameters and elemental analysis. The H NMR
spectrum of III contained signals from five CH2
groups in the cyclohexane ring (δ 1.23–1.98 ppm, m),
signals from aromatic protons as two doublets at δ 6.58
and 7.40 ppm, and a singlet at δ 9.45 ppm belonging to
13
the hydroxy proton. In the C NMR spectrum of III,
signals from methylene carbon atoms appeared at
δC 22.83, 24.21, and 34.34 ppm, two aromatic CH
carbon atoms resonated at δC 103.90 and 125.52 ppm,
and five quaternary carbon atoms gave signals at
δC 105.80, 133.18, 135.75, 153.24, and 160.21 ppm.
Presumably, the position of the N-oxide moiety in
molecule III is the same as in IIa. By reaction of
compound III with diazomethane we obtained 4-me-
thoxy-5-nitrospiro[benzimidazole-2,1′-cyclohexane]
1-oxide (IV). Compound III was also formed directly
from 1,3-dioxide I by the action of aqueous alkali.
N2
O2
N4
C9
C4
C5
N3
C8
C3a
C10
C11
O3
C6
C2
N1
C7a
C7
C12
Primary and secondary amines readily reacted with
compound I to produce mono-N-oxides IIb–IIm. The
position of the N-oxide moiety in the products was the
same as in compound IIa. This follows from the
Structure of the molecule of 5-nitrospiro[benzimidazole-2,1′-
cyclohexan]-4-amine 1-oxide (IIa) according to the X-ray
diffraction data.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 48 No. 3 2012

REACTIONS OF 5-NITROSPIRO[BENZIMIDAZOLE-2,1′-CYCLOHEXANE] 1,3-DIOXIDE
401
Scheme 2.
3-O2NC6H4NH2 ·HCl
O2N
IXb
XI
N
HNR1R2
IIc, IIk, IIl
NaCN
N
O–
VI
formation of N-oxide III in the reaction of nitro
amines IIc, IIk, and IIl with aqueous alkali as a result
of replacement of the amino group by hydroxy. Com-
pound III thus obtained was identified by comparing
the IR spectra and melting points. Amines IIc, IIk, and
IIl were also synthesized by reaction of 5-nitrospiro-
[benzimidazole-2,1′-cyclohexane] 1-oxide (VI) report-
ed by us previously [11] with 2-aminoethanol, piperi-
dine, and morpholine, respectively (Scheme 2). Al-
kylation of IIa with methyl iodide gave compound IIb.
The above findings allowed us to presume the same
position of the N-oxide oxygen atom in all compounds
IIa–IIm.
compound I is a strong oxidant, and it loses N-oxide
oxygen atoms on heating. This is likely to be respon-
sible for the formation of a considerable amount of tars
in the reaction of I with aromatic amines.
The reaction of I with sodium azide occurred as
nucleophilic replacement of the nitro group by azido
with conservation of the N-oxide groups and formation
of 5-azidospiro[benzimidazole-2,1′-cyclohexane]
1,3-dioxide (VIII) (Scheme 3). The IR spectrum of
VIII contained an absorption band at 2117 cm–1, which
is typical of stretching vibrations of azido group.
The other analytical and spectral parameters of VIII
were also consistent with the assumed structure (see
Experimental).
5-Nitrospiro[benzimidazole-2,1′-cyclohexan]-4-
amine 1,3-dioxide (Va) was synthesized by reaction of
compound I with ammonia in the presence of MnO2 as
oxidant. Presumably, the reaction involves initial nu-
cleophilic 1,6-addition of ammonia to molecule I with
formation of adduct A which is oxidized with MnO2 to
give Va. The structure of 5-nitrospiro[benzimidazole-
2,1′-cyclohexan]-4-amine 1,3-dioxide (Va) was deter-
mined on the basis of its spectral parameters and
elemental composition (see Experimental). Protons in
the amino group resonated in the 1H NMR spectrum of
Va as two singlets at δ 8.75 and 9.22 ppm, presumably
due to formation of intramolecular hydrogen bond
between the N-oxide oxygen atom and hydrogen atom
in the amino group, as well as between the nitro group
and the other amino hydrogen atom. Likewise, in the
reaction of I with MeNH2 in the presence of MnO2
both N-oxide groups were conserved, and the product
was N-methyl-5-nitrospiro[benzimidazole-2,1′-cyclo-
hexan]-4-amine 1,3-dioxide (Vb) (Scheme 1).
Compound I reacted with aromatic amine hydro-
chlorides (aniline, 4-methoxyaniline, and 3-nitroaniline
hydrochlorides) to give the corresponding N-arylspiro-
[benzimidazole-2,1′-cyclohexan]-5-amine 1-oxides
IXa–IXc whose structure was confirmed by spectral
and analytical data. The position of the N-oxide group
was determined taking into account the formation of
compound IXb in the reaction of VI with 3-nitro-
aniline hydrochloride. It should be noted that the reac-
tion of N,N′-dioxide I with aniline hydrochloride was
accompanied by formation of a small amount of
N-phenylspiro[benzimidazole-2,1′-cyclohexan]-5-
amine 1,3-dioxide (IXd).
The reaction of I with sodium cyanide in methanol
afforded 5-methoxyspiro[benzimidazole-2,1′-cyclo-
hexane]-4-carbonitrile 1-oxide (X) and 5-oxo-3,5-di-
hydrospiro[benzimidazole-2,1′-cyclohexane]-4-carbo-
nitrile 1-oxide (XI). Initially, cyanide ion is likely to
react with I to give intermediate B, and next follows
nucleophilic replacement of the nitro group by me-
thoxy or hydroxy, as described in [11] for 5-nitrospiro-
[benzimidazole-2,1′-cyclohexane]. Compound XI was
formed as the only product when the reaction was
carried out in a two-phase system (chloroform–water).
The reactions of compound I with aromatic amines
were accompanied by loss of both N-oxide oxygen
atoms with formation of N-arylspiro[benzimidazole-
2,1′-cyclohexan]-4-amines VIIa–VIIf (Scheme 3).
These reactions were carried out by prolonged heating
of a mixture of I and aromatic amine in boiling
benzene or alcohol. Presumably, initial elimination of
N-oxide oxygen atoms from molecule I gives the
corresponding 2H-benzimidazole which then reacts
with aromatic amine. As shown by us previously [10],
The structure of 5-methoxyspiro[benzimidazole-
2,1′-cyclohexane]-4-carbonitrile 1-oxide (X) was
determined on the basis of analytical and spectral data.
The IR spectrum of X contained an absorption band at
2228 cm–1, which is typical of stretching vibrations of
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 48 No. 3 2012

SAMSONOV et al.
402
Scheme 3.
NHAr
O2N
N
N
ArNH2
O–
VIIa–VIIf
O–
N3
N
NaN3
N
O–
VIII
O–
I
ArNH
PhNH
N
N
N
ArNH2 ·HCl
+
N
O–
O–
IXa–IXc
IXd
CN
MeO
N
N
MeO–
CN
O–
O2N
N
N
NaCN
X
CN
CN
Me
H
N
O–
O
O
N
HO–
MeI
+ X
B
N
N
O–
O–
XI
XII
VII, Ar = Ph (a), 2-MeOC6H4 (b), 4-MeOC6H4 (c), 4-O2NC6H4 (d), 4-H2NSO2 (e), 2-ClC6H4 (f); IX, Ar = Ph (a),
3-O2NC6H4 (b), 4-MeOC6H4 (c).
a three-proton singlet at δ 3.47 ppm, and two doublets
at δ 6.40 and 7.44 ppm were assigned to 6-H and 7-H.
In the 13C NMR spectrum of XII we observed three
signals from methylene carbon atoms in the cyclohex-
ane ring, and a signal at δC 31.43 ppm due to methyl
carbon atom attached to nitrogen. The cyano group
gave a signal at δC 78.4 ppm, and two CH signals
appeared at δC 120.35 and 131.01 ppm. The signal at
δC 95.35 ppm was assigned to the spiro carbon atom
(C2), and the other quaternary carbon atoms resonated
at 116.37, 131.84, and 154.12 ppm; the signal at
δC 181.75 ppm was typical of carbonyl carbon atom.
