Studies of imidazo[1,2-a]benzimidazoles 32. Synthesis and properties of 2,3-dihydroimidazo-and 2,3,4,10-tetrahydropyrimido[1,2-a]benzimidazol-9(10)- ylacetic acids

Article abstract of DOI:10.1007/s10593-014-1427-1

Reaction of unsubstituted 2,9-dihydro-3H-imidazo- and 2,3,4,10- tetrahydropyrimido[1,2-a]benz-imidazoles with haloacetates has given hetaryl-9(10)-acetates. The basic and acid hydrolysis of these esters yields the corresponding acids. The zwitterionic structure of the acids obtained has been proved. They were also prepared by the direct alkylation of unsubstituted azaheterocycles using sodium chloroacetate or by hydrolysis of the corresponding acetonitriles. The synthesized esters readily undergo aminolysis and hydrazinolysis.

Full text of DOI:10.1007/s10593-014-1427-1

Chemistry of Heterocyclic Compounds, Vol. 49, No. 12, March, 2014 (Russian Original Vol. 49, No. 12, December, 2013)
STUDIES OF IMIDAZO[1,2-a]BENZIMIDAZOLES
32*. SYNTHESIS AND PROPERTIES OF 2,3-DIHYDROIMIDAZO-
AND 2,3,4,10-TETRAHYDROPYRIMIDO[1,2-a]BENZIMIDAZOL-
9(10)-YLACETIC ACIDS
V. A. Anisimova1**, I. E. Tolpygin1, and O. I. Askalepova2
Reaction of unsubstituted 2,9-dihydro-3H-imidazo- and 2,3,4,10-tetrahydropyrimido[1,2-a]benz-
imidazoles with haloacetates has given hetaryl-9(10)-acetates. The basic and acid hydrolysis of these
esters yields the corresponding acids. The zwitterionic structure of the acids obtained has been proved.
They were also prepared by the direct alkylation of unsubstituted azaheterocycles using sodium
chloroacetate or by hydrolysis of the corresponding acetonitriles. The synthesized esters readily
undergo aminolysis and hydrazinolysis.
Keywords: amides, betaines, 2,9-dihydro-3H-imidazo[1,2-a]benzimidazoles, hetarylacetic acids,
hydrazides, 2,3,4,10-tetrahydropyrimido[1,2-a]benzimidazoles, basicity, protolytic equilibrium.
Interest in an annelated benzimidazole system with a common nitrogen atom is due to their high
biological activity and their range of observed action (spasmolytic, antiaggregation, hypotensive, antioxidant,
hypoglycemic etc.) [2-4].
One of the most efficient routes for increasing the physiological action of medications is their structural
modification through the introduction of fragments of aliphatic acids and their derivatives into the
heteroaromatic ring [5-10]. Azaheterocyclic structures containing a carboxyalkyl substituent at an endocyclic
nitrogen atom with a structural similarity to amino acids are promising for study [11-13].
However, the direction of the synthetic work in this area needs detailed knowledge of the structural and
chemical properties of the synthesized compounds. In many cases it is determined by which tautomeric form
these compounds exist in. The study of the equilibrium in systems able to form zwitterionic species plays a
special role [14, 15]. In a number of cases, such as decarboxylation, amidation, polymerization etc., reaction can
occur via zwitterionic structures [16-18].
_______
*For Communication 31, see [1].
**To whom correspondence should be addressed, e-mail: anis@ipoc.sfedu.ru.
1Scientific-Research Institute of Physical and Organic Chemistry, Southern Federal University, 194/2 Stachki
Ave., Rostov-on-the-Don 344090, Russia.
2Chemistry Faculty, Southern Federal University, 7 Zorge St., Rostov-on-the-Don 344090, Russia; e-mail:
ask-olga@yandex.ru.
_________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 12, pp. 1887-1895, December, 2013.
Original article submitted October 5, 2013.
1748
0009-3122/14/4912-1748©2014 Springer Science+Business Media New York

In connection with these factors and with the aim of a study of the tautomeric equilibrium in
hetarylacetic acids we have treated the 2,9-dihydro-3H-imidazo- and 2,3,4,10-tetrahydropyrimido[1,2-a]benz-
imidazoles 1, 2 with alkylhaloacetates to give the 9(10)-alkoxycarbonylmethyl derivatives 3-8 of these hetero-
cycles. Using acid or base agents they are readily converted to the free acids.
The reactions of the tricycles 1, 2 with haloesters can be carried out in different solvents (acetone,
toluene, or DMF) but also in an excess of the haloester itself. Since the starting tricyclic systems exist in the 1H-
isomer form the alkylation under neutral conditions occurs at position 9(10) of the heterocycles [19].
