Imidazo[1,2-a]benzimidazole derivatives: XXVIII. Syntheses and heterocyclizations on the basis of 1-allyl-2-aminobenzimidazole

Article abstract of DOI:10.1134/S1070428011090156

Addition of hydrogen bromide at the double bond of 1-allyl-2-amino-1H- benzimidazole and 3-alkyl-(benzyl)-1-allyl-2-amino-1H-benzimidazolium halides was studied. The resulting 1-(2-bromopropyl) derivatives were subjected to thermolysis under different conditions, and the structure of dehydrobromination products was determined and proved by independent synthesis via prototropic isomerization of the allyl group by the action of bases. Pleiades Publishing, Ltd., 2011.

Full text of DOI:10.1134/S1070428011090156

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2011, Vol. 47, No. 9, pp. 1346–1353. © Pleiades Publishing, Ltd., 2011.
Original Russian Text © V.A. Anisimova, I.E. Tolpygin, 2011, published in Zhurnal Organicheskoi Khimii, 2011, Vol. 47, No. 9, pp. 1326–1332.
Imidazo[1,2-a]benzimidazole Derivatives:
XXVIII.* Syntheses and Heterocyclizations on the Basis
of 1-Allyl-2-aminobenzimidazole
V. A. Anisimova and I. E. Tolpygin
Institute of Physical and Organic Chemistry, Southern Federal University,
pr. Stachki 194/2, Rostov-on-Don, 344090, Russia
e-mail: anis@ipoc.sfedu.ru
Received November 3, 2010
Abstract—Addition of hydrogen bromide at the double bond of 1-allyl-2-amino-1H-benzimidazole and 3-alkyl-
(benzyl)-1-allyl-2-amino-1H-benzimidazolium halides was studied. The resulting 1-(2-bromopropyl) deriva-
tives were subjected to thermolysis under different conditions, and the structure of dehydrobromination
products was determined and proved by independent synthesis via prototropic isomerization of the allyl group
by the action of bases.
DOI: 10.1134/S1070428011090156
Allyl-substituted aromatic and heterocyclic com-
pounds attract researchers’ attention due to their high
reactivity and the possibility for synthesizing fused
heterocyclic systems on their basis. Intramolecular
cyclizations of α-allyl-substituted hetarenethiones
[2–4] and hetarenamines [5, 6] were reported in a num-
ber of publications. Development of new methods for
the synthesis of imidazo[1,2-a]benzimidazole deriva-
tives from 1-allyl-2-aminobenzimidazole (I) is promis-
ing, taking into account broad spectrum of biological
activity intrinsic to that tricyclic system [7–11].
First of all, the procedure for the synthesis of amine
I was optimized. N-Substituted 2-aminobenzimid-
azoles were commonly prepared by amination of
Scheme 1.
H
CH2=CHCH2Br, OH–
N
N
N
N
HBr
NH2
NH2
CH2
NH2 Br–
Me
N
H
N
Br
I
II
Me
N
N
· HBr
NH
N
NH2
OH–
IV
N
Me
Br
N
N
III
NH2
Me
NH2
Δ
+
+ I
N
N
Me
V
VI
* For communication XXVII, see [1].
1346

IMIDAZO[1,2-a]BENZIMIDAZOLE DERIVATIVES: XXVIII.
1347
N-substituted benzimidazoles according to Chichiba-
bin [12]. However, treatment of 1-allylbenzimidazole
with sodium amide resulted in formation of only poly-
merization products [13]. Later on [14] we examined
alkylation of 2-aminobenzimidazole with allyl bromide
under different conditions and found that this reaction
in the two-phase system acetone–40–50% NaOH or
KOH selectively yields 1-allyl-2-aminobenzimidazole
(96–97%; cf. [15]). Presumably, the nucleophilicity of
nitrogen-centered anion in acetone sharply increases
[16], so that no side reactions occur. The allylation of
2-aminobenzimidazole in alcoholic alkali was accom-
panied by formation of small amounts of 1,3-diallyl-
and 1,2,3-triallyl-substituted derivatives.
(prop-2-en-1-yl)-1H-benzimidazoles V and VI, and
initial amine III. Some signals in the spectrum were
not identified. Presumably, compounds V and VI are
formed due to strong basicity of amine III, which is
also typical of other 1-substituted 2-aminobenzimid-
azoles [16]; compound III acts as hydrogen bromide
acceptor, leading to dehydrobromination products.
Migration of the double bond is accompanied by
1
appearance in the H NMR spectra of signals from
protons in the CH3 and NCH= groups as doublets of
doublets with coupling constants characteristic of each
isomer (3JHH = 7.8 and 14.0 Hz for cis and trans
isomers, respectively).