These data in combination with the mass spectrum and
elemental analysis allowed us to identify compound
XII as 3-methyl-5-oxo-3,5-dihydrospiro[benzimidaz-
ole-2,1′-cyclohexane]-4-carbonitrile 1-oxide. In addi-
cyano group. The other spectral parameters of X also
confirmed the assumed structure. The structure of
compound XI is likely to be similar to the structure of
its known [11] analog having no N-oxide group. Com-
pound XI displayed in the 13C NMR spectrum a signal
at δC 181.61 ppm, which is characteristic of quinoid
carbonyl carbon atom. The position of the N-oxide
group in XI was confirmed by its synthesis via reac-
tion of VI with sodium cyanide (Scheme 2). The
alkylation of XI with methyl iodide involved nitrogen
atom in the imidazole ring with formation of com-
pound XII. The IR spectrum of XII contained absorp-
tion bands at 2205 (C≡N), 1541 (C=N), and 1616 cm–1
1
(C=O). In the H NMR spectrum of this compound,
10 protons in the cyclohexane ring resonated in the
region δ 1.32–2.97 ppm, the N-methyl group gave
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 48 No. 3 2012

REACTIONS OF 5-NITROSPIRO[BENZIMIDAZOLE-2,1′-CYCLOHEXANE] 1,3-DIOXIDE
403
Scheme 4.
Nu
Nu
H
H
N
R3
R3
R3
R1
R2
R1
R2
R1
R2
N
N
N
NuH
N
H
N
H
Scheme 5.
Nu
Nu
O–
O–
OH
Nu
H
R3
R3
R3
R3
R1
R2
R1
R2
R1
R2
R1
R2
N
N
N
N
N
NuH
–H2O
N
N
N
O–
OH
OH
O–
C
purity of products were monitored by TLC on Sorbfil
UV-254 plates (Sorbpolimer, Krasnodar, Russia); the
chromatograms were developed under UV light and by
treatment with iodine vapor. The melting points were
measured on a Kofler hot stage. The elemental com-
positions were determined at the Microanalysis Labo-
ratory, Novosibirsk Institute of Organic Chemistry,
Siberian Division of the Russian Academy of Sciences.
Compounds I [7] and VI [10] were synthesized by
known methods.
tion, a small amount of O-alkylation product X was
isolated (Scheme 3).
The results of addition of nucleophilic reagents to
5-nitrospiro[benzimidazole-2,1′-cyclohexane] 1,3-di-
oxide (I) were compared with the results of analogous
reactions with 2H-benzimidazoles which are known to
produce the corresponding 2,3-dihydro-1H-benzimid-
azoles [11–13] (Scheme 4). It may be presumed that
addition of nucleophiles to 2H-benzimidazole 1,3-di-
oxide could give rise to 1,3-dihydroxy-2,3-dihydro-
1H-benzimidazoles like C (Scheme 5). In fact, inter-
mediate C loses water molecule, and the ortho-quinoid
structure is retained. We believe that this is the main
difference between 2H-benzimidazole 1,3-dioxides
and 2H-benzimidazoles in reactions with nucleophiles.
Single crystals of compound IIa for X-ray analysis
were obtained by recrystallization from ethyl acetate–
hexane (1:1). The X-ray diffraction data were acquired
at 296 K on a Bruker KAPPA APEX II CCD diffrac-
tometer; λ(MoKα) 0.71073 Å, graphite monochroma-
tor, ω,φ-scanning, 2θ <50°. Crystallographic data for
compound IIa: monoclinic crystal system, space group
P21/c; unit cell parameters: a = 6.5118(3), b =
22.2201(8), c = 8.4692(3) Å; β = 101.814(2)°; V =
1199.47(8) Å3; C12H14N4O3; Z = 4, dcalc = 1.452 g/cm3;
μ = 0.108 cm–1; crystal dimensions 0.06 × 0.38×
0.40 mm. Absorption by the crystal was taken into
account empirically using SADABS program
(Tmin/Tmax = 0.84/0.97). Intensities of 9846 reflections
were measured, 2613 of which were independent
(Rint = 0.0483). The structure was solved by the direct
method. The positions and temperature factors of non-
hydrogen atoms were refined in anisotropic approx-
imation by the full-matrix least-squares procedure.
Hydrogen atoms in the amino group were localized by
difference synthesis, while the other hydrogen atoms
were placed into positions calculated on the basis of
geometry considerations. The final divergence factors
were wR2 = 0.1156 (all reflections; S = 1.050), R1 =
0.0405 [2049 reflections with I ≥ 2σ(I)]. All calcula-
tions were performed using SHELX and PLATON.
EXPERIMENTAL
The IR spectra were recorded in KBr (sample con-
centration 0.25%) on a Bruker Vector-22 spectrometer;
given are the most intense absorption bands. The UV
spectra were measured on a Hewlett–Packard 4853
spectrophotometer from solutions in ethanol. The
13
1H and C NMR spectra were obtained on a Bruker
AV-300 instrument at 25°C from 10% solutions in
CDCl3 or DMSO-d6; the chemical shifts were deter-
mined relative to the residual proton and carbon
signals of the solvent (CHCl3, δ 7.24, δC 76.90 ppm;
DMSO-d5, δ 2.50, δC 39.50 ppm). Signal multiplicities
in the 13C NMR spectra were determined using
J-modulation (JMOD) technique. The mass spectra
(electron impact, 70 eV) were recorded on a Thermo
Scientific DFS mass spectrometer with direct sample
admission into the ion source (ion source temperature
180°C); ion peaks with a relative intensity higher than
10% are given. The progress of reactions and the
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 48 No. 3 2012

SAMSONOV et al.
404
The crystallographic data for compound IIa were de-
posited to the Cambridge Crystallographic Data Centre
(entry no. CCDC 827016).
2-[(5-Nitro-1-oxidospiro[benzimidazole-2,1′-cy-
clohexan]-4-yl)amino]ethanol (IIc). 2-Aminoethanol,
1.5 g (0.025 mol), was added to a solution of 5.26 g
(0.02 mol) of compound I in 50 ml of chloroform, and
the mixture was stirred for 1 h at room temperature.
The solvent was distilled off under reduced pressure,
and the residue was purified by chromatography on
silica gel using chloroform–methanol (10:1) as eluent.
Yield 86%, mp 195–197°C. IR spectrum, ν, cm–1: 3400
(NH), 1616 (C=N), 1450, 1329 (NO2). UV spectrum,
λmax, nm (logε): 230 (4.19), 360 (4.25), 520 (3.64).
1H NMR spectrum (CDCl3), δ, ppm: 1.20–2.17 m
(10H, CH2), 2.24 br.s (1H, OH), 3.98– 4.02 m (2H,
CH2), 4.46–4.51 m (2H, CH2), 6.43 d (1H, CH, J =
10.1 Hz), 7.63 d (1H, CH, J = 10.1 Hz), 10.67 s (1H,
NH). 13C NMR spectrum, δC, ppm: 23.50, 24.45,
35.02, 48.54, 61.61 (CH2); 102.05, 126.08 (CH);
105.72, 126.96, 135,98, 144.38, 160.12. Mass spec-
trum, m/z (Irel, %): 306 (97) [M]+, 289 (15), 275 (100),
259 (58), 247 (56), 229 (37), 216 (39), 213 (34), 199
(32). Found, %: C 55.18; H 5.91; N 18.20.
m/z 306.1328 [M]+. C14H18N4O4. Calculated, %:
C 54.89; H 5.92; N 18.29. M 306.1323.