The IR spectra of the salts 3-8 show absorption bands typical of the stretching vibrations of a C=O
group (1725-1744 cm-1) and a C=N group (1652-1675 cm-1). The 1H NMR spectra show a typical singlet signal
for the CH2 group of the alkoxycarbonylmethyl fragment at 5.17-5.32 ppm.
Hydrolysis of esters 3-8 using concentrated HCl gives the acid hydrochlorides 9, 10.
The free acids 11, 12 can be prepared by the basic hydrolysis of esters 3-8 using sodium carbonate in
dilute ethanol or by treating the hydrochlorides 9, 10 with ammonia solution. Acids 11, 12 can also be
synthesized directly by treating the tricyclic systems 1, 2 with sodium chloroacetate [20].
The IR spectra of compounds 9, 10 show an absorption for a carbonyl group at 1739 and 1746 cm-1
while in the spectra of the acids 11, 12 it is seen at 1660 and 1672 cm-1. A such shift of the absorption band to
lower frequencies and the marked broadening of the OH group band to 2200-3500 cm-1 points to the formation
of a zwitterionic structure [21]. Additionally, it was found that a change from the hydrochlorides 9, 10 to the
free acids 11, 12 caused a high-field shift of 0.7-0.8 ppm for the CH2CO group signals in their 1H NMR spectra.
1) conc. HCl, , 24 h;
2) NH4OH
ClCH2CN
( )n MeCN
–
ClCH2CO2 Na+
( )n
( )n
N
N
N
N
N
N
, 5–6 h
N
H
N
N
N
·HCl
CN
OH
1, 2
13, 14
Na2CO3
11, 12
A
O
XCH2CO2R
H2O
EtOH
3–4 h, 
( )n
( )n
N
N
(from 3, 4)
( )n
N
N
N
R1 NH, 
+
N
2
N
N
H
O
NR12
·HX
OR
conc. HCl
, 2–4 h
O
O
15, 16
3–8
B
11, 12
O
N2H4·H2O
, 15–20 min
(from 3, 4)
NH4OH
( )n
( )n
( )n
N
N
N
ArCHO
N
N
N
EtOH, 
15–20 min
N
N
N
·HCl
OH
H
N
H
N
N
NH2
Ar
O
19, 20
O
O
9, 10
17, 18
3, 4 R = Me; 5, 6 R = Et; 7, 8 R = n-Bu; 15 R1 = H; 16 R1+R1 = (CH2CH2)2O;
19 Ar = 2-HO-3,5-(O2N)2C6H2; 20 Ar = anthracen-9-yl;
1, 3, 5, 7, 9, 11, 13, 15, 17, 19 n = 1; 2, 4, 6, 8, 10, 12, 14, 16, 18, 20 n = 2; 3–6 Х = Br, 7, 8 Х = Cl
Methods of preparing different derivatives of the acids 11, 12 were also studied. The most convenient
route for preparing the hetaryl-substituted acetonitriles 13, 14 is the reaction of compounds 1, 2 with chloro-
1749

acetonitrile when heated in MeCN, toluene, or DMF. The introduction of a cyanomethyl fragment is confirmed
by the appearance in the 1H NMR spectra of the additional CH2 group signal as a singlet at 5.72 and 5.79 ppm,
respectively. Acid hydrolysis of nitriles 13, 14 using conc. HCl and subsequent treatment with an ammonia
solution give the acids 11, 12.
The esters 3, 4 react with a concentrated ammonia solution and morpholine to give the amides 15, 16.
Brief heating of esters 3, 4 with hydrazine hydrate for 15-20 min gives the acid hydrazides 17, 18. The IR
spectra of compounds 17, 18 show a carbonyl group absorption band and deformation vibrations of the NH
group at 1674, 1678 and 1627, 1631 cm-1, respectively. The NH2 group stretching vibrations are seen as two
bands at 3161-3312 cm-1. The hydrazides 17, 18 readily condense with aromatic aldehydes to give the
hydrazones 19, 20.
The electron absorption spectra of the ester hydrobromides 3, 4 show a strong band (log  ~ 4.5) at
205 nm. A small bathochromic shift to 209 nm is seen for the hydrochlorides 9, 10. In the long wavelength
region of their electronic spectra the salts 3, 4, 9, 10 show absorption bands with two maxima at 275-285 nm
(log  ~ 3.6).
The electronic spectra of compounds 3, 4, 9-12 do not show a significant change over the pH range 1-7.
Neutralization of the hydrobromides of esters 3, 4, the acid hydrochlorides 9, 10, and the acids 11, 12 show the
disappearance of the band at 275-285 nm and the appearance of a new band maximum with log  ~ 4.0 at
298 nm. The electronic spectra of the ester hydrobromides 3, 4 and acids 11, 12 are identical pointing to the
existence of the free acids 11, 12 as zwitterionic form B in their solutions.