In order to exclude dehydrobromination by the
action of amine III, its thermolysis was performed in
the presence of excess triethylamine. Nevertheless, in
this case a mixture of several compounds was formed
as well, whereas no cyclic system IV was obtained.
Amine III also failed to undergo cyclization in
acetic acid.
By heating 1-allyl-2-aminobenzimidazole (I) in
48% hydrobromic acid we obtained stable 2-amino-1-
(2-bromopropyl)-1H-benzimidazole hydrobromide
(II). The addition of HBr followed the Markovnikov
1
pattern. The H NMR spectrum of the product lacked
signals assignable to vinyl fragment, while a signal
from methyl protons appeared as a doublet at
δ 1.75 ppm (JHH = 7.1Hz). Unlike 1-alkyl-3-(2-chloro-
ethyl)-2,3-dihydro-1H-benzimidazol-2-imines [17] and
1-alkyl-2-(ω-chloroalkylamino)-1H-bezimidazoles
[18] which were reported previously to readily
undergo intramolecular cyclization on heating, free
base III obtained by treatment of hydrobromide II
with aqueous ammonia turned out to be thermally
stable; no cyclization was observed when compound
III was heated to the melting point (mp 126–127°C) or
15–20°C above, whereas further rise in temperature
led to tarring.
It is known that 2-amino-1-(ω-dialkylaminoalkyl)-
benzimidazoles are not only pharmacologically active
compounds [19] but also potential intermediate prod-
ucts for their synthesis [20–22]. To obtain new deriv-
atives of this series we examined nucleophilic replace-
ment of bromine in compound III by morpholine. The
reaction was not selective, and, apart from the desired
2-amino-1-(2-morpholinopropyl)-1H-benzimidazole
(VII), cis- and trans-isomeric 2-amino-1-(prop-2-en-1-
yl)-1H-benzimidazoles V and VI were formed
1
(Scheme 2). According to the H NMR data, the prod-
uct ratio was 9:2:9.
When amine III was heated in xylene over a period
of 1 h, an oily material separated from the reaction
mixture and crystallized on further heating under
reflux. According to the TLC data, the product was
a mixture of several compounds which we failed to
separate by column chromatography (further decom-
position occurred during chromatography on alumi-
num oxide). With a view to identify the components,
the product mixture was treated with picric acid.
The formation of cis- and trans-2-amino-1-(prop-2-
en-1-yl)benzimidazoles V and VI was confirmed by
studying prototropic isomerization of 1-allyl-2-amino-
benzimidazole by the action of potassium hydroxide in
dimethyl sulfoxide. When the reaction mixture was
kept for 20 h at room temperature, the conversion was
only 30% with formation of cis isomer V. Subsequent
keeping at room temperature over a period of 30 day
resulted in complete migration of the double bond with
formation of a 1:1 mixture of cis and trans isomers. At
elevated temperature, 75–80°C, the migration of the
1
According to the H NMR data, the resulting mixture
contained amine I, cis- and trans-isomeric 2-amino-1-
Scheme 2.
NH2
Me
N
NH
N
N
III
+
+ V + VI
O
O
VII
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 47 No. 9 2011

ANISIMOVA, TOLPYGIN
1348
Scheme 3.
R
N
N
N
CH2=CHCH2Br
Br–
NH2
NH2
CH2
N
R
VIIIa–VIIId
R
(1) RX; (2) OH–
N
OH–
I
NH
CH2
N
IXa–IXd
R
N
R
R
N
N
OH–
HBr
Δ
· HX
NH2
Me
NH
Me
N
Br–
N
N
N
Me
Br
Br
Xa–Xd
XIa–XId
XIIa–XIId
R = Me (a), PhCH2 (b), Et2NCH2CH2 (c), 2-morpholinoethyl (d); XII, HX = HBr (a, b), 2HCl (c, d).
double bond was complete in 4 h, and the ratio of cis
and trans isomers V and VI was 6:5. The isomeriza-
tion of 1-allyl-2-aminobenzimidazole by the action of
potassium hydroxide in DMSO at 100°C required
15 min, the cis/trans isomer ratio being 1:1.
imidazole ring (due to the presence of methyl group in
the 2-position) and appearance of a chiral center at C2
makes protons in the endocyclic methylene group
(C3H2) nonequivalent, and they resonate in the 1H NMR
spectra of XIIa–XIId (free bases) as two triplets at
δ 3.32–3.35 (Hax, JHH = 6.5–7.5 Hz) and 3.95–3.98 ppm
(Heq, JHH = 8.1–8.6 Hz).
