Imidazo[1,2-a]benzimidazole derivatives: XXIX. 1-Allyl-2-amino-3- acylmethylbenzimidazolium halides and syntheses on their base

Article abstract of DOI:10.1134/S1070428011090168

Cyclization of 1-allyl-2-amino-3-acylmethylbenzimidazolium halides under alkaline conditions gave 9-allyl-substituted imidazo[1,2-a]benzimidazoles. Cyclization of the same compounds on heating in concentrated hydrobromic acid was accompanied by addition o

Full text of DOI:10.1134/S1070428011090168

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2011, Vol. 47, No. 9, pp. 1354–1361. © 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. 1333–1340.
Imidazo[1,2-a]benzimidazole Derivatives:
XXIX.* 1-Allyl-2-amino-3-acylmethylbenzimidazolium Halides
and Syntheses on Their Base
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 January 26, 2011
Abstract—Cyclization of 1-allyl-2-amino-3-acylmethylbenzimidazolium halides under alkaline conditions
gave 9-allyl-substituted imidazo[1,2-a]benzimidazoles. Cyclization of the same compounds on heating in con-
centrated hydrobromic acid was accompanied by addition of hydrogen bromide at the exocyclic double bond.
Competing cyclizations with participation of the 1-(2-bromopropyl) and 3-acylmethyl substituents in 2-imino-
2,3-dihydro-1H-benzimidazole were studied. Functionalization of the imidazo[1,2-a]benzimidazole system was
performed via introduction of substituents into the 3-position and replacement of bromine in the 2-bromopropyl
group in the 9-position.
DOI: 10.1134/S1070428011090168
Taking into account that a large number of biologi-
cally active compounds with various properties (about
50 kinds of biological activity) were found among
imidazo[1,2-a]benzimidazole derivatives and interme-
diate products in their synthesis [2–5], we continued
our studies on new synthetic routes to derivatives of
this tricyclic system. As shown in [1], 1-allyl-3-alkyl-
(arylalkyl, dialkylaminoalkyl)-2-imino-2,3-dihydro-
1H-benzimidazoles take up hydrogen bromide at the
allyl group, and next follows heterocyclization with
formation of 9-substituted 2-methyl-2,3-dihydroimid-
azo[1,2-a]benzimidazoles. Some cyclization products
exhibited interesting biological properties [6]. In con-
tinuation of these studies, we synthesized 1-allyl-2-
aminobenzimidazoles containing an acylmethyl group
in the 3-position. We anticipated that these polyfunc-
tional compounds could give rise to various derivatives
via reactions involving both allyl and carbonyl groups.
[1,2-a]benzimidazoles IVa–IVd (Scheme 1). However,
the latter were formed much more readily when imines
IIIa–IIId (obtained from bromides IIa–IId by treat-
ment with an ammonia solution) were heated for a short
time at the melting point. Closure of new imidazole
ring resulted in disappearance of CH2 (δ 5.45–
6.05 ppm) and NH2 (NH) proton signals from the
1H NMR spectra of cyclization products IV, as well as
of absorption band typical of stretching vibrations of
carbonyl (1724–1690 cm–1 for salts II and 1690–
1675 cm–1 for free bases III), amino (3340–3190 and
3175–3150 cm–1), and imino groups (3280–3240 cm–1)
from the IR spectra.
Like 1-allyl-3-alkyl(arylalkyl)-2-aminobenzimid-
azolium salts [1], compounds IIa–IIc take up hydro-
gen bromide at the allyl group on heating in boiling
concentrated hydrobromic acid; simultaneously, intra-
molecular cyclization with participation of the amino
and carbonyl groups occurred to give tricyclic
2-R-9-(2-bromopropyl)imidazo[1,2-a]benzimidazoles
Va–Vc [8]. The latter can also be obtained by heating
9-allyl derivatives IVa–IVc with concentrated hydro-
1-Allyl-1H-benzimidazol-2-amine (I) was subject-
ed to quaternization with acylmethyl bromides in ace-
tone [7] or acetonitrile; alternatively, compound I was
fused with a small excess of chloroacetone. By
cyclization of benzimidazolium halides IIa–IId on
heating in boiling aqueous alcohol in the presence of
NaHCO3 or Na2CO3 we obtained 2-R-9-allylimidazo-
1
bromic acid. The H NMR spectrum of V contained
a doublet at 1.76–1.82 ppm (JHH = 6.7 Hz) from the
methyl protons instead of signals typical of vinyl group
(CH=CH2) in initial compounds II or IV. In the re-
action with salt IId, the cyclization and hydrogen
* For communication XXVIII, see [1].
1354

IMIDAZO[1,2-a]BENZIMIDAZOLE DERIVATIVES: XXIX.
1355
Scheme 1.
Me
O
Me
O
δ–
Me
O
N
Ac2O
AcONa
Me
N
N
N
N
δ+
N
R = Me
–H2O
All
All
VII
R
CH2COR
CH2COR
N
N
N
N
N
N
OH–
BrCH2COR
Δ
N
NH2
NH2 X–
NH
–H2O
N
N
All
All
IIa–IId
All
All
I
IIIa–IIId
IVa–IVd
R
R
NH
O
N
N
N
N
HBr
N
·HBr
N
Me
Me
N
Br
O
Va–Vc, Ve
VIb, VIc
S
O
NHPh
R'
(R'CO)2O
PhNCS
N
N
R
R
IVc, IVd
N
N
N
N
All
IXc, IXd
HBr, Δ
Ve
All
VIIIc, VIIId
II–IX, R = Me (a), t-Bu (b), Ph (c), 4-MeOC6H4 (d), 4-HOC6H4 (e); IX, R′ = Me (c), Et (d); X = Cl, Br.
Scheme 2.