The marked differences in the electronic absorption spectra with protonation and deprotonation of the
pyridine nitrogen atom allows a spectrophotometric determination of their basicity constant [22]. The protolytic
equilibrium constants (pKa) of the esters 3, 4 were 8.27 and 9.61, respectively. This difference can be explained
by both changes in their steric structure and the effect of the substituents at the nitrogen atoms and also by the
efficiency of solvation of the protonated forms.
The protolytic equilibrium constants for compounds 3, 4, 9, 10 were determined by potentiometric
titration using NaOH solution in a mixture of water and ethanol (4:5 v/v) with constant solution ionic strength
( = 0.1, NaCl). The calculation was carried out using the formula (1) which was obtained as a combined
solution of the material balance equation and the electroneutrality equation [23]:
(1 – a) · CR – [H+] + [OH–]
(1)
pKa = pH + lg
,
a · CR + [H+] – [OH–]
where Ka is the dissociation constant, a is the degree of neutralization, and CR is the overall concentration.
Analysis of the obtained data in Table 1 shows that the pKa of esters 3, 4 (8.38 and 9.72) and the second
dissociation constants pKa2 of acids 9, 10 (9.94 and 11.40) characterize the basicity of the pyridine nitrogen
atom of the heterocycles [24, 25] while the pKa1 values for compounds 9, 10 (3.08 and 3.09) are for the mobile
hydrogen atom of the carboxyl group. Similar values of the dissociation constants are also typical of guanidine
alkanoic acids. The marked difference between the first and second ionization constants for the ampholytes
indicates their existence in a zwitterionic form. The content of the zwitterionic form at the isoelectric point
depends on the tautomeric equilibrium constant and on the ratio of ionization constants [26]. The content of
zwitterionic forms depends on the medium pH and can be calculated using the formula (2).
100
[A+]max, K
=
,
[H+]
Ka2
[H+]
m
(2)
1 +
+
Ka1
where Ka1 and Ka2 are the equilibrium constants, [H]+ is the hydrogen ion concentration at the isoelectric point,
and Km = [A ]/[A] ([A] is the concentration of the molecular form of the ampholyte).
1750

Calculation of the zwitterionic form content values dependent upon pH have shown that, in the pH
region 4-8, compound 11 at least 90% or more exists in the zwitterionic form whereas for compound 12 this
range is greater (pH 4-10). The greater the difference in the Ka1 and Ka2 values the broader is the range of
existence of the zwitterionic form (Fig. 1).
TABLE 1. Protolytic Equilibrium Constants for Compounds 3, 4, 9, 10
Compound
Protolytic equilibrium constants
pKа = 8.38
pKа = 9.72
3
4
pKа1 = 3.08; pKа2 = 9.94
pKа1 = 3.09; pKа2 = 11.40
9
10
Fig 1. Zwitterionic form content in solutions of compound 11 (–––) and 12 (-----) depending on the medium pH
(c = 2×10-4 mol/l; H2O–EtOH 4:5;  = 0.1)
Hence methods have been developed for the synthesis of ester, amide, nitrile, hydrazide, and hydrazone
derivatives of 2,3-dihydroimidazo- and 2,3,4,10-tetrahydropyrimido[1,2-a]benzimidazol-9(10)-ylacetic acids,
based on the results of our study. Acid dissociation constants have been determined by potentiometric titration
and the range of medium acidity in which the investigated acids exist as a zwitterionic form has been described.
EXPERIMENTAL
IR spectra were recorded on a Varian Excalibur 3100 FT-IR spectrometer by the method of attenuated
1
total reflectance using a ZnSe crystal. Н NMR spectra were recorded on a Varian Unity 300 (300 MHz)
in DMSO-d6 using the residual signals of the solvent as a reference (δ 2.50 ppm). UV-vis spectra were recorded
on a Varian Cary 100 spectrometer. Elemental analysis was carried out on an EuroVector EA-3000 instrument.
The melting points were determined in glass capillaries on a PTP (М) apparatus. The progress of reactions and
the purity of the synthesized compounds were controlled by TLC on Silufol UV-254 plates, eluent CHCl3, with
visualization by iodine vapor in a wet chamber. The starting compounds 1 and 2 were obtained by known
methods [27, 28].