Quaternization of initial amine I with alkyl (benzyl)
halides or the reaction of 1-substituted 2-aminobenz-
imidazoles with allyl bromide gave the corresponding
3-substituted 1-allyl-2-aminobenzimidazolium halides
VIIIa–VIIIf. Like compound I, quaternary salts
VIIIa–VIIIf readily took up hydrogen bromide at the
double bond in the allyl substituent to produce 3-R-2-
amino-1-(2-brompropyl)-1H-benzimidazolium halides
Xa–Xd, and treatment of the latter with basic reagents
(NH4OH, Na2CO3, etc.) afforded benzimidazol-2-
imines XIa–XId (Scheme 3).
When the reaction was performed in a solvent in
the presence of a base (e.g., triethylamine), the cycliza-
tion was accompanied by dehydrobromination to give
cis/trans-isomeric 1-(prop-2-en-1-yl)-substituted benz-
imidazole derivatives XIII and XIV (Scheme 4).
Migration of the exocyclic double bond in 1-allyl-3-
methyl- and 1-allyl-3-benzyl-2,3-dihydro-1H-benz-
imidazol-2-imines IXa and IXb by the action of KOH
in DMSO confirmed the structure of the dehydro-
bromination products. In both cases, the isomerization
on short heating (15 min, 100°C) was selective and,
unlike the transformation of compound I under analo-
gous conditions, the products were the corresponding
trans isomers XIVa and XIVb. Increase of the reaction
time to 25 min leads to the formation of a mixture of
cis and trans isomers XIII and XIV at a ratio 1:3.
Further heating favors increased concentration of cis
isomers XIIIa and XIIIb.
Unlike 1-(2-bromopropyl) derivative III, heating of
3-substituted 1-(2-bromopropyl)-2,3-dihydro-1H-
benzimidazol-2-imines XIa–XId in boiling toluene or
without a solvent at a temperature exceeding their
melting points by 15–20°C led to intramolecular
cyclization with participation of the bromoalkyl frag-
ment and imino group with formation of 9-R-2-meth-
yl-2,3-dihydroimidazo[1,2-a]benzimidazoles which
were isolated as hydrohalides XIIa–XIId. The cycliza-
tion was accompanied by upfield shift of signals from
protons formerly belonging to the 2-bromopropyl sub-
stituent. The rigid structure of the terminal dihydro-
To conclude, we have found that thermolysis of
compounds XIa–XId should be carried out in the ab-
sence of basic reagents to obtain tricyclic derivatives.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 47 No. 9 2011

IMIDAZO[1,2-a]BENZIMIDAZOLE DERIVATIVES: XXVIII.
1349
Scheme 4.
R
R
R
N
N
N
KOH–DMSO
NH
CH2
NH
Me
NH
Me
+
N
N
N
IXa, IXb
XIIIa, XIIIb
XIVa, XIVb
R = Me (a), PhCH2 (b).
EXPERIMENTAL
1-(2-Bromopropyl)-1H-benzimidazol-2-amine
hydrobromide (II). A solution of 3.5 g (20 mmol) of
amine I in 20 ml of 48% hydrobromic acid was heated
for 10 h under reflux. The mixture was cooled, and the
precipitate was filtered off, repeatedly washed with
acetone to remove HBr, and dried in air. Yield 4.6 g
(68%), mp 186–187°C (from i-PrOH). IR spectrum, ν,
The progress of reactions and the purity of the
isolated compounds were monitored by TLC on
alumina plates using chloroform as eluent; spots were
visualized by treatment with iodine vapor in a moist
chamber. The IR spectra were recorded from samples
dispersed in mineral oil on a Specord 75IR spectrom-
1
cm–1: 3250, 3160 (NH2); 1670 (C=N). H NMR spec-
1
trum (DMSO-d6), δ, ppm: 1.75 d (3H, CH3, J =
7.1 Hz), 4.40–4.75 m (3H, CH2, CH), 7.17–7.70 m
(4H, Harom), 8.77 s (2H, NH2), 12.70 s (1H, N+H).
Found, %: C 35.78; H 3.88; Br 47.74; N 12.60.
C10H12BrN3 ·HBr. Calculated, %: C 35.85; H 3.91;
Br 47.70; N 12.54.
Hydrobromide II, 3.4 g (10 mmol), was dissolved
in 10 ml of water on heating, and 22% aqueous am-
monia was added to the hot solution until pH 9–10.
The mixture was cooled, and the precipitate was
filtered off, washed with water, dried in air, and recrys-
tallized from benzene. Yield 2.3 g (89%), mp 127–
128°C. Found, %: C 47.32; H 4.81; Br 31.38; N 16.49.
C10H12BrN3. Calculated, %: C 47.26; N 4.76; Br 31.44;
N 16.54.
eter. The H NMR spectra were obtained on a Varian
Unity 300 instrument at 300 MHz using the residual
solvent proton signals as reference (CHCl3,
δ 7.25 ppm; DMSO-d5, δ 2.50 ppm).