OH
OH
N
N
HBr
HBr
IId, IVd
–MeOH
N
N
N
N
·HBr
·HBr
Me
Br
All
A
Ve
bromide addition were accompanied by hydrolysis of
methoxy group in the aromatic ring. According to the
1H NMR data, the reaction begins with hydrolysis of
the ether moiety and simultaneous cyclization (the
MeO signal at δ 3.88 ppm disappeared) with formation
of poorly soluble phenol A, and then addition of HBr
at the allyl double bond starts (Scheme 2). Insofar as
the reaction requires fairly severe conditions, both
processes occur simultaneously, thus leading to a mix-
ture of products that are difficult to separate. Com-
pound Ve becomes the major product only when the
reaction time is considerably increased. Prolonged
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ANISIMOVA, TOLPYGIN
1356
Scheme 3.
O
Ph
Ph
N
N
N
N
N
BrCH2COPh
HBr, Δ
N
NH2
Br
NH2 Br–
·HBr
–H2O
N
Br
Br
Me
Me
Me
X
XI
Vc
CH2COPh
CH2COPh
N
N
OH–
MeCN, OH–
XI
NH
N
N
N
Br
Me
Me
XII
XIII
heating of compound IVd in concentrated hydro-
bromic acid also led to the formation of 2-bromopropyl
derivative Ve.
lacked 3-H signal but contained signals from the
COAlk fragment. The carbonyl absorption band ap-
peared in the IR spectra of IXc and IXd at 1640–
1615 cm–1.
The halogen atom in bromopropyl derivatives Va–
Vc and Ve is fairly labile; it is readily replaced by
morpholino group on heating to give previously un-
known 9-(2-morpholinopropyl) derivatives VIb and
VIc. Introduction of a bulky morpholine fragment
creates steric hindrances to rotation of the 9-alkyl
group, so that protons in the methylene group on N9
become magnetically nonequivalent, and they resonate
as two multiplets at δ 3.96–4.13 and 4.25–4.40 ppm.
Quaternization of 1-(2-bromopropyl)-1H-benzimid-
azol-2-amine (X) [1] with phenacyl bromide in acetone
gave salt XI which was found to undergo cyclization
along two pathways, depending on the conditions. By
heating bromide XI with excess 48% hydrobromic
acid we obtained hydrobromide Vc (Scheme 3). In this
case, the reaction followed the above pattern [7]
involving interaction of the carbonyl and amino groups
and subsequent aromatization via elimination of water.
Acylmethyl derivatives II can be used to obtain
3-acyl-9-allyl-2-R-imidazo[1,2-a]benzimidazoles [9].
Heating of salt IIa in acetic anhydride in the presence
of sodium acetate resulted in acetylation of the imino
group and subsequent cyclization with participation of
the carbonyl group on the nitrogen atom and acyl-
methyl substituent with formation of ketone VII
(Scheme 1).
1
The H NMR spectrum of the product contained
signals belonging to bromopropyl substituent, whereas
those assignable to CH2CO fragment were absent.
By treatment of salt XI with alkali we obtained
imine XII which was converted into 2-methyl-9-phen-
acyl-2,3-dihydroimidazo[1,2-a]benzimidazole hydro-
bromide (XIII) on heating in acetonitrile (Scheme 3).
Here, the cyclization occurred as a result of intramo-
lecular nucleophilic attack by the imino group on the
CHBr carbon atom and elimination of HBr molecule.
Ketone XIII displayed in the 1H NMR spectrum a dou-
blet at δ 5.21 ppm (J = 6.5 Hz) from the 9-CH2COPh
substituent, and protons in the C3H2 methylene group
resonated as two triplets at δ 3.41 (JHH = 7.9 Hz, axial)
and 4.03 ppm (JHH = 8.5 Hz, equatorial). The IR spec-
trum of XIII contained an absorption band at 1695 cm–1
due to stretching vibrations of the carbonyl group.
Imidazo[1,2-a]benzimidazoles IV are π-excessive
heterocycles [10–12] and are capable of reacting with
electrophiles at the C3 atom. For example, the reaction
of compounds IVc and IVd with such a weak electro-
phile as phenyl isocyanate afforded the corresponding
3-carbothioamides VIIIc and VIIId in almost quanti-
tative yield. The structure of compounds VIII is
1
confirmed by the presence in their H NMR spectra
of additional signals from aromatic protons and of
a downfield singlet at δ 11.64–11.89 ppm due to NH
proton. Likewise, reactions of IVc and IVd with car-
boxylic acid anhydrides gave 3-acetyl and 3-propanoyl
We can conclude that 1-allyl-2-amino-3-acyl-
methyl- and 2-amino-3-acylmethyl-1-(2-bromopropyl)-
benzimidazolium halides are convenient initial com-
1
derivatives IXc and IXd whose H NMR spectra
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IMIDAZO[1,2-a]BENZIMIDAZOLE DERIVATIVES: XXIX.
1357
pounds for the synthesis of imidazo[1,2-a]benzimid-
azole and 2,3-dihydroimidazo[1,2-a]benzimidazole
derivatives.
8.91 s (2H, NH2). Found, %: C 54.62; H 6.20;
Br 22.63; N 12.00. C16H22BrN3O. Calculated, %:
C 54.55; H 6.29; Br 22.68; N 11.93.
1-Allyl-2-amino-3-(2-oxo-2-phenylethyl)benz-
imidazolium bromide (IIc) was synthesized in a simi-
lar way from 1.7 g (10 mmol) of amine I and 2.0 g
(10 mmol) of phenacyl bromide in 40 ml of acetone.