Methyl 2,3-Dihydro-9Н-imidazo[1,2-а]benzimidazol-9-ylacetate Hydrobromide (3). Methyl
bromoacetate (1.0 ml, 11 mmol) was added to a hot solution of 2,9-dihydro-3Н-imidazo[1,2-а]benzimidazole
(1) (1.6 g, 10 mmol) in acetone (60-70 ml). The mixture was refluxed with stirring for 2.5-3.0 h. Already after
15-20 min, precipitation of snow-white crystals of the product in the form of salt could be observed. After the
completion of the reaction, the mixture was left overnight at 5-8°С. The precipitate was filtered off and washed
thoroughly with acetone. Yield 2.6 g (84%), mp 203-204°С (decomp., EtOH). IR spectrum, ν, cm-1: 1198 (С–О),
1751

1675 (С=N), 1738 (C=O), 2600-3200 (N+H). 1Н NMR spectrum, δ, ppm (J, Hz): 3.77 (3Н, s, ОСН3); 4.29-4.50
(4H, m, 2,3-СН2); 5.18 (2H, s, NCH2CO); 7.28-7.40 (2H, m, Н-6,7); 7.50 (1H, dd, 3J = 7.5, 4J = 1.5, Н-5); 7.61
3
4
(1H, dd, J = 7.6, J = 1.5, Н-8); 9.73 (1Н, br. s, N+H). Found, %: С 46.25; Н 4.46; Br 25.55; N 13.51.
C12H14BrN3O2. Calculated, %: С 46.17; Н 4.52; Br 25.60; N 13.46.
Methyl 3,4-Dihydropyrimido[1,2-а]benzimidazol-10(2H)-ylacetate Hydrobromide (4). A mixture
of 2,3,4,10-tetrahydropyrimido[1,2-а]benzimidazole (2) (1.7 g, 10 mmol) and methyl bromoacetate (1.4 ml,
15 mmol) in anhydrous DMF (5 ml) was heated to reflux and kept refluxing for 10 min, then heated on a boiling
water bath for 30 min. The reaction mixture was left overnight at room temperature then diluted with a mixture
of anhydrous Et2O (15 ml) and anhydrous acetone (5 ml). After 1 h, the precipitate was filtered off, washed with
acetone and ether. Yield 2.9 g (88%), mp 211-212°С (decomp., MeCN). IR spectrum, ν, cm-1: 1200 (С–О), 1660
(С=N), 1731 (C=O), 2650-3100 (N+H). 1Н NMR spectrum, δ, ppm (J, Hz): 2.20 (2Н, quin, J = 7.0, 3-СН2); 3.60
(2Н, t, J = 7.0, 4-СН2); 3.77 (3Н, s, ОСН3); 4.20 (2Н, t, J = 7.0, 2-СН2); 5.20 (2Н, s, NСН2СО); 7.25-7.35 (2Н,
m, H-7,8); 7.47-7.58 (2Н, m, H-6,9); 9.75 (1Н, s, N+H). Found, %: С 47.79; Н 5.00; Br 24.44; N 12.94.
C13H16BrN3O2. Calculated, %: С 47.87; Н 4.94; Br 24.50; N 12.88.
Ethyl 2,3-dihydro-9Н-imidazo[1,2-а]benzimidazol-9-ylacetate hydrobromide (5) was synthesized
from the tricyclic compound 1 and ethyl bromoacetate in DMF under the conditions used to synthesize
compound 3. Yield 98%, mp 210-211°С (2-PrOH). IR spectrum, ν, cm-1: 1191 (С–О), 1668 (С=N), 1725 (C=O),
1
2600-3100 (N+H). Н NMR spectrum, δ, ppm (J, Hz): 1.26 (3Н, t, J = 7.3, ОСН2СН3); 4.22 (2Н, q, J = 7.3,
ОСН2СН3); 4.30-4.49 (4Н, m, 2,3-СН2); 5.17 (2Н, s, NСН2СО); 7.26-7.39 (2Н, m, Н-6,7); 7.49 (1H, dd,
3J = 7.3, 4J = 1.7, Н-5); 7.60 (1H, dd, 3J = 7.3, 4J = 1.7, Н-8); 9.80 (1Н, br. s, N+H). Found, %: С 47.96; Н 4.88;
Br 24.44; N 12.95. C13H16BrN3O2. Calculated, %: С 47.87; Н 4.94; Br 24.50; N 12.88.
Ethyl 3,4-Dihydropyrimido[1,2-а]benzimidazol-10(2H)-ylacetate Hydrobromide (6). Ethyl
bromoacetate (1.3 ml, 12 mmol) was added with vigorous stirring to a solution of compound 2 (1.7 g, 10 mmol)
in abs. PhMe (50 ml), prepared under heating, and the stirring was continued until a precipitate had formed
(1.5-2.0 h). Then the mixture was heated on a boiling water bath for 2 h. On the next day, the precipitate was
filtered off and washed with petroleum ether. Yield 3.2 g (95%), mp 231-232°С (MeCN). IR spectrum, ν, cm-1:
1217 (С–О), 1656 (С=N), 1739 (C=O), 2650-3150 (N+H). 1Н NMR spectrum, δ, ppm (J, Hz): 1.26 (3Н, t, J = 7.0,
ОСН2СН3); 2.16 (2Н, quin, J = 6.8, 3-СН2); 3.56 (2Н, t, J = 5.5, 4-СН2); 4.14-4.27 (4Н, m, 2-СН2, ОСН2СН3);
5.17 (2Н, s, NСН2СО); 7.29-7.40 (2Н, m, Н-7,8); 7.53-7.65 (2Н, m, Н-6,9); 9.63 (1Н, s, N+H). Found, %:
С 49.36; Н 5.42; Br 23.54; N 12.28. C14H18BrN3O2. Calculated, %: С 49.43; Н 5.33; Br 23.49; N 12.35.