1-Allyl-1H-benzimidazol-2-amine (I). A solution
of 65.9 g (1 mol) of 85% KOH in 74 ml of water was
added under stirring to a suspension of 66.5 g
(0.5 mol) of 1H-benzimidazol-2-amine in 300 ml of
acetone. The mixture was stirred for 10–15 min at
room temperature and cooled to –2 to –3°C, and 46 ml
(0.53 mol) of allyl bromide was added over a period of
15 min. The mixture warmed up to 3–5°C; it was
stirred for 30–40 min at 0–5°C, allowed to spontane-
ously warm up to 20°C, and stirred for 2–2.5 h at that
temperature. The organic phase was separated, and the
aqueous phase was treated with 100 ml of acetone. The
acetone extract was combined with the organic phase
and evaporated, 200 ml of cold water was added to the
residue, and (after 30 min) the precipitate was filtered
off, washed on a filter with several portions of cold
water, and dried at 100–105°C. Yield 81.4–84.0 g (94–
97%). Amine I thus isolated was chromatographically
pure, and no additional purification was necessary for
subsequent transformations. The product can be re-
crystallized from benzene (2 g/10 ml) or from water
(1 g/35–40 ml), mp 128–129°C. IR spectrum, ν, cm–1:
1-(Prop-2-en-1-yl)-1H-benzimidazol-2-amine
(V/VI, a mixture of cis and trans isomers). Amine II,
0.9 g (5 mmol), was dissolved in 5 ml of DMSO, 3 ml
of a 0.5 M solution of potassium tert-butoxide in tert-
butyl alcohol was added, and the mixture was heated
for 4 h at 75–80°C, diluted with 50 ml of water, and
extracted with chloroform. The extract was washed
with water, dried over Na2SO4, and evaporated. The
crystalline residue was a mixture of cis and trans
isomers V and VI at a ratio 5:6. Yield 0.7 g (80%),
1
mp 120–121°C (from benzene). H NMR spectrum
3
4
(CDCl3), δ, ppm: V: 1.67 d.d (3H, CH3, J = 7.8, J =
1.8 Hz), 5.12 (2H, NH2), 5.95–6.12 m (1H, CH),
6.38 d.d (1H, NCH, 3J = 7.8, 4J = 1.8 Hz), 6.93–7.44 m
1
3445, 3335 (NH2); 1630 (C=N). H NMR spectrum
(DMSO-d6), δ, ppm: 4.57d (2H, NCH2, J = 4.8 Hz),
5.00–5.20 m (2H, CH2), 5.80–5.97 m (1H, CH), 6.20 s
(2H, NH2), 6.75–7.18 m (4H, Harom). Found, %:
C 69.28; H 6.37; N 24.35. C10H11N3. Calculated, %:
C 69.34; H 6.40; N 24.26.
3
4
(4H, Harom); VI: 1.92 d.d (3H, CH3, J = 6.8, J =
1.7 Hz), 5.12 br.s (2H, NH2), 5.95–6.12 m (1H, CH),
3
4
6.50 d.d (1H, NCH, J = 14.0, J = 1.7 Hz), 6.93–
7.44 m (4H, Harom).
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ANISIMOVA, TOLPYGIN
1350
1-(2-Morpholinopropyl)-1H-benzimidazol-2-
Br 22.58; N 15.77. C16H25BrN4. Calculated, %:
C 54.39; H 7.13; Br 22.62; N 15.86.
amine (VII). A mixture of 1.7 g (6 mmol) of hydro-
bromide II and 5 ml of morpholine was heated for 20 h
under reflux. The mixture was treated with 15–20 ml
of water and extracted with chloroform. The extract
was washed with water to remove excess morpholine
and passed through a layer of Al2O3 (1.5×10 cm) using
chloroform as eluent. The eluate was evaporated to
obtain white crystalline product which was a mixture
of cis and trans isomers of 1-(prop-2-en-1-yl)benz-
imidazol-2-amine V and VI and compound VII at
3-Allyl-2-amino-1-(2-morpholinoethyl)-1H-benz-
imidazolium bromide (VIIId). Yield 85%, mp 256–
257°C (from EtOH).
1-Allyl-3-methyl-2,3-dihydro-1H-benzimidazol-
2-imine (IXa) was obtained by treatment of bromide
VIIIa with 10 ml of a 30% solution of sodium hy-
droxide, followed by extraction of the free base into
benzene. Yield 99%, mp 67–68°C (from hexane). IR
spectrum, ν, cm–1: 3350 (NH), 1635, 1600, 1490, 1445
1
a ratio of 2:9:9. Yield 0.9 g. H NMR spectrum of VII
1
(C=C, C=N). H NMR spectrum (DMSO-d6), δ, ppm:
(CDCl3), δ, ppm: 1.10 d (3H, CH3, J = 7.1 Hz), 2.49–
2.75 m (4H, NCH2), 3.60–3.80 m (4H, OCH2), 3.81–
4.06 m (3H, CH2, CH), 5.94 s (2H, NH2), 6.93–7.47 m
(4H, Harom).
