Synthesis of some 1- and 2-carboxyalkyl substituted benzimidazoles and their derivatives

Article abstract of DOI:10.1007/s11164-013-1067-6

Mono- and disubstituted benzimidazoles were synthesized during alkaline hydrolysis or reactions with ethyl chloroacetate of 1-phenyl substituted 4-(1H-benzimidazol-2-yl)-2-pyrrolidinones. The properties of the synthesized ethyl-[2-(1-(substituted phenyl)-

Full text of DOI:10.1007/s11164-013-1067-6

Res Chem Intermed
DOI 10.1007/s11164-013-1067-6
Synthesis of some 1- and 2-carboxyalkyl substituted
benzimidazoles and their derivatives
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Kristina Mickeviciene Ausra Voskiene
•
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Vytautas Mickevicius
Received: 5 December 2012 / Accepted: 21 January 2013
Ó The Author(s) 2013. This article is published with open access at Springerlink.com
Abstract Mono- and disubstituted benzimidazoles were synthesized during
alkaline hydrolysis or reactions with ethyl chloroacetate of 1-phenyl substituted
4-(1H-benzimidazol-2-yl)-2-pyrrolidinones. The properties of the synthesized ethyl-
[2-(1-(substituted phenyl)-5-oxopyrrolidinyl-3-yl)-1H-benzimidazolyl]ethanoates
have been investigated and their benzimidazolium chlorides, 1-carboxymethyl
benzimidazoles, condensation products of 2-{2-[1-(3-methylphenyl)-5-oxo-3-pyrro-
lidinyl]-1H-benzimidazol-1-yl}acetohydrazide with various aromatic aldehydes and
aliphatic ketones have been obtained.
Keywords Heterocycles ꢀ Benzimidazoles ꢀ Pyrrolidinone ꢀ Carbohydrazide ꢀ
Condensation
Introduction
Benzimidazole heterosystems are present in many natural and synthetic biological
activity structures and are of great interest in medical chemistry and pharmacology.
Benzimidazole derivatives are distinguished for antimicrobial [1–4], antifungal
[5–7], antiviral [8], anthelmintic [9, 10], antihypertensive [11], antihistaminic [12],
analgesic [13], and anti-HIV [14] actions. Also, some of benzimidazoles are used in
coordination chemistry [15, 16], in optoelectronics [17], etc. The aim of this study
was to synthesize new potentially bioactive benzimidazole derivatives or its
intermediates containing carboxyalkyl, hydrazone, pyrrole, and dimethylpyrazole
fragments.
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K. Mickeviciene ꢀ A. Voskiene ꢀ V. Mickevicius (&)
Department of Organic Chemistry, Kaunas University of Technology, Radvilenu pl. 19,
50254 Kaunas, Lithuania
e-mail: vymic@ktu.lt
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K. Mickeviciene et al.
4
2
1
O
R
3
NH2
NH2
O
O
N
1. NaOH,
, HCl
H
2. CH3COOH
OH
NH
R N
R N
N
N
HCl
O
N
H
2a-2c
HO
1a-1c
3a-3c
O
Cl
O
CH3
O
O
O
H
N
R N
R N
1. NaOH,
2. CH3COOH
R N
N
N
N
HClkonc
+
N
N
O
O
O
Cl-
4a-4c
5a-5c
HO
HO
6a-6c
O
H3C
R = a) 3-CH3-C6H4, b) 2,5-(CH3)2-C6H3, c) 2-CH3-5-CI-C6H3
Scheme 1 Synthesis of benzimidazole derivatives 2–6
Results and discussion
We report here on the synthesis of some new 2- and 1,2-substituted benzimidazoles
prepared from 5-oxo-1-phenyl-3-pyrrolidinecarboxylic acids. One of the methods
for the synthesis of a benzimidazole heterosystem is condensation of carboxylic
acids with 1,2-diaminobenzenes. The target compounds were synthesized by the
Phillips method (heating of both reagents in 4 M hydrochloric acid); we obtained a
sufficient yield of benzimidazoles (Scheme 1).