5-Nitrospiro[benzimidazole-2,1′-cyclohexan]-4-
amine 1-oxide (IIa). Compound I, 1.32 g (0.005 mol),
was dissolved in 60 ml of chloroform, 5 ml of a 25%
solution of ammonia was added, and the mixture was
stirred for 1 h at room temperature. The mixture was
treated with 20 ml of water, the organic phase was
separated, washed with water (3×20 ml), and dried
over MgSO4, the drying agent was filtered off, the
filtrate was evaporated, the residue was dispersed in
hexane, and the precipitate was filtered off. Yield
1.15 g (87%), mp 251–253°C. IR spectrum, ν, cm–1 :
3451, 3331 (NH2), 1632 (C=N). UV spectrum, λmax
,
1
nm (logε): 350 (4.34), 500 (3.65). H NMR spectrum
(DMSO-d6), δ, ppm: 1.25–2.04 m (10H, CH2), 6.38 d
(1H, CH, J = 10.0 Hz), 7.49 d (1H, CH, J = 10.0 Hz),
8.87 br.s (2H, NH2). 13C NMR spectrum, δC, ppm:
22.88, 24.21, 34.28 (CH2); 101.50, 125.17 (CH);
106.23, 124.82, 134.13, 143.48, 159.07. Mass spec-
trum, m/z (Irel, %): 262 (100) [M]+, 245 (48), 219 (80),
208 (61), 191 (42), 189 (46). Found, %: C 54.60;
H 5.24; N 21.10. m/z 262.1068 [M]+. C12H14N4O3. Cal-
culated, %: C 54.95; H 5.38; N 21.37. M 262.1060.
Compounds IId–IIm were synthesized in a simi-
lar way.
N-Methyl-5-nitrospiro[benzimidazole-2,1′-cyclo-
hexan]-4-amine 1-oxide (IIb). a. Compound IIb was
synthesized as described above for IIa. Yield 76%,
mp 228–230°C. IR spectrum, ν, cm–1: 3205 (NH),
1616 (C=N). UV spectrum, λmax, nm (log ε): 229
5-Nitro-N-propylspiro[benzimidazole-2,1′-cyclo-
hexan]-4-amine 1-oxide (IId). Yield 76%, mp 198–
201°C. IR spectrum, ν, cm–1: 2967 (NH), 1609 (C=N).
UV spectrum, λmax, nm (logε): 229 (4.17), 364 (4.16),
1
401 (3.83), 529 (3.57). H NMR spectrum (CDCl3), δ,
1
(4.21), 363 (4.22), 401 (3.94), 527 (3.60). H NMR
ppm: 1.04 t (3H, CH3, J = 7.4 Hz), 1.23–2.17 m (12H,
CH2), 4.18–4.28 m (2H, CH2), 6.41 d (1H, CH, J =
10.0 Hz), 7.63 d (1H, CH, J = 10.0 Hz), 10.61 s (1H,
NH). 13C NMR spectrum, δC, ppm: 23.20, 23.34,
24.27, 34.70, 48.28 (CH2); 10.94 (CH3); 101.59,
125.75 (CH); 105.40, 126.08, 135.50, 144.29, 159.45.
Mass spectrum, m/z (Irel, %): 304 (100) [M]+, 287 (59),
275 (68), 247 (36), 241 (29). Found, %: C 58.95;
H 6.60; N 18.46. m/z 304.1541 [M]+. C15H20N4O3. Cal-
culated, %: C 59.19; H 6.62; N 18.41. M 304.1530
spectrum, δ, ppm (CDCl3): 1.23–2.18 m (10H, CH2),
3.81 d (3H, CH3, J = 6.0 Hz), 6.42 d (1H, CH, J =
10.1 Hz), 7.63 d (1H, CH, J = 10.1 Hz), 10.55 br.s
13
(1H, NH). C NMR spectrum, δC, ppm: 23.30, 24.46,
34.90 (CH2); 34.69 (CH3); 101.89, 125.86 (CH);
105.83, 126.31, 135.66, 145.03, 160.04. Mass spec-
trum, m/z (Irel, %): 276 (100) [M]+, 259 (41), 233 (80),
203 (56). Found, %: C 56.40; H 5.62; N 20.36.
m/z 276.1220 [M]+. C13H16N4O3. Calculated, %:
C 56.51; H 5.84; N 20.28. M 276.1217.
N-Butyl-5-nitrospiro[benzimidazole-2,1′-cyclo-
hexan]-4-amine 1-oxide (IIe). Yield 78%, mp 162–
164°C. IR spectrum, ν, cm–1: 3236 (NH), 1604 (C=N).
UV spectrum, λmax, nm (logε): 231 (4.23), 364 (4.26),
b. Compound IIa, 0.3 g (0.0011 mol), was dis-
solved in 20 ml of acetonitrile, 0.5 g (0.0036 mol) of
finely powdered calcined potassium carbonate and
2 ml (0.032 mol) of methyl iodide were added, and the
mixture was stirred for 24 h at room temperature. The
precipitate was filtered off, the solvent was removed,
the residue was treated with 10 ml of water, and the
precipitate was filtered off, washed with water, and
dried. Yield 0.25 g (79%), mp 228–230°C.
1
401 (3.94), 529 (3.70). H NMR spectrum (CDCl3), δ,
ppm: 0.90 t (3H, CH3, J = 7.6 Hz), 1.20–2.17 m (14H,
CH2), 4.20–4.32 m (2H, CH2), 6.37 d (1H, CH, J =
10.0 Hz), 7.59 d (1H, CH, J = 10.0 Hz), 10.60 s (1H,
NH). 13C NMR spectrum, δC, ppm: 19.63, 23.12,
24.20, 31.94, 34.63, 46.40 (CH2); 13.29 (CH3); 101.47,
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REACTIONS OF 5-NITROSPIRO[BENZIMIDAZOLE-2,1′-CYCLOHEXANE] 1,3-DIOXIDE
405
125.67 (CH); 105.32, 125.94, 135.44, 144.23, 159.39.
Mass spectrum, m/z (Irel, %): 318 (97) [M]+, 301 (62),
275 (100), 255 (29), 247 (41). Found, %: C 60.30;
H 6.76; N 17.58. m/z 318.1688 [M]+. C16H22N4O3. Cal-
culated, %: C 60.36; H 6.97; N 17.60. M 318.1686.
N-Benzyl-5-nitrospiro[benzimidazole-2,1′-cyclo-
hexan]-4-amine 1-oxide (IIi). Yield 68%, mp 172–
174°C. IR spectrum, ν, cm–1: 3247 (NH), 1609 (C=N).
UV spectrum, λmax, nm (logε): 228 (4.21), 363 (4.22),
1
526 (3.64). H NMR spectrum (CDCl3), δ, ppm: 1.22–
2.18 m (10H, CH2), 5.55 d (2H, CH2, J = 6.3 Hz),
7.38 s (5H, Harom), 6.48 d (1H, CH, J = 10.0 Hz),
7.67 d (1H, CH, J = 10.0 Hz), 10.70 br.s (1H, NH).
13C NMR spectrum, δC, ppm: 23.02, 24.14, 34.66,
50.29 (CH2); 102.05, 125.48, 127.04, 127.66, 128.57
(CH); 105.58, 127.03, 135.48, 136.65, 143.50, 159.45.
Mass spectrum, m/z (Irel, %): 352 (29) [M]+, 335 (63),
317 (65), 307 (28), 287 (45), 105 (100). Found, %:
C 64.73; H 5.69; N 16.08. m/z 352.1533 [M]+.
C19H20N4O3. Calculated, %: C 64.76; H 5.72; N 15.90.
M 352.1533.
N-tert-Butyl-5-nitrospiro[benzimidazole-2,1′-cy-
clohexan]-4-amine 1-oxide (IIf). Yield 74%, mp 211–
213°C. IR spectrum, ν, cm–1: 2970 (NH), 1612 (C=N),
1427 (NO2), 1226. UV spectrum, λmax, nm (logε): 231
1
(4.22), 368 (4.27), 536 (3.72). H NMR spectrum
(CDCl3), δ, ppm: 1.20–2.18 m (10H, CH2), 1.67 s (9H,
CH3), 6.41 d (1H, CH, J = 10.0 Hz), 7.65 d (1H, CH,
J = 10.0 Hz), 11.23 s (1H, NH). 13C NMR spectrum,
δC, ppm: 23.38, 24.24, 34.66 (CH2); 29.61 (CH3);
101.75, 136.02 (CH); 56.89, 105.00, 127.45, 135.94,
145.70, 157.92. Mass spectrum, m/z (Irel, %): 318 (66)
[M]+, 301 (5), 262 (81), 245 (62), 219 (100), 208 (93),
191 (39). Found, %: C 60.85; H 7.05; N 17.52.
m/z 318.1685 [M]+. C16H22N4O3. Calculated, %:
C 60.36; H 6.97; N 17.60. M 318.1686.