Yield 3.6 g (97%), mp 242–244°C (from EtOH). IR
spectrum, ν, cm–1: 3200, 3150 (NH2), 1690 (C=O),
EXPERIMENTAL
The progress of reactions was monitored, and the
purity of the isolated compounds was checked, by TLC
on aluminum oxide using chloroform as eluent; spots
were visualized by treatment with iodine vapor in
a moist chamber. The IR spectra were recorded on
a Specord 75IR spectrometer from samples dispersed
1
1665, 1600, 1500, 1460 (C=C, C=N). H NMR spec-
trum (DMSO-d6), δ, ppm: 4.95 d (2H, CH2, J =
5.4 Hz), 5.19–5.33 m (2H, CH2), 5.90–6.05 m (3H,
CH, CH2CO), 7.21–7.35 m (2H, 5-H, 6-H), 7.49–
7.78 m (5H, Harom), 8.10 d (1H, 4-H, J = 7.4 Hz),
8.95 s (2H, NH2). Found, %: C 58.00; H 4.95;
Br 21.54; N 11.22. C18H18BrN3O. Calculated, %:
C 58.08; H 4.87; Br 21.46; N 11.29.
1
in mineral oil. The H NMR spectra were obtained on
a Varian XL-300 spectrometer at 300 MHz.
1-Allyl-1H-benzimidazol-2-amine (I) was synthe-
sized according to the procedure described in [1].
1-Allyl-2-amino-3-(2-oxopropyl)benzimidazo-
lium chloride (IIa). A mixture of 1.7 g (10 mmol) of
amine I, 1.5 ml of chloroacetone, and 5 ml of acetone
(or 1.5 ml of methanol) was heated to 60–70°C and
was kept at that temperature until the solvent (acetone
or methanol) evaporated completely. The mixture was
then heated to 85–90°C and kept for 30 min at that
temperature. After cooling, the melt was ground with
acetone (20–25 ml), and the precipitate was filtered off
and washed with acetone. Yield 2.5 g (94%), colorless
fiber-like crystals, mp 189–190°C (decomp., from
EtOH). IR spectrum, ν, cm–1: 3190, 3150 (NH2), 1715
(C=O), 1665 (C=N), 1600, 1525, 1490 (C=C). 1H NMR
spectrum (DMSO-d6), δ, ppm: 2.29 s (3H, CH3), 4.92 d
(2H, CH2, J = 5.3 Hz), 5.03–5.28 m (2H, CH2), 5.45 s
(2H, CH2CO), 5.81–6.01 m (1H, CH), 7.21–7.61 m
(4H, Harom), 9.34 s (2H, NH2). Found, %: C 58.69;
H 6.12; Cl 13.40; N 15.9. C13H16ClN3O. Calculated,
%: C 58.76; H 6.07; Cl 13.34; N 15.75.
1-Allyl-2-amino-3-[2-(4-methoxyphenyl)-2-oxo-
ethyl]benzimidazolium bromide (IId) was synthe-
sized from equivalent amounts of amine I and
4-methoxyphenacyl bromide in acetone. Yield 99%,
mp 239–241°C (decomp., from EtOH). IR spectrum, ν,
cm–1: 3340, 3175 (NH2), 1690 (C=O), 1675, 1610,
1
1475 (C=C, C=N). H NMR spectrum (DMSO-d6), δ,
ppm: 3.88 s (3H, OCH3), 4.47 d (2H, CH2, J = 5.7 Hz),
5.12–5.22 m (2H, CH2), 5.35 s (2H, CH2CO), 5.80–
5.95 m (1H, CH), 6.72–6.89 (4H, Harom), 7.03 d (2H,
5-H, 6-H, J = 8.7 Hz), 8.05 d (2H, 4-H, 7-H, J =
8.7 Hz). Found, %: C 56.78; H 5.09; Br 20.77;
N 10.38. C19H20BrN3O2. Calculated, %: C 56.73;
H 5.01; Br 19.86; N 10.45.
1-(3-Allyl-2-imino-2,3-dihydro-1H-benzimid-
azol-1-yl)propan-2-one (IIIa). Chloride IIa, 2.7 g
(10 mmol), was treated with 15 ml of 22% aqueous
ammonia at room temperature. After 3 h, the precip-
itate was filtered off and dried in air. Yield quantita-
tive, mp 80–85°C. Melting was accompanied by cy-
clization into 9-allyl-2-methylimidazo[1,2-a]benzimid-
azole (IVa). Imine IIIa underwent spontaneous cy-
clization upon attempted recrystallization or storage at
room temperature. IR spectrum, ν, cm–1: 3280 (NH),
1675 (C=O), 1615, 1475, 1435 (C=C, C=N). Found,
%: C 68.15; H 6.62; N 18.43. C13H15N3O. Calculated,
%: C 68.10; H 6.59; N 18.35.
1-Allyl-2-amino-3-(3,3-dimethyl-2-oxobutyl)-
benzimidazolium bromide (IIb). Amine I, 1.7 g
(10 mmol), was dissolved in 60 ml of acetone, 2.2 ml
of technical grade 1-bromo-3,3-dimethylbutan-2-one
was added, and the mixture was thoroughly stirred and
left to stand overnight at room temperature. The pre-
cipitate was filtered off and washed with acetone.
Yield 3.3 g (98%), white fiber-like highly electrifiable
crystals, mp 261–262°C (decomp., from EtOH, sweats
at 234–235°C). IR spectrum, ν, cm–1: 3330, 3150
(NH2), 1724 (C=O), 1669, 1607, 1525, 1490, 1470
Compounds IIIb–IIId were synthesized in a simi-
lar way.