3.05 (2H, NH2), 3.35 s (3H, CH3), 4.42 d.d (2H, NCH2,
3
2J = 5.0, J = 1.6 Hz), 5.10–5.27 m (2H, CH2), 5.77–
5.97 m (1H, CH), 6.76–7.03 m (4H, Harom). Found, %:
C 70.49; H 6.97; N 22.54. C11H13N3. Calculated, %:
C 70.56; H 7.00; N 22.44.
3-Substituted 1-allyl-2-amino-1H-benzimidazo-
lium bromides VIIIa–VIIId (general procedure).
a. Allyl bromide, 0.9 ml (10 mmol), was added to
a solution of 10 mmol of 1-alkyl(benzyl)-1H-benz-
imidazol-2-amine in 10 ml of DMF, and the mixture
was heated under reflux until the reaction was com-
plete (TLC) and left overnight. The precipitate was
filtered off and washed with acetone. Yield 86–98%.
Compounds IXb–IXd were synthesized in a similar
way.
1-Allyl-3-benzyl-2,3-dihydro-1H-benzimidazol-
2-imine (IXb). Yield 95%, mp 107–108°C (from
hexane). IR spectrum, ν, cm–1: 3265 (NH), 1630, 1610,
1
1590, 1475, 1445 (C=C, C=N). H NMR spectrum
(DMSO-d6), δ, ppm: 4.50 d (2H, NCH2, J = 4.9 Hz),
5.07 s (2H, PhCH2), 5.10–5.24 m (2H, CH2), 5.80–
6.00 m (1H, CH), 6.72–7.30 m (9H, Harom). Found, %:
C 77.47; H 6.60; N 15.93. C17H17N3. Calculated, %:
C 77.54; H 6.51; N 15.95.
3-Substituted 1-allyl-2-amino-1H-benzimidazolium
halides were also synthesized by reaction of 1-allyl-
1H-benzimidazol-2-amine with the corresponding
alkyl halides.
b. Allyl bromide, 0.9 ml (10 mmol), was added to
a solution of 10 mmol of 1-(2-dialkylaminoethyl)-1H-
benzimidazol-2-amine in 30 ml of acetonitrile or 50 ml
of acetone, and the mixture was heated for 5 h under
reflux. After cooling, the precipitate was filtered off
and washed with acetone. Yield 82–85%.
3-Allyl-1-(2-diethylaminoethyl)-2,3-dihydro-1H-
benzimidazol-2-imine (IXc). Yield 90%. Unstable
oily substance.
1-Allyl-3-(2-morpholinoethyl)-2,3-dihydro-1H-
benzimidazol-2-imine (IXd). Yield 87%, mp 80–81°C
(from hexane). IR spectrum, ν, cm–1: 3280 (NH), 1600,
1-Allyl-2-amino-3-methyl-1H-benzimidazolium
bromide (VIIIa). Yield 93%, mp 293–294°C
(decomp., from water).
1
1580, 1475, 1440 (C=C, C=N). H NMR spectrum
(DMSO-d6), δ, ppm: 2.54 t (4H, NCH2, J = 4.5 Hz),
2.66 t (2H, CH2N, J = 7.1 Hz), 3.07 br.s (2H, N+H2),
3.69 t (4H, OCH2, J = 4.5 Hz), 3.95 t (2H, NCH2, J =
1-Allyl-2-amino-3-benzyl-1H-benzimidazolium
bromide (VIIIb). Yield 86–88%, mp 298–299°C
(decomp., from water).
3
4
7.1Hz), 4.43 d.d (2H, NCH2, J = 3.3, J = 1.6 Hz),
5.10–5.24 m (2H, CH2), 5.77–5.95 m (1H, CH), 6.77–
7.01 m (4H, Harom). Found, %: C 67.04; H 7.69;
N 19.65. C16H22N4O. Calculated, %: C 67.11; H 7.74;
N 19.56.
3-Allyl-2-amino-1-(2-diethylaminoethyl)-1H-
benzimidazolium bromide (VIIIc). Yield 83%,
mp 272–273°C (decomp., from i-PrOH). IR spectrum,
ν, cm–1: 3315, 3235 (NH2), 1650, 1605, 1580, 1505,
1
1465, 1455 (C=C, C=N). H NMR spectrum
3-Substituted 2-amino-1-(2-bromopropyl)-1H-
benzimidazolium bromides Xa–Xd (general proce-
dure). A mixture of 10 mmol of 3-R-1-allyl-2-amino-
benzimidazolium bromide and 25 ml of 48% hydro-
bromic acid was heated for 10 h (30 h in the reaction
with VIIIb) under reflux. The acid was removed from
(DMSO-d6), δ, ppm: 1.00 t (6H, CH3, J = 6.7 Hz),
2.64 q (4H, NCH2), 2.92 t (2H, CH2N, J = 7.5 Hz),
4.23 t (2H, NCH2, J = 7.5 Hz), 4.64–4.71 m (2H, CH2),
4.95–5.28 m (2H, CH2), 5.86–6.02 m (1H, CH), 7.27–
7.47 m (4H, Harom). Found, %: C 54.45; H 7.20;
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IMIDAZO[1,2-a]BENZIMIDAZOLE DERIVATIVES: XXVIII.