5-Nitro-N-(2-phenylethyl)spiro[benzimidazole-
2,1′-cyclohexan]-4-amine 1-oxide (IIj). Yield 66%,
mp 206–210°C. IR spectrum, ν, cm–1: 3199 (NH),
1615 (C=N). UV spectrum, λmax, nm (log ε): 229
1
N-Cyclohexyl-5-nitrospiro[benzimidazole-2,1′-
cyclohexan]-4-amine 1-oxide (IIg). Yield 64%,
mp 163–165°C. IR spectrum, ν, cm–1: 2928 (NH),
(4.13), 365 (4.15), 401 (3.79), 529 (3.60). H NMR
spectrum, δ, ppm (CDCl3): 1.18–2.12 m (10H, CH2),
3.03 t (2H, CH2, J = 7.0 Hz), 4.54 q (2H, CH2, J = 6.6,
14.6 Hz), 7.15– 7.31 m (5H, Harom), 6.35 d (1H, CH,
J = 10.3 Hz), 7.56 d (1H, CH, J = 10.3 Hz), 10.49 br.s
1605 (C=N), 1513, 1231 (NO2). UV spectrum, λmax
,
nm (logε): 230 (4.14), 366 (4.20), 401 (3.87), 530
1
13
(3.66). H NMR spectrum (CDCl3), δ, ppm: 1.20–
(1H, NH). C NMR spectrum, δC, ppm: 23.13, 24.17,
2.18 m (20H, CH2), 5.10 m (1H, CH), 6.37 d (1H, CH,
J = 10.0 Hz), 7.61 d (1H, CH, J = 10.0 Hz), 10.54 d
(1H, NH, J = 7.8 Hz). 13C NMR spectrum, δC, ppm:
23.68, 24.51, 25.06, 33.59, 34.90 (CH2); 54.77, 101.61,
126.07 (CH); 105.38, 126.01, 137.76, 143.53, 159.26.
Mass spectrum, m/z (Irel, %): 344 (66) [M]+, 327 (100),
309 (40), 301 (29). Found, %: C 63.0; H 6.96;
N 16.54. m/z 344.1844 [M]+. C18H24N4O3. Calculated,
%: C 62.77; H 7.02; N 16.27. M 344.18.43.
34.66, 36.24, 47.66 (CH2); 101.78, 125.63, 126.72,
128.34, 128.42 (CH); 105.39, 126.29, 134.46, 137.22,
143.98, 159.48. Mass spectrum, m/z (Irel, %): 366 (46)
[M]+, 349 (60), 316 (25), 275 (95), 259 (54), 247 (38).
m/z 366.1684 [M]+. C20H22N4O3. Calculated, %:
C 65.57; H 6.01; N 15.30. M 366.1686.
5-Nitro-4-piperidinospiro[benzimidazole-2,1′-cy-
clohexane] 1-oxide (IIk). Yield 48%, mp 159–162°C.
IR spectrum: ν 1596 cm–1 (C=N). UV spectrum, λmax
,
5-Nitro-N-(2,2,6,6-tetramethylpiperidin-4-yl)-
spiro[benzimidazole-2,1′-cyclohexan]-4-amine 1-ox-
ide (IIh). Yield 72%, mp 217–220°C. IR spectrum: ν
1607 cm–1 (C=N). UV spectrum, λmax, nm (logε): 231
nm (logε): 242 (4.11), 287 (3.75), 378 (3.91), 531
1
(3.70). H NMR spectrum (CDCl3), δ, ppm: 1.23–
2.20 m (16H, CH2), 3.51–3.70 m (4H, CH2), 6.53 d
(1H, CH, J = 9.8 Hz), 7.37 d (1H, CH, J = 9.8 Hz).
13C NMR spectrum, δC, ppm: 23.34, 23.25, 24.34,
25.94, 34.70, 52.80 (CH2); 103.20, 126.87 (CH);
104.60, 132.68, 135.91, 142.38, 161.18. Mass spec-
trum, m/z (Irel, %): 330 (54) [M]+, 313 (100), 287 (17),
274 (18), 257 (35). Found, %: C 61.68; H 6.66;
N 16.87. m/z 330.1686 [M]+. C17H22N4O3. Calculated,
%: C 61.80; H 6.75; N 16.96. M 330.1685
1
(4.29), 366 (4.33), 528 (3.83). H NMR spectrum
(CDCl3), δ, ppm: 1.20–2.27 m (14H, CH2), 1.15 s (6H,
CH3), 1.26 s (6H, CH3), 5.28 m (1H, CH), 6.38 d (1H,
CH, J = 10.0 Hz), 7.61 d (1H, CH, J = 10.0 Hz),
10.49 d (1H, NH, J = 8.0 Hz). 13C NMR spectrum, δC,
ppm: 23.15, 24.26, 34.88, 45.81 (CH2); 28.73, 34.60
(CH3); 49.15, 101.69, 126.05 (CH); 50.53, 105.40,
126.32, 135.83, 143.40, 159.59. Mass spectrum, m/z
(Irel, %): 401 (13) [M]+, 138 (9), 124 (100). Found, %:
C 63.0; H 7.70; N 17.30. m/z 401.2422 [M]+.
C21H31N5O3. Calculated, %: C 62.83; H 7.78; N 17.44.
M 401.2421.
4-Morpholino-5-nitrospiro[benzimidazole-2,1′-
cyclohexane] 1-oxide (IIl). Yield 43%, mp 180–
182°C. IR spectrum: ν 1591 cm–1 (C=N). UV spec-
trum, λmax, nm (logε): 293 (3.64), 375 (3.79), 521
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 48 No. 3 2012

SAMSONOV et al.
406
1
(3.62). H NMR spectrum (CDCl3), δ, ppm: 1.15–
2.20 m (10H, CH2), 3.55–3.70 m (4H, CH2), 3.75–
3.90 m (4H, CH2), 6.51 d (1H, CH, J = 10.0 Hz),
(CH); 105.80, 133.18, 135.75, 153.24, 160.21. Mass
spectrum: m/z (Irel, %): 263 (45) [M]+, 247 (100), 229
(23), 212 (46). Found, %: C 54.62; H 4.96, N 16.10.
m/z 263.0902 [M]+. C12H13N3O4. Calculated, %:
C 54.75; H 4.98; N 15.96. M 263.0901.
13
7.25 d (1H, CH, J = 10.0 Hz). C NMR spectrum, δC,
ppm: 23.58, 24.52, 35.03, 51.70, 66.63 (CH2); 104.80,
126.40 (CH); 105.25, 134.06, 136.08, 141.16, 161.43.
Found, %: C 57.78; H 5.94; N 16.62. C16H20N4O4. Cal-
culated, %: C 57.82; H 6.07; N 16.86.
Following a similar procedure, compound III was
obtained from compounds IIc, IIk, and IIl in 95, 72,
and 84% yield, respectively.
5-Nitro-4-(pyrrolidin-1-yl)spiro[benzimidazole-
2,1′-cyclohexane] 1-oxide (IIm). Yield 56%, mp 183–
188°C. IR spectrum: ν 1594 cm–1 (C=N). UV spec-
trum, λmax, nm (logε): 237 (4.24), 371 (4.01), 533
4-Methoxy-5-nitrospiro[benzimidazole-2,1′-cy-
clohexane] 1-oxide (IV). A solution of diazomethane
prepared from 1 g of nitrosomethylurea in 50 ml of
ether was added dropwise at room temperature to a so-
lution of 1.0 g (0.038 mol) of compound III in 25 ml
of methanol. The mixture was stirred for 2 h at 20°C,
the solvent was distilled off under reduced pressure,
and the residue was purified by chromatography on
silica gel using ethyl acetate–hexane (1:3) as eluent.