1
(C=C, C=N). H NMR spectrum (DMSO-d6), δ, ppm:
1-(3-Allyl-2-imino-2,3-dihydro-1H-benzimidaz-
ol-1-yl)-3,3-dimethylbutan-2-one (IIIb). Yield 98%,
mp 107–108°C (from hexane). IR spectrum, ν, cm–1:
3280 (NH), 1675 (C=O), 1615, 1475, 1435 (C=C,
1.23 s [9H, C(CH3)3], 4.90 d (2H, CH2, J = 4.9 Hz),
5.05–5.23 m (2H, CH2), 5.56 s (2H, CH2CO), 5.85–
6.03 m (1H, CH), 7.22–7.33 q (2H, 5-H, 6-H), 7.41 d
(1H, 7-H, J = 7.7 Hz), 7.56 d (1H, 4-H, J = 7.7 Hz),
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 47 No. 9 2011

ANISIMOVA, TOLPYGIN
1358
C=N). Found, %: C 70.88; H 7.74; N 15.55.
C16H21N3O. Calculated, %: C 70.82; H 7.80; N 15.48.
b. Benzimidazolium salt IIb, 0.8 g, was heated in
30 ml of a 5% solution of Na2CO3 at the boiling point.
When the reaction was complete (12–15 h), the mix-
ture was cooled, free base IVb was isolated by extrac-
tion, and hydrochloride IVb was obtained as described
above in a. Yield 0.6 g (91%), mp 261–262°C.
2-(3-Allyl-2-imino-2,3-dihydro-1H-benzimidaz-
ol-1-yl)-1-phenylethanone (IIIc). Yield 95–98%,
mp 157–158°C (from MeCN). IR spectrum, ν, cm–1:
3240 (NH), 1690 (C=O), 1630, 1620, 1600, 1500,
1475, 1455 (C=C, C=N). Found, %: C 74.16; H 5.90;
N 14.48. C18H17N3O. Calculated, %: C 74.21; H 5.88;
N 14.42.
9-Allyl-2-phenylimidazo[1,2-a]benzimidazole
(IVc) was synthesized by heating imine IIIc at 160–
165°C over a period of 15 min. Yield 95%, mp 101–
102°C (from i-PrOH or EtOAc). Found, %: C 79.18;
H 5.49; N 15.33. C18H15N3. Calculated, %: C 79.10;
H 5.53; N 15.37.
2-(3-Allyl-2-imino-2,3-dihydro-1H-benzimidaz-
ol-1-yl)-1-(4-methoxyphenyl)ethanone (IIId). Yield
quantitative, mp 148–149°C (from MeCN). IR spec-
trum, ν, cm–1: 3245 (NH), 1695 (C=O), 1630, 1600,
1510, 1475 (C=C, C=N). Found, %: C 70.94; H 6.04;
N 12.98. C19H19N3O2. Calculated, %: C 71.01; H 5.96;
N 13.07.
9-Allyl-2-phenylimidazo[1,2-a]benzimidazole
hydrochloride was obtained by acidification of a solu-
tion of free base IVc in acetone with concentrated hy-
drochloric acid. Yield 95%, mp 234–236°C (decomp.,
from EtOH). IR spectrum, ν, cm–1: 1650 (C=N), 1625,
9-Allyl-2-methylimidazo[1,2-a]benzimidazole
(IVa). Imine IIIa, 2.3 g (10 mmol), was placed into
an open test tube and was heated at 80–90°C until the
reaction was complete (10–15 min; the reaction was
accompanied by liberation of water). The resulting
material was dissolved in a minimal amount of chloro-
form, the solution was passed through a layer of Al2O3
with elution with chloroform, and the first fraction was
collected. Evaporation of the eluate gave colorless
crystals. Yield 1.8 g (85%), mp 82–83°C (from hex-
ane). IR spectrum, ν, cm–1: 1645 (C=N), 1600, 1505,
1
1620, 1610, 1500, 1475, 1455 (C=C). H NMR spec-
trum (DMSO-d6), δ, ppm: 5.21–5.57 m (4H, NCH2,
CH2), 6.02–6.17 m (1H, CH), 7.31–7.58 m (5H, Harom),
7.71 d (1H, Harom, J = 8.0 Hz), 7.92–8.05 m (3H,
H
arom), 8.62 s (1H, 3-H), 15.37 br.s (1H, N+H). Found,
%: C 69.88; H 5.15; Cl 11.35; N 13.62. C18H15N3·HCl.
Calculated, %: C 69.79; H 5.21; Cl 11.44; N 13.56.
9-Allyl-2-(4-methoxyphenyl)imidazo[1,2-a]benz-
imidazole (IVd). a. A mixture of 8 g (20 mmol) of
bromide IId, 4 g of Na2CO3, and 100 ml of water was
heated at the boiling point until the cyclization was
complete (~12 h). The mixture was cooled and extract-
ed with chloroform, the extract was passed through
a layer of γ-Al2O3 (eluent CHCl3), the eluate was
evaporated, and the residue was recrystallized from
isopropyl alcohol or acetonitrile. Yield 5.4–5.8 g (90–
96%), mp 128–129°C. Found, %: C 75.28; H 5.59;
N 13.93. C19H17N3O. Calculated, %: C 75.23; H 5.65;
N 13.85.
1
1475, 1460 (C=C). H NMR spectrum (DMSO-d6), δ,
ppm: 2.48 s (3H, CH3), 5.09 d (2H, CH2, J = 5.8 Hz),
5.27–5.45 m (2H, CH2), 6.02–6.13 m (1H, CH), 7.38–
7.54 m (2H, 6-H, 7-H), 7.76 d (1H, 5-H, J = 8.4 Hz),
7.95 s (1H, 3-H), 8.05 d (1H, 8-H, J = 8.4 Hz). Found,
%: C 73.85; H 6.20; N 19.95. C13H13N3. Calculated, %:
C 73.91; H 6.20; N 19.89.