It is known that the 5-oxopyrrolidine cycle is not resistant to alkaline hydrolysis
[18, 19]. In the present work, sodium salts of 4-arylamino-3-(1H-benzimidazol-2-
yl)butanoic acids were formed by decomposition of the pyrrolidinone cycle of
1-aryl-3-(1H-benzimidazol-2-yl)-5-oxopyrrolidines 2a–2c in refluxing a 20 %
solution of sodium hydroxide. Acidification of the aqueous solutions of these salts
with acetic acid up to pH 6 gave stable 3-(1H-benzimidazol-2-yl)-4-arylaminob-
utanoic acids 3a–3c (Scheme 1). They were purified by a double precipitation from
alkaline solution with acetic acid.
The opposite reaction of cyclization of the open-chain 3a–3c compounds to 2a–2c
was also carried out by boiling c-amino acids 3a–3c in diluted hydrochloric acid and
subsequently neutralizing the reaction mixture with aqueous ammonia. The cyclic
compounds 2a–2c were obtained in a 91–95 % yield.
The structural changes of series 3 compounds have been revealed by comparison of
their 13C NMR spectra with those of the corresponding compounds 2 containing a
pyrrolidinone ring. The resonance at *175 ppm clearly shows the presence of an
open-chain compound. Chemical shifts of atoms C-2 and C-3 of these compounds are
quite close—the difference is only 1.4–1.7 ppm, while in cyclic compounds it reaches
up to 5–6.5 ppm. In 1H NMR spectra, 3-(1H-benzimidazol-2-yl)-4-(substituted
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Synthesis of 1- and 2-carboxyalkyl substituted benzimidazoles
phenylamino)butanoic acids a broad 3a–3c singlet of NH in the region of
5.57–5.98 ppm confirmed the existence of open chain compounds. The broad
absorption band characteristic of the NH and OH groups is observed in the region
2,840–3,430 cm-1 in the IR spectra of these compounds. It partially overlaps with the
absorbtion bands of the aromatic system.
We investigated the alkylation reaction of benzimidazoles 3 with ethyl
chloroacetate (Scheme 1). Substituted benzimidazole derivatives 4a–4c were
synthesized by alkylation of 1-aryl-3-(1H-benzimidazol-2-yl)-5-oxopyrrolidines
3a–3c with ethyl chloroacetate in toluene in the presence of potassium carbonate,
potassium hydroxide, and a catalytic amount of tetrabutylammonium iodide.
Hydrolysis of the synthesized esters 4a–4c was carried out in refluxing concentrated
hydrochloric acid. In these conditions, not only hydrolysis of the ester group took
place but the corresponding benzimidazolium chlorides 5a–c were also formed.
They were converted to the respective bases 6a–6c by heating quaternary salts in a
sodium hydroxide solution and then acidifying with acetic acid. Compounds 6a–6c
were purified by dissolving them in a sodium alkaline solution, filtrating the
solution, and acidifying the filtrate with acetic acid up to pH 6. The IR, 1H and 13
C
NMR and mass spectra were in agreement with the suggested structures of
compounds 4–6.
New hydrazones and azoles containing benzimidazole and pyrrolidinone moieties
were synthesized from 2-{2-[1-(3-methylphenyl)-5-oxo-3-pyrrolidinyl]-1H-ben-
zimidazol-1-yl}acetohydrazide (7) (Scheme 2). Carbohydrazide 7 was obtained by
reaction of the ethyl ester 4a with hydrazine hydrate in refluxing 2-propanol. The
hydrazones 8–12 were synthesized by condensation of carbohydrazide 7 with
1
aromatic aldehydes or ketones—acetone and ethylmethylketone. Analysis of H
NMR spectra of 1-aryl-3-arylidenehydrazinocarbonyl-5-oxopyrrolidines 8–12
showed that a mixture of E/Z rotamers exists in DMSO-d6 solutions in which
Z isomer predominates due to a hindered rotation around the CO–NH bond [20, 21].
During reactions of carbohydrazide 7 with 2,4-pentanedione or 2,5-hexanedione,
performed with refluxing 2-propanol in the presence of a catalytic amount of acetic
or hydrochloric acid, the N-substituted pyrrazole or pyrrole derivatives 13, 14 were
synthesized. The structure of these compounds authenticates the spectral data. For
example, the formation of a 2,5-methylpyrrole ring included in the 14 composition
is displayed by the double-intensity resonances of CH at 109.7 ppm, =C at
128.5 ppm, and CH3 at 11.0 ppm in 13C NMR spectra, and singlets at 2.01 ppm
1
(CH3), 5.65 ppm (=CH), and 11.20 ppm (NH) in H NMR spectra.