Butyl 2,3-Dihydro-9Н-imidazo[1,2-а]benzimidazol-9-ylacetate Hydrobromide (7). A mixture of
compound 1 (1.6 g, 10 mmol) and butyl chloroacetate (7 ml) was heated on an oil bath at 110-120°С until full
conversion of the starting compound (2-3 h, TLC control, Silufol, СНCl3). Then the reaction mixture was
evaporated to dryness in vacuo, and the residue was recrystallized from MeCN. Yield 2.3 g (75%), mp 196-
1
197°С (decomp.). IR spectrum, ν, cm-1: 1205 (С–О), 1671 (С=N), 1738 (C=O), 2700-3100 (N+H). Н NMR
spectrum, δ, ppm (J, Hz): 1.00 (3Н, t, J = 7.0, O(CH2)3СН3); 1.33-1.44 (2Н, m, O(CH2)2СН2СН3); 1.49-1.62
(2Н, m, OCH2СН2СН2СН3); 4.08 (2Н, t, J = 6.4, ОСН2); 4.25-4.47 (4Н, m, 2,3-СН2); 5.17 (2Н, s, NСН2СО);
7.20-7.37 (2H, m, H-6,7); 7.48 (1H, dd, 3J = 7.1, 4J = 1.4, H-5); 7.57 (1H, dd, 3J = 7.1, 4J = 1.4, H-8); 9.91 (1Н,
s, N+H). Found, %: С 58.22; Н 6.47; Cl 11.38; N 13.61. C15H20BrN3O2. Calculated, %: С 58.16; Н 6.51;
Cl 11.44; N 13.56.
Butyl 3,4-dihydropyrimido[1,2-а]benzimidazol-10(2H)-ylacetate hydrobromide (8) was obtained
similarly to the synthesis of compound 6 by heating the tricyclic compound 2 with an excess of butyl
chloroacetate. Yield 61%, mp 170-171°С (decomp., MeCN). IR spectrum, ν, cm-1: 1210 (С–О), 1652 (С=N),
1
1744 (C=O), 2700-3150 (N+H). Н NMR spectrum, δ, ppm (J, Hz): 1.02 (3Н, t, J = 7.2, O(CH2)3СН3);
1.36-1.45 (2Н, m, O(CH2)2СН2СН3); 1.52-1.60 (2Н, m, OCH2СН2СН2СН3); 2.19 (2Н, quin, J = 6.7, 3-СН2);
3.63 (2Н, t, J = 5.8, 4-СН2); 4.02-4.30 (4Н, m, 2-СН2, ОСН2); 5.20 (2Н, s, NСН2СО); 7.24-7.39 (2Н, m,
H-7,8); 7.50-7.60 (2Н, m, H-6,9); 9.80 (1Н, br. s, N+H). Found, %: С 59.42; Н 6.79; Cl 11.02; N 13.04.
C16H22ClN3O2. Calculated, %: С 59.35; Н 6.85; Cl 10.95; N 12.98.
1752

2,3-Dihydro-9Н-imidazo[1,2-а]benzimidazol-9-ylacetic Acid Hydrochloride Hydrate (9). A
solution of ester 3 (2.0 g, 7.1 mmol) in concentrated HCl (10 ml) was refluxed for 2 h. After cooling, the
mixture was put into refrigerator (3-4°С). On the next day, the precipitated acid hydrochloride 9 was filtered
off, washed with acetone and Et2O. Recrystallization from water gives the corresponding monohydrate. Yield
1.5 g (77%), mp 274-275°С (decomp.). IR spectrum, ν, cm-1: 1204 (С–О), 1660 (С=N), 1739 (C=O), 2650-3200
(OH, N+H). 1Н NMR spectrum, δ, ppm (J, Hz): 4.28-4.47 (4Н, m, 2,3-СН2); 5.16 (2Н, s, NСН2СО); 7.25-7.38
3
4
3
4
(2Н, m, H-6,7); 7.47 (1Н, dd, J = 7.6, J = 1.5, H-5); 7.57 (1Н, dd, J = 7.6, J = 1.5, H-8); 10.38 (1Н, br. s,
N+H); 13.60 (1Н, br. s, COОH). Found, %: С 48.55; Н 5.11; Cl 13.14; N 15.54. C11H11N3O2·HCl·Н2О.