Yield 0.38 g (36%), mp 75–78°C. IR spectrum:
ν 1600 cm–1 (C=N). UV spectrum, λmax, nm (logε): 281
1
(3.76). H NMR spectrum (CDCl3), δ, ppm: 1.10–
2.20 m (14H, CH2), 3.79 s (4H, CH2), 6.37 d (1H, CH,
J = 10.0 Hz), 7.42 d (1H, CH, J = 10.0 Hz). 13C NMR
spectrum, δC, ppm: 23.36, 24.59, 25.48, 34.88, 55.31
(CH2); 100.99, 128.74 (CH); 104.66, 129.85, 136.16,
141.37, 160.66. Mass spectrum, m/z (Irel, %): 316 (40)
[M]+, 299 (100), 266 (48), 265 (58), 253 (47), 243
(80), 225 (47). Found, %: C 60.32; H 6.37; N 17.66.
m/z 316.1523 [M]+. C16H20N4O4. Calculated, %:
C 60.76; H 6.33; N 17.72. M 316.1530.
1
(3.78), 322 (3.76), 447 (3.64). H NMR spectrum
(CDCl3), δ, ppm: 1.19–1.98 m (10H, CH2), 4.48 s (3H,
OCH3), 6.86 d (1H, CH, J = 9.2 Hz), 7.06 d (1H, CH,
J = 9.2 Hz). 13C NMR spectrum, δC, ppm: 23.06,
24.18, 34.88 (CH2); 62.08 (OCH3); 109.44, 123.36
(CH); 106.70, 135.83, 140.02, 148.21, 158.16. Mass
spectrum: m/z (Irel, %): 277 (100) [M]+, 260 (55), 247
(43), 223 (36), 213 (31), 206 (86). Found, %: C 56.82;
H 5.60; N 15.05. m/z 277.1051 [M]+. C13H15N3O4. Cal-
culated, %: C 56.31; H 5.45; N 15.16. M 277.1057.
5-Nitrospiro[benzimidazole-2,1′-cyclohexan]-
4-ol 1-oxide (III). a. Compound I, 2.63 g (0.01 mol),
was added to a solution of 0.7 g (0.017 mol) of sodium
hydroxide in 100 ml of water, and the mixture was
vigorously stirred for 6 h at room temperature. The
solvent was distilled off to a volume of 20 ml, 5% hy-
drochloric acid was added until pH 3, and the precip-
itate was filtered off, washed with water, and dried.
The crude product, 2.25 g, was dissolved in alcohol
and subjected to chromatography on silica gel using
ethyl acetate–hexane (3:1 + 1% of methanol) as
eluent. Yield 1.99 g (76%).
5-Nitrospiro[benzimidazole-2,1′-cyclohexan]-4-
amine 1,3-dioxide (Va). Manganese(IV) oxide, 10 g,
was added to a solution of 2.63 g (0.01 mol) of com-
pound I in 100 ml of chloroform, and dry ammonia
was passed through the mixture over a period of 2 h
under vigorous stirring at room temperature. The
precipitate was filtered off, the solvent was distilled off
under reduced pressure, and the residue was subjected
to chromatography on silica gel using chloroform as
eluent to isolate 0.45 g (17%) of N-oxide IIa and
1.20 g (44%) of N,N-dioxide Va. mp 215–217°C. IR
spectrum, ν, cm–1: 3362, 3252 (NH2); 1617 (C=N). UV
spectrum, λmax, nm (logε): 265 (4.03), 335 (3.98), 621
b. A solution of 0.5 g (0.0125 mol) of sodium
hydroxide in 5 ml of water was added to a solution of
1.0 g (0.00386 mol) of compound IIa in 50 ml of
methanol, and the mixture was heated for 30 min under
reflux. The solvent was distilled off under reduced
pressure (water-jet pump), 10 ml of water was added to
the residue, and the mixture was acidified to pH 3 with
5% hydrochloric acid. The precipitate was filtered off,
washed with water, and dried. Yield 0.83 g (82%),
mp 165°C (decomp.). IR spectrum: ν 1606 cm–1
(C=N). UV spectrum, λmax, nm (logε): 227 (4.11), 282
1
(3.38). H NMR spectrum (CDCl3), δ, ppm: 1.53–
2.09 m (10H, CH2), 6.47 d (1H, CH, J = 10.1 Hz),
7.58 d (1H, CH, J = 10.1 Hz), 8.75 br.s (1H, NH),
9.22 br.s (1H, NH). 13C NMR spectrum, δC, ppm:
18.62, 22.86, 33.70 (CH2); 101.06, 126.76 (CH);
99.82, 123.64, 130.35, 134.61, 140.16. Mass spectrum,
m/z (Irel, %): 278 (100) [M]+, 262 (52), 207 (47), 180
(44). Found, %: C 52.11; H 5.12; N 20.20.
1
(3.45), 349 (3.98), 403 (4.02), 509 (3.34). H NMR
spectrum (DMSO-d6), δ, ppm: 1.23–1.98 m (10H,
CH2), 6.58 d (1H, CH, J = 10.0 Hz), 7.40 d (1H, CH,
13
J = 10.0 Hz), 9.43 br.s (1H, OH). C NMR spectrum,
δC, ppm: 22.83, 24.21, 34.34 (CH2); 103.90, 125.52
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407
m/z 278.1008 [M]+. C12H14N4O4. Calculated, %:
C 51.80; H 5.04; N 20.14. M 278.1010.
131.98 (CH); 109.08, 125.48, 126.80, 143.08, 153,40,
154.68, 158.13. Mass spectrum, m/z (Irel, %): 352 (21)
[M]+, 337 (25), 321 (100), 304 (12). Found, %:
C 64.70; H 5.68; N 15.85. m/z 352.1531 [M]+.
C19H20N4O3. Calculated, %: C 64.76; H 5.72; N 15.90.
M 352.1530.
N-Methyl-5-nitrospiro[benzimidazole-2,1′-cyclo-
hexan]-4-amine 1,3-dioxide (Vb) was synthesized in
a similar way. Yield 61%, mp 135–137°C. IR spec-
trum: ν 1592 cm–1 (C=N). UV spectrum, λmax, nm
1
(logε): 267 (4.18), 366 (4.00), 589 (3.48). H NMR
N-(4-Methoxyphenyl)-5-nitrospiro[benzimidaz-
ole-2,1′-cyclohexan]-4-amine (VIIc). Yield 35%,
mp 153–155°C. IR spectrum, ν, cm–1: 3204 (NH),
1631 (C=N). UV spectrum, λma1x, nm (log ε): 225
(4.25), 361 (4.04), 502 (3.70). H NMR spectrum
(CDCl3), δ, ppm: 1.09–1.88 m (10H, CH2), 3.84 s (3H,
OCH3), 6.59 d (1H, CH, J = 10.3 Hz), 7.94 d (1H, CH,
J = 10.3 Hz), 6.88 d (2H, Harom, J = 8.9 Hz), 7.14 d
(2H, Harom, J = 8.9 Hz), 11.56 s (1H, NH). 13C NMR
spectrum, δC, ppm: 24.06, 25.25, 33.05 (CH2); 55.48
(OCH3); 111.92, 113.85, 126.90, 132.22 (CH); 109.63,
125.80, 130.98, 143.24, 154,73, 158.52, 158.86. Mass
spectrum, m/z (Irel, %): 352 (100) [M]+, 337 (67), 318
(24), 290 (17). Found, %: C 64.85; H 5.65; N 16.10.
m/z 352.1527 [M]+. C19H20N4O3. Calculated, %:
C 64.76; H 5.72; N 15.90. M 352.1530.
spectrum (CDCl3), δ, ppm: 1.28–2.04 m (10H, CH2),
2.95 d (3H, CH3, J = 5.8 Hz), 6.39 d (1H, CH, J =
10.0 Hz), 7.38 d (1H, CH, J = 10.0 Hz), 9.50 br.s (1H,
NH). 13C NMR spectrum, δC, ppm: 18.64, 23.04, 33.45
(CH2); 33.78 (CH3); 101.65, 129.37 (CH); 100.04,
125.80, 131.63, 134.91, 139.90. Mass spectrum, m/z
(Irel, %): 292 (4) [M]+, 276 (17), 183 (100), 153 (63).