1351
the mixture by distillation on a rotary evaporator, the
residue was diluted with acetone, and the precipitate
was filtered off, washed with acetone to remove resid-
ual HBr, and dried in air.
1-Benzyl-3-(2-bromopropyl)-2,3-dihydro-1H-
benzimidazol-2-imine (XIb). Yield 80%, mp 118–
119°C (from EtOAc). IR spectrum, ν, cm–1: 3280
(NH), 1630, 1615, 1590, 1480, 1445 (C=C, C=N).
1H NMR spectrum (DMSO-d6), δ, ppm: 1.76 d (3H,
CH3, J = 6.7 Hz), 4.10–4.22 m (2H, NCH2), 4.50–
4.65 m (1H, CH), 4.99 s (2H, CH2Ph), 6.70–7.38 m
(9H, Harom). Found, %: C 59.34; H 5.32; Br 23.16;
N 12.18. C17H18BrN3. Calculated, %: C 59.31; H 5.27;
Br 23.21; N 12.21.
2-Amino-1-(2-bromopropyl)-3-methyl-1H-benz-
imidazolium bromide (Xa). Yield 80%, mp 251–
252°C (decomp., from i-PrOH). IR spectrum, ν, cm–1:
3265, 3205 (NH2), 1660, 1600, 1540, 1490, 1460
1
(C=C, C=N). H NMR spectrum (DMSO-d6), δ, ppm:
1.19 d (3H, CH3, J = 5.3 Hz), 3.67 s (3H, NCH3),
3.94–4.19 m (3H, CH2, CH), 7.25–7.36 m (2H, 5-H,
6-H), 7.50–7.62 m (2H, 4-H, 7-H), 8.68 s (2H, N+H2).
Found, %: C 37.92; H 4.29; Br 45.81; N 11.98.
C11H15Br2N3. Calculated, %: C 37.85; H 4.33;
Br 45.78; N 12.04.
2-Amino-3-benzyl-1-(2-bromopropyl)-1H-benz-
imidazolium bromide (Xb). Yield 77%, mp 257–
258°C (from aq. EtOH).
1-(2-Bromopropyl)-3-(2-diethylaminoethyl)-2,3-
dihydro-1H-benzimidazol-2-imine (XIc). Yield 67%,
oily substance. Compound XIc underwent intramolec-
ular cyclization on storage to give unstable 9-(2-di-
ethylaminoethyl)-2-methyl-2,3-dihydroimidazo[1,2-a]-
benzimidazole hydrobromide.
1-(2-Bromopropyl)-3-(2-morpholinoethyl)-2,3-
dihydro-1H-benzimidazol-2-imine (XId). Yield 72%,
oily substance. Compound XId underwent intramolec-
ular cyclization on storage to give unstable 2-methyl-
9-(2-morpholinoethyl)-2,3-dihydroimidazo[1,2-a]-
benzimidazole hydrobromide.
2-Amino-1-(2-bromopropyl)-3-(2-diethylamino-
ethyl)-1H-benzimidazolium bromide hydrobromide
(Xc). Yield 69%, mp 264–265°C (decomp., from
EtOH). IR spectrum, ν, cm–1: 3255, 3215 (NH2), 1660,
1
1610, 1580, 1460 (C=C, C=N). H NMR spectrum
9-Substituted 2-methyl-2,3-dihydroimidazo-
[1,2-a]benzimidazole hydrohalides XIIa–XIId (gen-
eral procedure). Compound XIa–XId, 3 mmol, was
heated above its melting point by 15–20°C until its
complete conversion (30–90 min, TLC). The melt was
cooled and ground with acetone, and the precipitate
was filtered off, washed with acetone, and recrystal-
lized from appropriate solvent. If purification of XIIa–
XIId from decomposition products was necessary
(a spot at the start on TLC), the melt was ground with
22% aqueous ammonia, the free base was extracted
into chloroform, and the extract was passed through
a layer of Al2O3 (3×4 cm) using chloroform as eluent.
The eluate was evaporated, the residue was dissolved
in 15–20 ml of acetone, and the free base was con-
verted into hydrochloride by adding a solution of HCl
in isopropyl alcohol.