9-Allyl-2-tert-butylimidazo[1,2-a]benzimidazole
hydrochloride (IVb). a. Free base IVb was synthe-
sized by heating 1.1 g (4 mmol) of imine IIIb at 140–
145°C (20–25 min, Rf 0.9). Chromatographic purifica-
tion gave an oily substance which was dissolved in
acetone, and the solution was acidified with a solution
of HCl in isopropyl alcohol. Yield 1.1 g (93%),
mp 261–262°C (from i-PrOH). IR spectrum, ν, cm–1:
2385–2670 (N+H), 1660, 1605, 1520, 1480, 1460
b. Imine IIId was heated at 150°C until water no
longer evolved (10–15 min). The melt was recrystal-
lized from acetonitrile. Yield 89%.
9-Allyl-2-(4-methoxyphenyl)imidazo[1,2-a]benz-
imidazole hydrochloride was obtained by acidifica-
tion of a solution of free base IVd in acetone with con-
centrated hydrochloric acid. Yield 96%, mp 252–
254°C (decomp., from EtOH). IR spectrum, ν, cm–1:
1655, 1620, 1610, 1505, 1475, 1450 (C=C, C=N).
1H NMR spectrum (DMSO-d6), δ, ppm: 3.84 s (3H,
OCH3), 5.33 d (2H, CH2, J = 5.7 Hz), 5.40–5.61 m
1
(C=C, C=N). H NMR spectrum (DMSO-d6), δ, ppm:
1.40 s [9H, C(CH3)3], 5.19–5.42 m (4H, NCH2, CH2),
5.96–6.16 m (1H, CH), 7.40–7.56 m (2H, 6-H, 7-H),
7.72 d (1H, 5-H, J = 8.6 Hz), 7.95 s (1H, 3-H), 8.04 d
(1H, 8-H, J = 8.6 Hz). Found, %: C 66.24; H 7.04;
Cl 12.15; N 14.57. C16H19N3 ·HCl. Calculated, %:
C 66.31; H 6.96; Cl 12.23; N 14.50.
(2H, CH2), 6.03–6.20 m (1H, CH), 6.98 d (2H, Harom
J = 4.5 Hz), 7.35–7.52 m (2H, Harom), 7.76 d (1H,
arom, J = 6.4 Hz), 7.92–8.04 m (3H, Harom), 8.36 s
,
H
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IMIDAZO[1,2-a]BENZIMIDAZOLE DERIVATIVES: XXIX.
1359
(1H, 3-H). Found, %: C 67.22; H 5.29; Cl 10.35;
N 12.44. C19H17N3O·HCl. Calculated, %: C 67.16;
H 5.34; Cl 10.43; N 12.37.
b. Compound XI was heated in boiling concentrat-
ed hydrobromic acid over a period of 3 h. Yield 90%.
Free base Vc was isolated from the hydrobromide
by treatment with alkali. Yield quantitative. mp 42–
43°C (from EtOAc). IR spectrum, ν, cm–1: 1635, 1600,
9-(2-Bromopropyl)-2-methylimidazo[1,2-a]benz-
imidazole (Va). A mixture of 1.3 g (5 mmol) of
chloride IIa and 15 ml of concentrated hydrobromic
acid (bp 128°C) was heated for 18 h under reflux. The
mixture was evaporated to a small volume under
reduced pressure (water-jet pump), and the residue was
left to stand in a refrigerator. The precipitate of salt Va
was filtered off, thoroughly washed with acetone to
remove traces of acid, dried in air, and treated with
a 22% solution of ammonia at room temperature. Yield
0.9 g (62%), mp 81–82°C (from hexane). IR spectrum,
ν, cm–1: 1625, 1600, 1555, 1500, 1470 (C=C, C=N).
1H NMR spectrum (CDCl3), δ, ppm: 1.76 d (3H, CH3,
J = 6.7 Hz), 2.36 s (3H, CH3), 4.37–4.46 m (2H, CH2),
4.60–4.77 m (1H, CH), 7.00–7.50 m (5H, Harom).
Found, %: C 53.36; H 4.79; Br 27.41; N 14.44.
C13H14BrN3. Calculated, %: C 53.44; H 4.83; Br 27.35;
N 14.38.
1
1550, 1500, 1475 (C=C, C=N). H NMR spectrum
(CDCl3), δ, ppm: 1.80 d (3H, CH3, J = 6.7 Hz), 4.45–
4.54 m (2H, CH2), 4.68–4.88 m (1H, CH), 7.14–
7.44 m (6H, Harom), 7.52 d (1H, Harom, J = 7.4 Hz), 7.63 s
(1H, 3-H), 7.84 d (2H, 5-H, 8-H, J = 7.6 Hz). Found,
%: C 61.10; H 4.48; Br 22.48; N 11.94. C18H16BrN3.
Calculated, %: C 61.03; H 4.55; Br 22.56; N 11.86.
9-(2-Bromopropyl)-2-(4-hydroxyphenyl)imidazo-
[1,2-a]benzimidazole hydrobromide (Ve). A mixture
of 2.0 g (5 mmol) of bromide IId and 30 ml of 48%
hydrobromic acid was heated for 30 h at the boiling
point. The mixture was cooled, and the precipitate of
hydrobromide Ve was filtered off and washed with
acetone. Yield 1.8 g (81%), mp 239–240°C (decomp.,
from EtOH–DMF). IR spectrum, ν, cm–1: 3410, 1640,
1
1600, 1550, 1500, 1475 (C=C, C=N). H NMR spec-
trum (DMSO-d6), δ, ppm: 1.84 d (3H, CH3, J =
5.7 Hz), 4.74–4.98 m (3H, CH2, CH), 7.37–7.63 m
(5H, Harom), 7.80–8.08 m (3H, Harom), 8.60 s (1H, 3-H).
Found, %: C 47.84; H 3.74; Br 35.51; N 9.40.
C18H16BrN3O·HBr. Calculated, %: C 47.92; H 3.80;
Br 35.42; N 9.31.