Found, %: C 53.38; H 5.35; N 18.85. m/z 292.1172
[M]+. C13H16N4O4. Calculated, %: C 53.42; H 5.52;
N 19.17. M 292.1166.
5-Nitro-N-phenylspiro[benzimidazole-2,1′-cyclo-
hexan]-4-amine (VIIa). Aniline, 2.0 g (0.02 mol), was
added to a solution of 2.63 g (0.01 mol) of compound I
in 80 ml of benzene, and the mixture was heated for
6 h under reflux. The solvent was distilled off, and the
residue was purified by chromatography on silica gel
using ethyl acetate–hexane (1:3) as eluent. Yield 1.70 g
(55%), mp 187–190°C. IR spectrum, ν, cm–1: 3194
(NH), 1631 (C=N). UV spectrum, λmax, nm (logε): 248
5-Nitro-N-(4-nitrophenyl)spiro[benzimidazole-
2,1′-cyclohexan]-4-amine (VIId). Yield 70%,
mp 108–110°C. IR spectrum: ν 1636 cm–1 (C=N). UV
spectrum, λmax, nm (logε): 268 (4.15), 344 (4.13), 494
1
1
(4.13), 360 (4.06), 500 (3.75). H NMR spectrum
(3.88). H NMR spectrum (CDCl3), δ, ppm: 1.20–
(CDCl3), δ, ppm: 0.95–1.94 m (10H, CH2), 6.60 d (1H,
CH, J = 10.1 Hz), 7.91 d (1H, CH, J = 10.1 Hz), 7.17–
7.24 m (2H, Harom), 7.29–7.39 m (3H, Harom), 11.49 s
1.85 m (10H, CH2), 6.76 d (1H, CH, J = 10.1 Hz),
7.32 d (2H, Harom, J = 9.0 Hz), 7.87 d (1H, CH, J =
10.1 Hz), 8.19 d (2H, Harom, J = 9.0 Hz), 11.07 s (1H,
NH). 13C NMR spectrum, δC, ppm: 23.90, 24.77, 32.46
(CH2); 114.43, 123.72, 125.00, 130.84 (CH); 110.11,
128.84, 139.50, 143.78, 145.28, 154.11, 157.94. Mass
spectrum, m/z (Irel, %): 367 (61) [M]+, 350 (100), 332
(22), 320 (47). Found, %: C 58.92; H 5.09; N 19.21.
m/z 367.1267 [M]+. C18H17N5O4. Calculated, %:
C 58.85; H 4.66; N 19.07. M 367.1275.
13
(1H, NH). C NMR spectrum, δC, ppm: 23.77, 24.95,
32.76 (CH2); 112.05, 131.69, 125.43, 127.10, 128.33
(CH); 109.45, 129.89, 137.85, 142.39, 154.35, 161.05.
Mass spectrum, m/z (Irel, %): 322 (100) [M]+, 305 (27),
287 (30), 275 (32). Found, %: C 67.37; H 5.51;
N 17.11. m/z 322.1347 [M]+. C18H17N4O2. Calculated,
%: C 67.20; H 5.60; N 17.30. M 322.1424.
Compounds VIIb–VIIf were synthesized in a simi-
lar way.
4-[(5-Nitro-1-oxidospiro[benzimidazole-2,1′-cy-
clohexan]-4-yl)amino]benzenesulfonamide (VIIe).
Yield 36%, mp 182–185°C. IR spectrum: ν 1634 cm–1
(C=N). UV spectrum, λmax, nm (logε): 268 (3.98), 358
N-(2-Methoxyphenyl)-5-nitrospiro[benzimidaz-
ole-2,1′-cyclohexan]-4-amine (VIIb). Yield 41%,
mp 172–174°C. IR spectrum, ν, cm–1: 3425 (NH),
1633 (C=N). UV spectrum, λmax, nm (log ε): 252
1
(3.74), 500 (3.56). H NMR spectrum (DMSO-d6), δ,
ppm: 1.30–1.87 m (10H, CH2), 6.77 d (1H, CH, J =
9.9 Hz), 7.35–7.42 m (4H, Harom, NH2), 7.69–7.81 m
(3H, Harom), 11.05 s (1H, NH). 13C NMR spectrum, δC,
ppm: 23.96, 24.92, 32.46 (CH2); 113.48, 123.52,
125.84, 132.34 (CH); 109.01, 128.39, 138.89, 140.67,
142.53, 155.99, 158.34. Mass spectrum, m/z (Irel, %):
401 (68) [M]+, 366 (77), 338 (17), 303 (20), 274 (100).
Found, %: C 54.05; H 4.70; N 17.20; S 8.10.
1
(4.03), 272 (4.06), 361 (4.00), 500 (3.68). H NMR
spectrum (CDCl3), δ, ppm: 0.78–1.90 m (10H, CH2),
3.68 s (3H, OCH3), 6.55 d (1H, CH, J = 10.2 Hz),
7.90 d (1H, CH, J = 10.2 Hz), 6.88–6.96 m (2H, CH),
7.16–7.30 m (2H, CH), 11.30 s (1H, NH). 13C NMR
spectrum, δC, ppm: 23.78, 24.91, 32.74 (CH2); 54.86
(OCH3); 110.49, 111.54, 119.84, 125.90, 128.24,
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SAMSONOV et al.
408
m/z 401.1158 [M]+. C18H19N5O4S. Calculated, %:
C 53.87; H 4.74; N 17.46; S 7.98. M 401.1152.
chloroform as eluent to isolate compounds IXa (first
fraction) and IXd (second fraction). Compound IXa:
Yield 1.65 g (56%), mp 168–170°C. IR spectrum:
ν 1623 cm–1 (C=N). UV spectrum, λmax, nm (logε): 249
N-(2-Chlorophenyl)-5-nitrospiro[benzimidazole-
2,1′-cyclohexan]-4-amine (VIIf). Yield 52%,
mp 192–195°C. IR spectrum: ν 1633 cm–1 (C=N). UV
spectrum, λmax, nm (logε): 255 (4.13), 352 (4.06), 488
1
(4.31), 369 (4.46), 511 (3.63). H NMR spectrum, δ,
ppm: in CDCl3: 1.20–2.10 m (10H, CH2), 6.43 d (1H,
CH, J = 0.8 Hz), 6.57 d.d (1H, CH, J = 9.6, 1.5 Hz),
7.08–7.20 m (4H, Harom), 7.28–7.35 m (2H, Harom); in
DMSO-d6: 0.81–2.14 m (10H, CH2), 6.28 s (1H, 4-H),
6.77 d.d (1H, 6-H, J = 9.8, J = 1.4 Hz), 7.17 d (1H,
7-H, J = 9.8 Hz, 7.06–7.17 m (1H, Harom), 7.24–7.31 m
(2H, Harom), 7.35–7.44 m (2H, Harom), 8.96 br.s (1H,
NH). 13C NMR spectrum (CDCl3), δC, ppm: 23.52,
24.78, 35.05 (CH2); 94.87, 117.52, 122.48, 124.62,
127.52, 129.34 (CH); 104.74, 132.64, 139.07, 148.88,
161.82. Mass spectrum: m/z (Irel, %): 293 (88) [M]+,
277 (100), 264 (45), 250 (52). Found, %: C 73.49;
H 6.48; N 14.34. m/z 293.1521 [M]+. C18H19N3O. Cal-
culated, %: C 73.69; H 6.53; N 14.33. M 293.1523.
1
(3.73). H NMR spectrum (CDCl3), δ, ppm: 0.93–
1.97 m (10H, CH2), 6.62 d (1H, CH, J = 10.1 Hz),
7.23–7.33 m (3H, Harom), 7.38–7.44 m (1H, Harom),
7.91 d (1H, CH, J = 10.1 Hz), 11.22 s (1H, NH).