(DMSO-d6), δ, ppm: 1.45 t (6H, CH3, J = 6.4 Hz),
1.64 d (3H, CH3, J = 6.7 Hz), 3.31 q (4H, CH3CH2),
3.54 t (2H, CH2N, J = 7.2 Hz), 4.04–4.21 m (2H,
NCH2), 4.32–4.55 m (3H, NCH2, CH, J = 7.2 Hz),
7.18–7.52 m (4H, Harom). Found, %: C 37.26; H 5.31;
Br 46.60; N 10.83. C16H26Br2N4·HBr. Calculated, %:
C 37.31; H 5.28; Br 46.53; N 10.88.
2-Amino-1-(2-bromopropyl)-3-(2-morpholino-
ethyl)-1H-benzimidazolium bromide hydrobromide
(Xd). Yield 70%, mp 287–288°C (from aq. EtOH).
IR spectrum, ν, cm–1: 3270, 3205 (NH2), 1660, 1600,
1
1580, 1505, 1450 (C=C, C=N). H NMR spectrum
(DMSO-d6), δ, ppm: 1.64 d (3H, CH3, J = 6.5 Hz),
3.31 s (4H, NCH2), 3.50 t (2H, CH2N, J = 7.4 Hz),
3.83 s (4H, OCH2), 4.30–4.80 m (3H, CH2N, CH2,
CH), 7.20–7.50 m (4H, Harom). Found, %: C 36.40;
N 4.81; Br 45.20; N 10.54. C16H24Br2N4O·HBr. Calcu-
lated, %: C 36.32; H 4.76; Br 45.30; N 10.59.
3-Substituted 1-(2-bromopropyl)-2,3-dihydro-
1H-benzimidazol-2-imines XIa–XId (general proce-
dure). Compound Xa–Xd, 5 mmol, was dissolved on
heating in 10–40 ml of water, the solution was cooled
to 50–60°C, and 22% aqueous ammonia was added
until pH 9–10. The precipitate was filtered off, washed
with water, and dried in air.
2,9-Dimethyl-2,3-dihydroimidazo[1,2-a]benz-
imidazole hydrobromide (XIIa) was obtained in 98%
yield by heating imine XIa at 80–85°C. mp 236–
237°C (from EtOH). IR spectrum, ν, cm–1: 1660, 1600,
1
1535, 1495, 1465 (C=C, C=N). H NMR spectrum
(DMSO-d6), δ, ppm: 1.75 d (3H, CH3, J = 5.8 Hz),
3.66 s (3H, NCH3), 4.41–4.73 m (3H, CH2, CH), 7.23–
7.73 m (4H, Harom), 8.94 br.s (1H, N+H). Found, %:
C 49.34; H 5.32; Br 29.75; N 15.59. C11H13N3·HBr.
Calculated, %: C 49.27; H 5.26; Br 29.80; N 15.67.
Hydrobromide XIIa can also be obtained by heating
1-(2-Bromopropyl)-3-methyl-2,3-dihydro-1H-
benzimidazol-2-imine (XIa). Yield 86%, mp 66–67°C
(intramolecular cyclization occurred on melting).
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 47 No. 9 2011

ANISIMOVA, TOLPYGIN
1352
2 mmol of imine XIa in 8 ml of boiling anhydrous
toluene over a period of 30 min.
7.0 Hz), 2.43–2.60 m (4H, NCH2), 2.63–2.76 m (2H,
CH2N), 3.33 t (1H, 3-Hax, J = 7.5 Hz), 3.60–3.72 m
(4H, CH2O), 3.80–4.02 m (3H, NCH2, 3-Heq), 4.49–
4.64 m (1H, CH), 6.63–6.95 m (4H, Harom).
9-Benzyl-2-methyl-2,3-dihydroimidazo[1,2-a]-
benzimidazole hydrobromide (XIIb) was obtained
by heating imine XIb for 2 h at 125–130°C. Yield
95%, mp 230–232°C (from EtOH). IR spectrum, ν,
cm–1: 1660, 1600, 1620, 1540, 1500, 1475 (C=C,
C=N). Found, %: C 59.40; H 5.18; Br 23.15; N 12.27.
C17H17N3 ·HBr. Calculated, %: C 59.31; H 5.27;
1-Methyl-3-[(E)-prop-2-en-1-yl]-2,3-dihydro-1H-
benzimidazol-2-imine (XIVa). A solution of 0.9 g
(5 mmol) of imine IXa in 10 ml of a 5% solution of
potassium hydroxide in dimethyl sulfoxide was heated
for 15 min at 100°C. The mixture was cooled, diluted
with 100 ml of water, and extracted with chloroform.
The extract was washed with water and evaporated.