2-tert-Butyl-9-(2-bromopropyl)imidazo[1,2-a]-
benzimidazole hydrobromide (Vb). A mixture of
3.5 g (10 mmol) of bromide IIb and 40 ml of 48%
hydrobromic acid was heated for 12–15 h under reflux.
After cooling, the precipitate was filtered off on a glass
filter, thoroughly squeezed, and washed with acetone.
Yield 2.9 g, mp 233–234°C (from EtOH). IR spectrum,
ν, cm–1: 3100, 2550–2720 (N+H), 1645, 1615, 1515,
Salt Vd was synthesized by prolonged heating of
compound IVd or its hydrobromide in concentrated
hydrobromic acid. Yield 85%.
1
1470 (C=C, C=N). H NMR spectrum (DMSO-d6), δ,
2-tert-Butyl-9-(2-morpholinopropyl)imidazo-
[1,2-a]benzimidazole (VIb). A mixture of 2.1 g
(5 mmol) of hydrobromide Vb and 8 ml of morpholine
was heated for 6–8 h under reflux. The mixture was
cooled and diluted with 30–40 ml of water, the oily
material was extracted into chloroform, and the extract
was washed with water to remove excess morpholine,
dried over anhydrous sodium sulfate, and passed
through a layer of γ-Al2O3 (3×5 cm) using chloroform
as eluent. The eluate was evaporated to isolate com-
pound VIb as a colorless oily substance. Yield 1.8 g
(87%). IR spectrum, ν, cm–1: 1640, 1600, 1590, 1460
ppm: 1.40 s [9H, C(CH3)3], 1.77 d (3H, CH3, J =
6.7 Hz), 4.70–4.90 m (3H, CH2, CH), 7.40–7.62 m
(2H, Harom), 7.93–8.10 m (3H, Harom), 13.75 br.s (1H,
N+H). Found, %: C 46.20; H 5.24; Br 38.57; N 10.19.
C16H20BrN3 ·HBr. Calculated, %: C 46.29; H 5.10;
Br 38.49; N 10.12.
9-(2-Bromopropyl)-2-phenylimidazo[1,2-a]benz-
imidazole hydrobromide (Vc). a. A mixture of 7.4 g
(20 mmol) of bromide IIc and 80 ml of 48% hydro-
bromic acid was heated for 10 h under reflux
(Rf values of the initial compound and final product
0.3 and 0.9, respectively). Bromide IIc did not dissolve
during the process but was transformed into a dif-
ficultly filterable solid. Therefore, the mixture was
cooled, diluted with an equal volume of acetone, and
thoroughly stirred. After 2 h, the precipitate was
filtered off and washed with acetone. Yield 7.6 g
(87%), mp 231–232°C (from 50% EtOH). Found, %:
C 49.59; H 3.89; Br 36.81; N 9.71. C18H16BrN3·HBr.
Calculated, %: C 49.68; H 3.94; Br 36.72; N 9.66.
1
(C=C, C=N). H NMR spectrum (CDCl3), δ, ppm:
1.02 d (3H, CH3, J = 7.4 Hz), 1.33 s [9H, C(CH3)3],
2.28–2.40 m (2H, CH2), 2.60–2.78 m [4H, N(CH2)2],
3.18–3.31 m (1H, CH), 3.35–3.53 m [4H, O(CH2)2],
3.96–4.10 m and 4.25–4.37 m (1H each, 9-CH2), 7.00 s
(1H, 3-H), 7.06–7.23 m (3H, 6-H, 7-H, 8-H), 7.42 d
(1H, 5-H, J = 7.8 Hz). Found, %: C 70.49; H 8.35;
N 16.51. C20H28N4O. Calculated, %: C 70.56; H 8.29;
N 16.46.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 47 No. 9 2011

ANISIMOVA, TOLPYGIN
1360
2-tert-Butyl-9-(2-morpholinopropyl)imidazo-
IR spectrum, ν, cm–1: 1625, 1600, 1545, 1500, 1475
(C=C, C=N). H NMR spectrum (DMSO-d6), δ, ppm:
4.92 d (2H, CH2, J = 5.5 Hz), 5.11–5.28 m (2H, CH2),
5.95–6.14 m (1H, CH), 7.14–7.90 m (13H, Harom),
8.06 d (1H, 5-H, J = 8.2 Hz), 11.89 s (1H, NH). Found,
%: C 73.44; H 5.00; N 13.80; S 7.76. C25H20N4S. Cal-
culated, %: C 73.51; H 4.93; N 13.71; S 7.85.
1
[1,2-a]benzimidazole dihydrochloride was obtained
by acidification of a solution of free base VIb in
acetone with a solution of HCl in isopropyl alcohol to
pH 1–2. Yield 84%, mp 232–233°C (decomp., from
acetonitrile).
9-(2-Morpholinopropyl)-2-phenylimidazo[1,2-a]-
benzimidazole (VIc) was synthesized as described
above for VIb. Yield 94%, colorless oily substance. IR
spectrum, ν, cm–1: 1660, 1615, 1600, 1495, 1480
9-Allyl-2-(4-methoxyphenyl)-N-phenylimidazo-
[1,2-a]benzimidazole-3-carbothioamide (VIIId) was
synthesized in a similar way. Yield 96%, mp 211–
212°C (from DMF). IR spectrum, ν, cm–1: 1620, 1600,
1
(C=N, C=C). H NMR spectrum (CDCl3), δ, ppm:
1
1.08 d (3H, CH3, J = 7.7 Hz), 2.40–2.53 m (2H, CH2),
2.69–2.82 m (4H, NCH2), 3.24–3.40 m (1H, CH),
3.44–3.61 m (4H, OCH2), 4.01–4.13 m and 4.27–
4.40 m (1H each, 9-CH2), 7.10–7.44 m (6H, Harom),
7.52 d (1H, Harom, J = 8.8 Hz), 7.62 s (1H, 3-H), 7.84 d
(2H, 5-H, 8-H, J = 7.7 Hz). Found, %: C 73.25;
H 6.65; N 15.62. C22H24N4O. Calculated, %: C 73.31;
H 6.71; N 15.54.