13C NMR spectrum, δC, ppm: 23.76, 24.87, 32.63
(CH2); 112.51, 126.77, 127.56, 128.40, 129.33, 131.46
(CH); 109.58, 125.98, 131.00, 135.75, 142.32, 154.36,
157.88. Mass spectrum, m/z (Irel, %): 356 (33) [M]+,
321 (100), 304 (32), 274 (29). Found, %: C 61.1;
H 4.70; Cl 10.4; N 20.11. m/z 356.1036 [M]+.
C18H17ClN4O2. Calculated, %: C 60.67; H 4.78;
Cl 9.97; N 19.93. M 356.1035.
5-Azidospiro[benzimidazole-2,1′-cyclohexane]-
1,3-dioxide (VIII). Sodium azide, 0.80 g (0.012 mol),
was added to a solution of 2.63 g (0.01 mol) of
compound I in 80 ml of methanol, and the mixture was
stirred for 24 h at room temperature. The solvent was
distilled off under reduced pressure, the residue was
extracted with chloroform, the extract was dried over
MgSO4, the drying agent was filtered off, the solvent
was distilled off, and the residue was purified by chro-
matography on silica gel using chloroform as eluent.
Yield 1.0 g (38%), mp 83°C (decomp.) IR spectrum, ν,
cm–1: 2117 (N3), 1589 (C=N). UV spectrum, λmax, nm
N-Phenylspiro[benzimidazole-2,1′-cyclohexan]-
5-amine 1,3-dioxide (IXd). Yield 0.15 g (5%), dark
green crystals, mp 142–145°C. IR spectrum, ν, cm–1:
3268 (NH), 1595 (C=N). UV spectrum, λmax, nm
(logε): 257 (4.48), 279 (4.72), 413 (4.38), 620 (3.5).
1H NMR spectrum (CDCl3), δ, ppm: 1.48–2.06 m
(10H, CH2), 6.43 d (1H, CH, J = 1.6 Hz), 6.74 d.d (1H,
CH, J = 9.9, 1.6 Hz), 7.04–7.13 m (4H, Harom), 7.22–
7.28 m (2H, Harom), 7.34 br.s (1H, NH). 13C NMR
spectrum, δC, ppm: 19.45, 23.63, 33.62 (CH2); 87.25,
116.24, 122.30, 124.67, 129.05, 129.44 (CH); 96.83,
134.09, 136.95, 138.98, 146.18. Mass spectrum, m/z
(Irel, %): 309 (37) [M]+, 293 (63), 277 (100), 276 (65),
264 (23), 250 (22), 222 (55), 213 (35), 181 (20), 167
(35), 154 (42). Found, %: C 70.49; H 6.48; N 13.34.
m/z 309.1472 [M]+. C18H19N3O2. Calculated, %:
C 69.90; H 6.14; N 13.59. M 309.1471.
1
(logε): 266 (4.37), 292 (4.36), 543 (3.66). H NMR
spectrum (CDCl3), δ, ppm: 1.39–2.04 m (10H, CH2),
6.48 d.d (1H, CH, J = 9.8, 1.8 Hz), 6.80 d (1H, CH, J =
13
1.8 Hz), 7.19 d (1H, CH, J = 9.8 Hz). C NMR spec-
trum, δC, ppm: 18.65, 23.06, 33.27 (CH2); 101.25,
116.80, 123.43 (CH); 97.75, 134.33, 135.40, 142.55.
Found, %: C 55.10; H 4.90; N 26.88. C12H13N5O2. Cal-
culated, %: C 55.59; H 5.05; N 27.02.
N-(3-Nitrophenyl)spiro[benzimidazole-2,1′-cyclo-
hexan]-5-amine 1-oxide (IXb) was synthesized in
a similar way. Yield 51%, mp 186–189°C. IR spec-
trum, ν, cm–1: 3327 (NH), 1598 (C=N). UV spectrum,
N-Phenylspiro[benzimidazole-2,1′-cyclohexan]-
5-amine 1-oxide (IXa). Aniline hydrochloride, 1.3 g
(0.01 mol), was added to a solution of 2.63 g
(0.01 mol) of compound I in 80 ml of methanol, and
the mixture was heated for 4 h under reflux. The
solvent was distilled off, 30 ml of water was added to
the residue, and the mixture was adjusted to pH 8 by
adding a 10% solution of sodium hydroxide and
extracted with chloroform (3×20 ml), The extract was
dried over MgSO4, the drying agent was filtered off,
the solvent was distilled off, and the residue was
subjected to chromatography on aluminum oxide using
λ
max, nm (logε): 368 (4.18), 486 (3.78). 1H NMR spec-
trum, δ, ppm: in CDCl3: 1.24–2.13 m (10H, CH2),
6.56 s (1H, 4-H), 6.62 d.d (1H, CH, J = 10.0, 1.5 Hz),
7.22 d (1H, 7-H, J = 10.0 Hz), 7.50 t (1H, Harom, J =
8.0 Hz), 7.57 d (1H, Harom, J = 8.0 Hz), 7.93 d (1H,
Harom, J = 8.0 Hz), 8.01 s (1H, Harom); in DMSO-d6:
1.10–1.90 m (10H, CH2), 6.53 br.s (1H, 4-H), 6.77 d.d
(1H, 6-H, J = 10.0, 2.0 Hz), 7.22 d (1H, 7-H, J =
10.0 Hz), 7.63 t (1H, Harom, J = 8.0 Hz), 7.70 d (1H,
H
arom, J = 8.0 Hz), 7.87 d (1H, Harom, J = 8.0 Hz),
8.01 br.s (1H, Harom), 9.37 br.s (1H, NH). 13C NMR
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REACTIONS OF 5-NITROSPIRO[BENZIMIDAZOLE-2,1′-CYCLOHEXANE] 1,3-DIOXIDE
409
13
spectrum (CDCl3), δC, ppm: 23.46, 24.58, 35.08 (CH2);
97.11, 116.04, 118.08, 118.56, 126.96, 130.21 (CH);
105.02, 132.73, 140.96, 147.89, 148. 96, 161.36. Mass
spectrum, m/z (Irel, %): 338 (40) [M]+, 322 (100), 320
(42), 309 (16), 295 (19), 276 (27), 275 (22), 274 (18),
255 (13) 221 (25). Found, %: C 63.25; H 5.10;
N 16.34. m/z 338.1369 [M]+. C18H18N4O3. Calculated,
%: C 63.90; H 5.32; N 16.57. M 338.1373.
7.39 d (1H, CH, J = 9.0 Hz). C NMR spectrum, δC,
ppm: 22.94, 24.28, 34.93 (CH2); 57.76 (OCH3);
119.24, 122.07 (CH); 92.44, 104.44, 112.71, 131.55,
158.27, 169.23. Mass spectrum, m/z (Irel, %): 257 (100)
[M]+, 240 (58), 228 (49), 212 (20). Found, %: C 65.66;
H 5.77; N 16.31. m/z 257.1161 [M]+. C14H15N3O2. Cal-
culated, %: C 65.35; H 5.88; N 16.33. M 257.1159.
Compound XI. Yield 0.50 g (20%), mp 241–242°C.
IR spectrum, ν, cm–1: 2226, 2213 (CN); 1630, 1615,
1538 (C=O, C=N). UV spectrum, λmax, nm (logε): 249
N-(4-Methoxyphenyl)spiro[benzimidazole-2,1′-
cyclohexan]-5-amine 1-oxide (IXc). Yield 41%,
mp 193–195°C. IR spectrum: ν 1619 cm–1 (C=N). UV
spectrum, λmax, nm (logε): 251 (4.12), 369 (4.02), 507
1
(3.88), 345 (4.20), 438 (3.41). H NMR spectrum
(DMSO-d6), δ, ppm: 0.96–1.98 m (10H, CH2), 6.35 d
(1H, CH, J = 9.8 Hz), 7.41 d (1H, CH, J = 9.8 Hz),
11.18 br.s (1H, NH). 13C NMR spectrum, δC, ppm:
21.39, 23.90, 35.02 (CH2); 120.67, 131.82 (CH);
79.35, 96.32, 115.73, 131.52, 156.91, 181.61. Mass
spectrum, m/z (Irel, %): 243 (100) [M]+, 226 (70), 214
(23), 200 (32). Found, %: C 63.93; H 5.23; N 16.85.
m/z 243.1002 [M]+. C13H13N3O2. Calculated, %:
C 64.18; H 5.39; N 17.28. M 243.1006.