Conclusion
1-Phenyl substituted 4-(1H-benzimidazol-2-yl)-2-pyrrolidinones have been synthe-
sized, their properties have been investigated, and it has been determined that during
alkaline hydrolysis, the pyrrolidinone cycle cleaves forming sodium 3-(1H-ben-
zimidazol-2-yl)-4-arylaminobutanoates which transform into 3-(1H-benzimidazol-
2-yl)-4-arylaminobutanoic acids when treated with acetic acid. By alkylation of the
benzimidazole cycle with ethyl chloroacetate, N-alkylated products are formed. The
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K. Mickeviciene et al.
H3C
O
H3C
H3C
O
O
N
N
N
NH2NH2
RCHO
N
N
N
N
N
N
H
H
O
N
N
H3C
O
N
O
H2N
O
R
7
8-10
4a
CH3COCH2CH2COCH3, H+
H3C
CH3COR'
CH3COCH2COCH3, H+
H3C
O
O
N
N
N
H3C
O
N
N
H
N
N
R'
H3C
N
H
N
N
O
N
H3C
CH3
O
N
N
CH3
11, 12
14
N
N
O
H3C
13
R = 8) C6H5, 9) 4-CH3O-C6H4, 10) 4-(CH3)2N-C6H4;
R' = 11) CH3, 12) C2H5.
Scheme 2 Synthesis of N-substituted benzimidazole derivatives 7–14
properties of the synthesized ethyl-[2-(1-(substituted phenyl)-5-oxopyrrolidinyl-3-
yl)-1H-benzimidazolyl]etanoates have been investigated, and their benzimidazolium
chlorides, 1-carboxymethylbenzimidazoles, have been obtained, and products of the
condensation of 2-{2-[1-(3-methylphenyl)-5-oxo-3-pyrrolidinyl]-1H-benzimidazol-
1-yl}acetohydrazide with aromatic aldehydes and mono and diketones have been
synthesized.
Experimental
The starting materials and solvents were obtained from Sigma–Aldrich Chemie
(Germany) and Fluka (Switzerland) and were used without further purification. The
methods used to follow the reactions were TLC and NMR. The NMR spectra were
recorded on a Varian Unity Inova (300 MHz) spectrometer (Varian, USA).
Chemical shifts are expressed as d, ppm relative to TMS. IR spectra (m, cm-1) were
recorded on a Perkin Elmer BX FT-IR spectrometer (PerkinElmer, USA) using KBr
tablets. Mass spectra were obtained on a Waters ZQ 2000 spectrometer (Waters,
Germany) using the electrospray ionization (ESI) mode and operating at 25 V.
Elemental analyses were performed with a CE-440 elemental analyzer (Exeter
Analytical, USA). Melting points were determined with a B-540 melting point
analyzer (Bu¨chi, USA) and are uncorrected. TLC was performed using Merck silica
gel 60 F254 (Kieselgel 60 F254) plates.
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Synthesis of 1- and 2-carboxyalkyl substituted benzimidazoles
General procedure for preparation of benzimidazoles 2a–2c
Method A
A mixture of the corresponding 1-substituted phenyl-4-carboxy-2-pyrrolidinone
1a–1c (0.1 mol) and 1,2-diaminobenzene (16.2 g, 0.15 mol) was refluxed with
hydrochloric acid (4 M, 80 ml) for 24 h. The reaction mixture was cooled to the
room temperature and neutralized with sodium hydroxide (10 %) up to pH 8–9. The
obtained solid was filtered off and washed with water. Products were purified by
crystallizing from the corresponding solvent.
Method B
The corresponding amino acid 3 (2 mmol) and 10 ml of 10 % hydrochloric acid
were refluxed for 30 min. Then, the reaction mixture was neutralized with aqueous
ammonia to pH 8. The precipitated product was filtered off, washed with water, and
dried.