1545, 1500, 1475 (C=C, C=N). H NMR spectrum
(DMSO-d6), δ, ppm: 3.76 s (3H, OCH3), 4.91 d (2H,
CH2, J = 5.8 Hz), 5.20–5.33 m (2H, CH), 5.99–6.14 m
(1H, CH), 6.76–7.93 m (12H, Harom), 8.10 d (1H, 5-H,
J = 7.8 Hz), 11.64 s (1H, NH). Found, %: C 71.14;
H 5.12; N 12.86; S 7.22. C26H22N4OS. Calculated, %:
C 71.21; H 5.06; N 12.78; S 7.31.
1-(9-Allyl-2-phenylimidazo[1,2-a]benzimidazol-
3-yl)ethanone (IXc). A mixture of 1.4 g (5 mmol) of
compound IVc and 10 ml of acetic anhydride was
heated for 2.5 h under reflux. The mixture was poured
into 50 ml of cold water and (after decomposition of
excess acetic anhydride) neutralized with sodium hy-
drogen carbonate. The precipitate was filtered off and
purified first by column chromatography on Al2O3
using chloroform as eluent and then by recrystalliza-
tion from acetonitrile or ethyl acetate. Yield 1.3 g
(79%), mp 143–144°C. IR spectrum, ν, cm–1: 1640
(C=O), 1620, 1610, 1505, 1475 (C=C, C=N). 1H NMR
spectrum (CDCl3), δ, ppm: 2.13 s (3H, CH3), 4.91 d
(2H, CH2, J = 6.0 Hz), 5.20–5.31 m (2H, CH2), 5.91–
6.07 m (1H, CH), 7.23–7.61 m (8H, Harom), 8.77 d (1H,
5-H, J = 7.5 Hz). Found, %: C 76.26; H 5.35; N 13.26.
C20H17N3O. Calculated, %: C 76.17; H 5.43; N 13.32.
9-(2-Morpholinopropyl)-2-phenylimidazo[1,2-a]-
benzimidazole dihydrochloride. Yield 88%, mp 252–
253°C (from EtOH).
1-(9-Allyl-2-methylimidazo[1,2-a]benzimidazol-
3-yl)ethanone (VIIa). A mixture of 1.3 g (5 mmol) of
chloride IIa, 10 ml of acetic anhydride, and 1.0 g of
anhydrous sodium acetate was heated for 1 h under
reflux. The mixture was cooled, poured into 30 ml of
cold water, and (after decomposition of excess acetic
anhydride) neutralized with sodium hydrogen carbon-
ate. The oily material was extracted into chloroform,
the extract was passed through a column charged with
γ-Al2O3 using chloroform as eluent, the eluate was
evaporated, and the residue was recrystallized from
a small amount of ethyl acetate. Yield 1.1 g (84%),
mp 79–80°C. IR spectrum, ν, cm–1: 1645 (C=N), 1600,
1
1505, 1475, 1460 (C=C). H NMR spectrum (CDCl3),
1-[9-Allyl-2-(4-methoxyphenyl)imidazo[1,2-a]-
benzimidazol-3-yl]propan-1-one (IXd) was synthe-
sized by heating 1.2 g (4 mmol) of compound IVd in
10 ml of propionic anhydride under reflux over a peri-
od of 3.5 h. The product was isolated as described
above for IXc. Yield 1.1 g (78%), mp 137–138°C
(from EtOAc). IR spectrum, ν, cm–1: 1630 (C=O),
δ, ppm: 2.13 s (3H, CH3), 2.62 s (3H, CH3), 4.92 d
(2H, CH2, J = 5.7 Hz), 5.18–5.30 m (2H, CH2), 5.92–
6.06 m (1H, CH), 7.21–7.32 m (3H, 6-H, 7-H, 8-H),
8.46 d (1H, 5-H, J = 7.7 Hz). Found, %: C 71.18;
H 5.90; N 16.67. C15H15N3O. Calculated, %: C 71.13;
H 5.97; N 16.59.
1
1615, 1475 (C=C, C=N). H NMR spectrum (CDCl3),
9-Allyl-2,N-diphenylimidazo[1,2-a]benzimidaz-
ole-3-carbothioamide (VIIIc). A mixture of 5 mmol
of free base IVc and 1.5 ml of phenyl isothiocyanate
was heated until it became homogeneous and was then
heated for 15–20 min on a boiling water bath. The
mixture was cooled and ground with diethyl ether, and
the precipitate was filtered off and washed with diethyl
ether. Yield quantitative, mp 234–235°C (from DMF).
δ, ppm: 1.10 t (3H, CH3), 2.55 q (2H, COCH2), 3.88 s
(3H, OCH3), 5.33–5.60 m (4H, NCH2, CH2), 5.95–
6.20 m (1H, CH), 7.02–7.73 m (7H, Harom), 8.81 d
(1H, 5-H). Found, %: C 73.45; H 5.94; N 11.78.
C22H21N3O2. Calculated, %: C 73.52; H 5.89; N 11.69.
2-Amino-1-(2-bromopropyl)-3-(2-oxo-2-phenyl-
ethyl)benzimidazolium bromide (XIa). Phenacyl
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 47 No. 9 2011

IMIDAZO[1,2-a]BENZIMIDAZOLE DERIVATIVES: XXIX.