1
(3.38). H NMR spectrum, δ, ppm: in CDCl3: 1.17–
2.08 m (10H, CH2), 3.77 s (3H, OCH3), 6.18 d (1H,
4-H, J = 1.5 Hz), 6.51 d.d (1H, 6-H, J = 9.8, 1.5 Hz),
6.84 d (2H, Harom, J = 8.9 Hz), 7.11 d (2H, Harom, J =
8.9 Hz), 7.12 d (1H, 7-H, J = 9.8 Hz); in DMSO-d6:
0.92–1.95 m (10H, CH2), 3.76 s (3H, OCH3), 6.01 s
(1H, 4-H), 6.73 d.d (1H, 6-H, J = 9.6, 1.8 Hz), 6.97 d
(2H, Harom, J = 9.0 Hz), 7.14 d (1H, Harom, J = 9.6 Hz),
7.20 d (2H, Harom, J = 9.0 Hz), 8.77 br.s (1H, NH).
13C NMR spectrum (CDCl3), δC, ppm: 23.49, 24.66,
35.07 (CH2); 93.57, 114.56, 117.53, 125.44, 127.22
(CH); 65.42 (OCH3); 104.46, 131.54, 132.60, 150.29,
157.25, 161.63. Mass spectrum, m/z (Irel, %): 323 (100)
[M – 32]+, 307 (98), 292 (97), 290 (16), 280 (56), 265
(15). Found, %: C 64.00; H 6.12; N 11.34.
m/z 323.1682 [M – 32]+. C19H21N3O4. Calculated, %:
C 64.22; H 5.91; N 11.83. M 355.1629.
b. A solution of 0.70 g (0.014 mol) of sodium
cyanide in 10 ml of water was added to a solution of
2.63 g (0.01 mol) of compound I in 80 ml of chloro-
form. The mixture was vigorously stirred for 4 h at
room temperature, 20 ml of water was added, and the
organic phase was separated and washed with water
(2×10 ml). The aqueous phase was acidified to pH 3
with 5% hydrochloric acid and extracted with chloro-
form (3×50 ml), the extract was dried over MgSO4,
the drying agent was filtered off, the solvent was dis-
tilled off, and the residue was purified by chromatog-
raphy on silica gel using chloroform–methanol (10:1)
as eluent. Yield of XI 1.84 g (71%).
5-Methoxyspiro[benzimidazole-2,1′-cyclohex-
ane]-4-carbonitrile 1-oxide (X) and 5-oxo-3,5-dihy-
drospiro[benzimidazole-2,1′-cyclohexane]-4-carbo-
nitrile 1-oxide (XI). a. Sodium cyanide, 0.70 g
(0.014 mol), was added to a solution of 2.63 g
(0.01 mol) of compound I in 40 ml of methanol, and
the mixture was stirred for 4 h at room temperature.
The solvent was distilled off under reduced pressure,
40 ml of water was added to the residue, and the mix-
ture was acidified to pH 3 with 5% hydrochloric acid
and extracted with ethyl acetate. The extract was
washed with a saturated solution of sodium chloride
and dried over MgSO4, the drying agent was filtered
off, the solvent was distilled off, and the residue was
subjected to chromatography on silica gel using
chloroform–methanol (10:1) as eluent to isolate com-
pounds X (first fraction) and XI. Compound X: Yield
0.60 g (23%), mp 193–196°C. IR spectrum, ν, cm–1:
2228 (CN), 1600 (C=N). UV spectrum, λmax, nm
3-Methyl-5-oxo-3,5-dihydrospiro[benzimidazole-
2,1′-cyclohexane]-4-carbonitrile 1-oxide (XII). Com-
pound XI, 1.0 g (0.0041 mol), was dissolved in 80 ml
of acetone, 11.35 g (0.008 mol) of methyl iodide and
3.0 g (0.02 mol) of calcined potassium carbonate were
added, and the mixture was stirred for 16 h at room
temperature. The precipitate was filtered off, the sol-
vent was distilled off from the filtrate, and the residue
was subjected to chromatography on silica gel using
chloroform as eluent to isolate 0.08 g (8%) of methoxy
derivative X and 0.87 g (82%) of compound XII,
mp 256°C (decomp.). IR spectrum, ν, cm–1: 2204
(CN), 1616 (C=N). UV spectrum, λmax, nm (logε): 234
(3.30), 259 (3.18), 270 (3.10), 351 (3.70), 447 (3.00).
1H NMR spectrum (DMSO-d6), δ, ppm: 1.20–2.17 m
(10H, CH2), 3.47 s (3H, CH3), 6.40 d (1H, CH, J =
10.0 Hz), 7.44 d (1H, CH, J = 10.0 Hz). 13C NMR
1
(logε): 224 (4.44), 352 (4.00), 465 (3.45). H NMR
spectrum (CDCl3), δ, ppm: 1.17–2.00 m (10H, CH2),
4.15 s (3H, OCH3), 6.72 d (1H, CH, J = 9.0 Hz),
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SAMSONOV et al.
410
ma, H., Arias, A.R., Vega, C., Rolan, M., Gomez-
Barrio, A., Cerecetto, H., and Gonzalez, M., J. Med.
Chem., 2006, vol. 49, p. 3215.
spectrum, δC, ppm: 19.30, 22.64, 31.43 (CH2); 30.04
(CH3); 120.35, 131.01 (CH); 78.40, 95.53, 116.37,
131.84, 154.12, 181.75. Mass spectrum, m/z (Irel, %):
257 (65.6) [M]+, 241 (82.3), 240 (40.6), 198 (82),
186 (100). Found, %: C 64.97; H 5.60; N 16.30.
m/z 257.1162 [M]+. C14H15N3O2. Calculated, %:
C 65.35; H 5.88; N 16.33. M 257.1159.
5. Boiani, M., Boiani, L., Merlino, A., Hernandez, P.,
Chidichimo, A., Cazzulo, J.J., Cerecetto, H., and Gonza-
lez, M., Eur. J. Med. Chem., 2009, vol. 44, p. 4426.
6. Merlino, A., Benitez, D., Chavez, S., Da Cunha, J.,
Hernandez, P., Tinoco, L.W., Campillo, N.E., Paez, J.A.,
Cerecetto, H., and Gonzalez, M., Med. Chem. Commun.,
2010, vol. 1, p. 216.
7. Samsonov, V.A., Volodarskii, L.B., and Shamirzae-
va, O.V., Khim. Geterotsikl. Soedin., 1994, p. 524.
8. Samsonov, V.A. and Volodarskii, L.B., Zh. Org. Khim.,
Reactions of 5-nitrospiro[benzimidazole-2,1′-cy-
clohexane] 1-oxide (VI) with nucleophilic reagents.
The conditions for the reactions of compound VI with
2-aminoethanol, morpholine, piperidine, 3-nitroaniline
hydrochloride, and sodium cyanide were the same as
in the corresponding reactions with compound I. The
yields of IIc, IIk, IIl, IXb, and XI were 48, 18, 49, 15,
and 17%, respectively.
1982, vol. 18, p. 656.
9. Kafluoroy, M., Shteiman, V., and Botoshansky, M., Acta
Crystallogr., Sect. C, 2002, vol. 58, p. o183.
10. Samsonov, V.A., Bagryanskaya, I.Yu., Gatilov, Yu.V.,
and Savel’ev, V.A., Izv. Ross. Akad. Nauk, Ser. Khim.,
2011, p. 1697.
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