Calculated, %: С 48.63; Н 5.19; Cl 13.05; N 15.47.
3,4-Dihydropyrimido[1,2-а]benzimidazol-10(2H)-ylacetate Hydrochloride (10). A solution of ester
4 (1.9 g, 6 mmol) in concentrated HCl (10 ml) was refluxed for 3-4 h and evaporated in vacuo to dryness. The
residue was recrystallized from 2-PrOH. Yield 1.3 g (81%), mp 287-289°С (decomp.). IR spectrum, ν, cm-1:
1
1196 (С–О), 1667 (С=N), 1746 (C=O), 2400-3200 (OH, N+H). Н NMR spectrum, δ, ppm (J, Hz): 2.13 (2Н,
quin, J = 6.7, 3-СН2); 3.53 (2Н, t, J = 5.1, 4-СН2); 4.15 (2Н, t, J = 5.7, 2-СН2); 5.10 (2Н, s, NСН2СО);
7.20-7.40 (2Н, m, H-7,8); 7.48-7.67 (2Н, m, H-6,9); 9.87 (1Н, s, N+H); 13.50 (1Н, br. s, COОН). Found, %:
С 53.89; Н 5.21; Cl 13.32; N 15.62. C12H14ClN3O2. Calculated, %: С 53.84; Н 5.27; Cl 13.24; N 15.70.
2,3-Dihydro-9Н-imidazo[1,2-а]benzimidazol-9-ylacetic Acid (11). Hydrochloride 9 (1.10 g, 4 mmol)
was dissolved upon heating in EtOH (10 ml). To the hot solution, 22% NH4OH solution (10 ml) was added. The
reaction mixture was cooled, and after 30 min the precipitate was filtered off, washed with acetone, dried in air,
and recrystallized from 90% EtOH. Yield 0.85 g (98%), mp 269-270°С (decomp.). IR spectrum, ν, cm-1: 1600
1
(С=N), 1660 (C=O), 2200-3500 (OH, N+H). Н NMR spectrum, δ, ppm: 4.22-4.41 (6Н, m, 2,3-СН2,
NСН2СО); 7.17-7.29 (2Н, m, Н-6,7); 7.34-7.43 (2Н, m, Н-5,8). Found, %: С 60.75; Н 5.04; N 19.42.
C11H11N3O2. Calculated, %: С 60.82; Н 5.10; N 19.34.
Acid 11 can also be obtained through the hydrolysis of the corresponding nitrile. A solution of nitrile
hydrochloride 13 (1.2 g, 5 mmol) in concentrated HCl (20 ml) was refluxed for 20 h, evaporated to a minimum
volume, neutralized to рН 4-5 with 22% NH4OH solution and cooled. After 3-4 h, the precipitated acid was
filtered off and washed with acetone. Yield 0.7 g (64%), mp 269-270°С (decomp., Н2О). The spectral
characteristics are identical to those above.
Compound 11 can also be obtained through the hydrolysis of esters 3, 5, 7 according to the procedure
given below for the synthesis of compound 12 from esters 4, 6, 8, as well as by direct alkylation of the
unsubstituted heterocycle 1 with sodium chloroacetate following the procedure for the alkylation of compound 2
(see below). The obtained product was identical to that described above.
3,4-Dihydropyrimido[1,2-а]benzimidazol-10(2H)-ylacetic Acid Hydrate (12). A mixture of ester 4,
6, or 8 (5 mmol), Na2CO3 (1.10 g, 10 mmol), and 50% EtOH (20 ml) was refluxed until the complete hydrolysis
of the ester group was achieved (3-4 h, TLC control). The solution was filtrated, and the filtrate was evaporated
to dryness. The residue was recrystallized from 95% EtOH. Yield 72-80% as monohydrate, mp 236-237°С
1
(decomp., EtOH). IR spectrum, ν, cm-1: 1605 (С=N), 1672 (C=O), 2400-3400 (OH, N+H). Н NMR spectrum,
δ, ppm (J, Hz): 2.14 (2Н, quin, J = 6.8, 3-СН2); 3.53 (2Н, t, J = 5.4, 4-СН2); 4.15 (2Н, t, J = 5.9, 2-СН2); 4.48
(2Н, s, NСН2СО); 7.23-7.32 (2Н, m, Н-7,8); 7.37-7.52 (2Н, м, Н-6,9); 8.60 (1Н, br. s, ОН (N+H)). Found, %:
57.90; Н 5.99; N 16.91. C12H15N3O3. Calculated, %: С 57.82; Н 6.07; N 16.86.