1361
bromide, 1.1 g (5.5 mmol), was added to a solution of
1.3 g (5 mmol) of amine X [1] in 20 ml of acetone, and
the mixture was stirred and left overnight at room tem-
perature. The precipitate was filtered off and washed
with acetone. Yield 96%, mp 223–224°C (from aque-
ous EtOH). IR spectrum, ν, cm–1: 3152, 3327 (NH2),
1690 (C=O), 1663 (C=N), 1630, 1603, 1524, 1492,
1467 (C=C). Found, %: C 47.64; H 4.31; Br 35.19;
N 9.35. C18H19Br2N3O. Calculated, %: C 47.71;
H 4.23; Br 35.26; N 9.27.
CH2CO, J = 4.8 Hz), 6.58–7.00 m (4H, Harom), 7.40–
7.66 m (3H, Harom), 7.98–8.08 m (2H, 5-H, 8-H).
Found, %: C 74.30; H 5.82; N 14.35. C18H17N3O. Cal-
culated, %: C 74.21; H 5.88; N 14.42.
REFERENCES
1. Anisimova, V.A. and Tolpygin, I.E., Russ. J. Org.
Chem., 2011, vol. 47, p. 1346.
2. Spasov, A.A., Iezhitsa, I.N., Bugaeva, L.I., and Anisi-
mova, V.A., Khim.-Farm. Zh., 1999, vol. 33, no. 5, p. 6.
2-[3-(2-Bromopropyl)-2-imino-2,3-dihydrobenz-
imidazol-1-yl]-1-phenylethanone (XII). Bromide XI,
1.8 g (4 mmol), was treated with 20 ml of 22% aque-
ous ammonia at 20–25°C. After 3 h, the precipitate
was filtered off, washed with water, and dried in air.
Yield 1.4 g (92%), mp 76–78°C (from EtOAc). IR
spectrum, ν, cm–1: 3285 (NH), 1670 (C=O), 1620,
3. Anisimova, V.A., Osipova, V.V., Kuzmenko, T.A.,
Caignard, D.-H., Renard, P., and Manechez, D., FR
Patent no. 2765223, 1998; Bull., 1998, no. 98/53;
WO 99/00390.
4. Anisimova, V.A., Tolpygin, I.E., Minkin, V.I., Spa-
sov, A.A., Stepanov, A.V., Ar’kova, N.V., Naumen-
ko, L.V., and Petrov, V.I., Russian Patent no. 2290404,
2006; Byull. Izobret., 2006, no. 36.
1
1560, 1495, 1475, 1435 (C=C, C=N). H NMR spec-
5. Anisimova, V.A., Galenko-Yaroshevskii, A.P., Min-
kin, V.I., Tolpygin, I.E., Spasov, A.A., Varlashkina, I.A.,
Piskunov, A.V., Lugovaya, I.A., and Futoryan-
skaya, T.N., Russian Patent no. 2314312, 2008; Byull.
Izobret., 2008, no. 1.
6. Anisimova, V.A., Levchenko, M.V., Kovalev, G.V., Spa-
sov, A.A., Dudchenko, G.P., Antonyan, S.G., Bessud-
nova, N.V., and Libinzon, R.E., Khim.-Farm. Zh., 1987,
vol. 21, no. 3, p. 313.
7. Pozharskii, A.F., Anisimova, V.A., and Tsupak, E.B.,
Prakticheskie raboty po khimii geterotsiklov (Labo-
ratory Works on the Chemistry of Heterocycles),
Rostov-on-Don: Rostov. Gos. Univ., 1988, p. 14.
8. Simonov, A.M. and Anisimova, V.A., Khim. Geterotsikl.
Soedin., 1968, p. 1102.
trum (CDCl3), δ, ppm: 1.74 d (3H, CH3, J = 6.7 Hz),
4.00–4.23 m (2H, CH2), 4.37–4.52 m (1H, CH), 5.27 s
(2H, CH2CO), 6.67 m (1H, Harom), 6.88–7.04 m (3H,
Harom), 7.45–7.68 m (3H, Harom), 8.04 d (2H, 5-H, 8-H,
J = 7.2 Hz). Found, %: C 58.00; H 4.94; Br 21.54;
N 11.20. C18H18BrN3O. Calculated, %: C 58.08;
H 4.87; Br 21.46; N 11.29.
2-(2-Methyl-2,3-dihydroimidazo[1,2-a]benzimid-
azol-9-yl)-1-phenylethanone (XIII). A mixture of
0.74 g (2 mmol) of imine XII and 10 ml of acetonitrile
was heated for 5–6 h under reflux. The mixture was
evaporated, and the residue, compound XIII hydro-
bromide, was recrystallized from ethanol. Yield 0.7 g
(94%), mp 223–224°C.
9. Anisimova, V.A. and Simonov, A.M., Khim. Geterotsikl.
Soedin., 1976, p. 121.
10. Anisimova, V.A., Cand. Sci. (Chem.) Dissertation,
Free base XIII was isolated by treatment of its
hydrobromide with 22% aqueous ammonia, followed
by extraction with chloroform. Evaporation of the
extract gave yellowish crystals. Yield 96%, mp 133–
134°C (from MeCN). IR spectrum, ν, cm–1: 1695
(C=O), 1640, 1585, 1475, 1445 (C=C, C=N). 1H NMR
spectrum (CDCl3), δ, ppm: 1.39 d (3H, CH3, J =
6.5 Hz), 3.41 t (1H, 3-Hax, J = 7.9 Hz), 4.03 t (1H,
3-Heq, J = 8.5 Hz), 4.53–4.68 m (1H, CH), 5.21 d (2H,
Rostov-on-Don, 1973.
11. Pozharskii, A.F., Teoreticheskie osnovy khimii getero-
tsiklov (Theoretical Foundations of the Chemistry of
Heterocycles), Moscow: Khimiya, 1985, p. 145.
12. Anisimova, V.A., Avdyunina, N.I., Pozharskii, A.F.,
Simonov, A.M., and Talanova, L.N., Khim. Geterotsikl.
Soedin., 1980, p. 528.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 47 No. 9 2011