Yield 81%, mp 50–51°C (from petroleum ether). IR
spectrum, ν, cm–1: 3285 (NH); 1660, 1635, 1615, 1500,
1
Br 23.21; N 12.21. H NMR spectrum of free base
XIIb (CDCl3), δ, ppm: 1.37 d (3H, CH3, J = 6.5 Hz),
3.35 t (1H, 3-Hax, J = 6.5 Hz), 3.98 t (1H, 3-Heq, J =
8.6 Hz.), 4.50–4.68 m (1H, CH), 4.94 q (2H, NCH2),
6.54–7.36 m (9H, Harom).
1
1475 (C=C, C=N). H NMR spectrum (CDCl3), δ,
3
4
ppm: 1.89 d.d (3H, CH3, J = 6.8, J = 1.7 Hz), 3.41 s
(3H, NCH3), 5.86–6.08 m (1H, CH), 6.43 d.d (1H,
NCH, 3J = 14.1, 4J = 1.5 Hz), 6.65–7.10 m (4H, Harom).
Found, %: C 70.49; H 7.05; N 22.46. C11H13N3. Cal-
culated, %: C 70.56; H 7.00; N 22.44.
After prolonged heating, a mixture of two isomers
was formed with gradually increasing fraction of
1-methyl-3-[(Z)-prop-2-en-1-yl]-2,3-dihydro-1H-benz-
imidazol-2-imine (XIIIa). 1H NMR spectrum (CDCl3),
δ, ppm: 1.65 d.d (3H, CH3, 3J = 7.1, 4J = 1.7 Hz), 3.34 s
(3H, NCH3), 5.86–6.08 m (1H, CH), 6.15 d.d (1H,
NCH, 3J = 7.5, 4J = 1.5 Hz), 6.65–7.10 m (4H, Harom).
9-(2-Diethylaminoethyl)-2-methyl-2,3-dihydro-
imidazo[1,2-a]benzimidazole dihydrochloride
(XIIc). Hydrobromide Xc, 5.2 g (10 mmol), was dis-
solved in 25 ml of water, 5 ml of 22% aqueous am-
monia was added, and the free base was extracted into
chloroform (2×25 ml). The extracts were combined,
dried over Na2SO4, and evaporated, and the residue
was heated in 25 ml of boiling toluene until the reac-
tion was complete (TLC, Al2O3, CHCl3). The mixture
was then treated with water (2×15 ml), the aqueous
extracts were combined and made alkaline by adding
aqueous ammonia, and free base XIIc was extracted
into chloroform (3×10 ml). The extracts were com-
bined and passed through a layer of Al2O3 (3×4 cm),
the sorbent was eluted with chloroform, the eluate was
evaporated, and the residue was dissolved in 15–20 ml
of acetone and acidified to pH 2–3 with a solution of
HCl in isopropyl alcohol. Yield 41%, mp 241–242°C
(decomp., from MeCN or EtOH). IR spectrum, ν, cm–1:
1660, 1620, 1600, 1540, 1500, 1475 (C=C, C=N).
Found, %: C 55.74; H 7.65; Cl 20.43; N 16.18.
C16H24N4 ·2HCl. Calculated, %: C 55.65; H 7.59;
3-Benzyl-1-(prop-2-en-1-yl)-2,3-dihydro-1H-
benzimidazol-2-imine (XIIIb/XIVb, a mixture of cis
and trans isomers). Isomer mixture XIIIb/XIVb was
synthesized according to the procedure described
1
above for isomers of XIVa. H NMR spectrum
3
(CDCl3), δ, ppm: cis isomer: 1.69 d.d (3H, CH3, J =
4
6.8, J = 1.6 Hz), 5.10 s (2H, CH2Ph), 5.88–6.12 m
3
4
(1H, CH), 6.21 d.d (1H, NCH, J = 8.7, J = 1.5 Hz),
6.67–7.43 m (9H, Harom); trans isomer: 1.91 d.d (3H,
CH3, 3J = 7.7, 4J = 1.6 Hz), 5.04 s (2H, CH2Ph), 5.88–
3
4
1
6.12 m (1H, CH), 6.49 d.d (1H, NCH, J = 13.7, J =
Cl 20.53; N 16.23. H NMR spectrum of the free base
1.5 Hz), 6.67–7.43 m (9H, Harom).
(CDCl3), δ, ppm: 0.98 t (6H, CH3, J = 7.2 Hz), 1.37 d
(3H, CH3, J = 7.1 Hz), 2.50–2.67 m (6H, CH2N), 2.76 t
(2H, NCH2, J = 7.2 Hz), 3.32 t (1H, 3-Hax, J = 7.9 Hz),
3.70–4.05 m (3H, NCH2, 3-Heq), 4.50–4.67 m (1H,
CH), 6.62–6.96 m (4H, Harom).
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RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 47 No. 9 2011