The interaction of concentrated HCl with a suspension of the obtained acid 12 in acetone led to
hydrochloride 10, identical with that described above. Yield 94%, mp 287-289°С (decomp., 2-PrOH). In turn, a
treatment of salt 10 with 22% ammonia solution, using the procedure described above for the synthesis of
compound 11 from salt 9, resulted in acid 12 in its neutral form.
Acid 12 has also been obtained by a direct alkylation of unsubstituted tricyclic compound 2 with
sodium chloroacetate. Sodium chloroacetate (1.75 g, 15 mmol) was added to a solution of compound 2 (1.70 g,
10 mmol) in H2O–DMF, 1:2 (20 ml) and refluxed fot 10 h. The reaction mixture was then evaporated to dryness
under reduced pressure, cold water (10 ml) and 22% ammonia solution (2 ml) were added to the residue; the
1753

contents was carefully mixed and cooled. The resulting precipitate was filtered off, washed with acetone, and
crystallized from EtOH. Yield 1.60 g (68%), mp 235-236°С (decomp., EtOH).
Acid 12 can also be obtained by acid hydrolysis of nitrile 14 (see the procedure for the synthesis of
compound 11 from nitrile 13). The obtained product was identical to that described above.
2,3-Dihydro-9Н-imidazo[1,2-а]benzimidazol-9-ylacetonitrile Hydrochloride (13). Freshly distilled
chloroacetonitrile (2.0 ml, 32 mmol) was added to a hot solution of tricyclic compound 1 (1.6 g, 10 mmol) in
MeCN (50 ml). The reaction mixture was refluxed for 5-6 h, cooled to 3-5°С, and left overnight. The precipitate
was separated by filtration, and thoroughly washed with cold MeCN and acetone. Yield 2.0 g (85%), mp
272-274°С (decomp., EtOH). IR spectrum, ν, cm-1: 1680 (С=N), 2450-3150 (N+H). 1Н NMR spectrum, δ, ppm
(J, Hz): 4.25-4.44 (4Н, m, 2,3-СН2); 5.72 (2Н, s, NСН2СN); 7.31-7.66 (4Н, m, Н Ar); 10.66 (1Н, s, N+H).
Found, %: С 56.38; Н 4.66; Cl 15.02; N 23.94. C11H11ClN4. Calculated, %: С 56.30; Н 4.72; Cl 15.11; N 23.87.
3,4-Dihydropyrimido[1,2-а]benzimidazol-10(2H)-ylacetonitrile hydrochloride (14) was obtained
from tricyclic compound 2 analogously to the synthesis of compound 13. Yield 88%, mp 286-288°С (decomp.,
1
EtOH). IR spectrum, ν, cm-1: 1668 (С=N), 2600-3150 (N+H). Н NMR spectrum, δ, ppm (J, Hz): 2.15 (2Н,
quin, J = 6.9, 3-СН2); 3.57 (2Н, t, J = 5.4, 4-СН2); 4.10 (2Н, t, J = 5.7, 2-СН2); 5.79 (2Н, s, NСН2СN);
7.35-7.44 (2Н, m, Н-7,8); 7.53-7.59 (1Н, m, Н-6); 7.62-7.69 (1Н, m, Н-9); 10.75 (1Н, s, N+H). Found, %:
С 58.04; Н 5.19; Cl 14.62; N 22.45. C12H13ClN4. Calculated, %: С 57.95; Н 5.27; Cl 14.25; N 22.53.
2-(2,3-Dihydro-9H-imidazo[1,2-а]benzimidazol-9-yl)acetamide Hydrochloride (15). A suspension
of ester 3 (1.6 g, 5 mmol) was refluxed in 22% ammonia solution (50 ml) for 10 h, evaporated under reduced
pressure, cooled, and acidified with concentrated HCl to рН 2-3. After 3-4 h, the resulting precipitate was
filtered off and washed with acetone. Yield 0.9 g (72%), mp 285-286°С (decomp., EtOH). According to its
spectral data, the product was identical to the compound obtained by the direct alkylation of heterocycle 1 with
chloroacetamide [9].
(3,4-Dihydropyrimido[1,2-а]benzimidazol-10(2H)-yl)-1-morpholinoethan-1-one (16). A solution of
ester 4 (1.7 g, 5 mmol) in morpholine (10 ml) was refluxed for 2 h and evaporated to dryness at reduced
pressure. The residue was treated with petroleum ether twice in order to remove the remaining morpholine,
dried, washed with water, and recrystallized from a small amount of MeCN or a large quantity of hexane. Yield
1.1 g (75%), mp 109-110°С (decomp.). According to its spectral data, the product was identical to the
compound obtained by the direct alkylation of tricyclic compound 2 with 2-chloro-1-(morpholin-4-yl)ethan-
1-one [9].
2,3-Dihydro-9Н-imidazo[1,2-а]benzimidazol-9-ylacetohydrazide (17). A mixture of ester 3 (1.00 g,
3 mmol) and N2H4·H2O (10 ml) was refluxed for 10-15 min. The solution was evaporated on a rotary
evaporator, cooled, and the residue was crystallized from 90% EtOH. Yield 0.53 g (76%), mp 256-257°С
(decomp., H2O). IR spectrum, ν, cm-1: 1627 (N–H), 1632 (С=N), 1674 (C=O), 3021, 3161, 3263 (NH, NH2).
1Н NMR spectrum, δ, ppm (J, Hz): 2.91 (2Н, t, J = 6.3, 2-СН2); 3.72 (2Н, br. s, NН2); 3.81 (2Н, t, J = 6.3,
3-СН2); 4.42 (2Н, s, NСН2CO); 6.92-7.11 (4Н, m, Н Ar); 10.23 (1Н, s, CONH). Found, %: С 57.21; Н 5.62;
N 30.34. C11H13N5O. Calculated, %: С 57.13; Н 5.67; N 30.28.
3,4-Dihydropyrimido[1,2-а]benzimidazol-10(2H)-ylacetohydrazide (18) was obtained from ester 4
analogously to the synthesis of compound 17. Yield 80%, mp 234-235°С (decomp., EtOH). IR spectrum, ν, cm-1:
1
1631 (N–H), 1647 (С=N), 1678 (C=O), 3276, 3312 (NH, NH2). Н NMR spectrum, δ, ppm (J, Hz): 1.81 (2Н,
quin, J = 6.8, 3-СН2); 3.32 (2Н, t, J = 5.1, 4-СН2); 4.10 (2Н, t, J = 5.9, 2-СН2); 4.24 (2Н, br. s, NН2); 4.31 (2Н,
s, NСН2СО); 6.78-7.89 (4Н, m, Н Ar); 9.24 (1Н, br. s, СОNH). Found, %: С 58.84; Н 6.09; N 28.63.
C12H15N5O. Calculated, %: С 58.76; Н 6.16; N 28.55.
2-(2,3-Dihydro-9Н-imidazo[1,2-а]benzimidazol-9-yl)-N'-(2-hydroxy-3,5-dinitrobenzylidene)aceto-
hydrazide (19). 3,5-Dinitrosalicylic aldehyde (0.43 g, 2 mmol) was added to a solution of hydrazide 17 (0.46 g,
2 mmol) in EtOH (10 ml). The reaction mixture was refluxed for 15-20 min, cooled, and the resulting
precipitate was filtered off and washed with EtOH. Yield 0.76 g (89%), mp >295°С (decomp., 1-BuOH). IR
spectrum, ν, cm-1: 1228 (C–N), 1316, 1550 (N–O), 1615 (С=N), 1675 (C=O), 3225, 3264 (NH, OH). 1Н NMR
1754

spectrum, δ, ppm (J, Hz): 3.97 (2Н, t, J = 5.7, 2-СН2); 4.19 (2Н, t, J = 5.7, 3-СН2); 4.42 (2Н, s, NСН2СО);
6.83-7.11 (4Н, m, Н Ar); 7.82 (1Н, br. s, NH); 8.46-8.76 (2Н, m, H Ar); 10.27 (0.7H, s) and 10.31 (0.3Н, s,
N=CH–Ar); 13.28 (1Н, br. s, OH). Found, %: С 50.75; Н 3.61; N 23.12. C18H15N7O6. Calculated, %: С 50.83;
Н 3.55; N 23.05.
N'-(Anthracen-9-ylmethylidene)(3,4-dihydropyrimido[1,2-а]benzimidazol-10(2H)-yl)acetohydr-
azide (20) was obtained from compound 18 and anthracene-9-carbaldehyde analogously to the synthesis of
compound 19. Yield 81%, mp >280°С (decomp., 1-BuOH). IR spectrum, ν, cm-1: 1228 (C–N), 1621 (С=N),
1668 (C=O), 3178 (NH). 1Н NMR spectrum, δ, ppm (J, Hz): 1.82 (2Н, quin, J = 6.7, 3-СН2); 3.80 (2Н, t, J = 5.1,
4-СН2); 4.61 (2Н, t, J = 5.4, 2-СН2); 5.00 (2Н, s, NСН2СО); 6.87-7.06 (4Н, m, Н Ar); 7.53-7.77 (5Н, m, Н Ar,
NH); 8.17 (2Н, d, J = 8.1, Н Ar); 8.60-8.75 (3Н, m, Н Ar); 9.26 (0.6H, s) and 9.43 (0.4Н, s, N=СH–Ar). Found,
%: С 74.75; Н 5.42; N 16.08. C27H23N5O. Calculated, %: С 74.81; Н 5.35; N 16.15.
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