4-(1H-benzimidazol-2-yl)-1-(3-methylphenyl)pyrrolidin-2-one (2a)
Yield 20.9 g (72 %) (A), 0.55 g (94 %) (B); m.p.: 182–183 °C (from 1,4-dioxane);
1H NMR (300 MHz, DMSO-d6): d = 2.34 (s, 3H, CH3), 2.97–3.15 (m, 2H, 3-CH2),
4.01–4.19 (m, 1H, 4-CH), 4.25–4.38 (m, 2H, 5-CH2), 6.97–7.55 (m, 8H, ArH),
11.61 (s, 1H, NH) ppm; 13C NMR (75 MHz, (CD3)2CO): d = 22.5 (CH3), 33.0
(4-C), 39.5 (3-C), 54.2 (5-C), 118.2, 118.5, 121.9, 121.9, 126.5, 126.5, 130.2, 140.0,
141.7 (ArC), 156.6 (CN), 173.5 (CO); IR (KBr): m = 2,874 (NH), 1,700
(CO) cm-1; MS (25 V): m/z = 292 [M?H]? (100); anal. calcd. for C18H17N3O,
(%): C, 74.21; H, 5.88; N, 14.42; found, (%): C, 74.49; H, 5.81; N, 14.39.
4-(1H-benzimidazol-2-yl)-1-(2,5-dimethylphenyl)pyrrolidin-2-one (2b)
Yield 24.9 g (82 %) (A), 0.56 g (91 %) (B); m.p.: 260–261 °C (from dimethyl-
1
formamide); H NMR (300 MHz, DMSO-d6): d = 2.14 (s, 3H, CH3), 2.27 (s, 3H,
CH3), 3.04–3.18 (m, 2H, 3-CH2), 4.13–4.28 (m, 2H, 5-CH2), 4.44–4.52 (m, 1H,
4-CH), 7.06–7.82 (m, 7H, ArH) ppm; 13C NMR (75 MHz, DMSO-d6): d = 17.1
(CH3), 20.2 (CH3), 30.3 (4-C), 35.3 (3-C), 52.8 (5-C), 113.8, 113.8, 125.4, 125.4,
127.1, 128.3, 130.4, 131.2, 132.2, 135.7, 136.7 (ArC), 153.5 (CN), 170.1 (CO) ppm;
IR (KBr): m = 2,712 (NH), 1,687 (CO) cm-1; MS (25 V): m/z = 306 [M?H]?
(100); anal. calcd. for C19H19N3O, (%): C, 74.73; H, 6.27; N, 13.76; found, (%): C,
74.59; H, 6.51; N, 13.59.
4-(1H-benzimidazol-2-yl)-1-(5-chloro-2-methylphenyl)pyrrolidin-2-one (2c)
Yield 30.6 g (94 %) (A), 0.62 g (95 %) (B); m.p.: 264–265 °C (from dimethyl-
1
formamide); H NMR (300 MHz, DMSO-d6): d = 2.19 (s, 3H, CH3), 3.03–3.16
(m, 2H, 3-CH2), 4.16–4.32 (m, 2H, 5-CH2), 4.49–4.62 (m, 1H, 4-CH), 7.33–7.80
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(m, 7H, ArH) ppm; 13C NMR (75 MHz, DMSO-d6): d = 17.1 (CH3), 30.1 (4-C),
35.3 (3-C), 52.7 (5-C), 113.8, 113.8, 125.4, 125.4, 126.7, 127.5, 130.1, 131.1, 132.1,
134.8, 138.3 (ArC), 153.5 (CN), 170.4 (CO) ppm; IR (KBr): m = 2,713 (NH), 1,704
(CO) cm-1; MS (25 V): m/z = 326 [M?H]? (100), 328 [M?2?H]? (50); anal.
calcd. for C18H16ClN3O, (%): C, 66.36; H, 4.95; N, 12.90; found, (%): C, 66.28; H,
4.21; N, 12.62.
General procedure for preparation of 3-(1H-benzimidazol-2-yl)-4-(substituted
phenylamino)butanoic acids 3a–3c
The corresponding substituted pyrrolidinone 2a–2c (5 mmol) was refluxed in
sodium hydroxide solution (20 %, 20 ml) for 4 h. After cooling, the reaction
mixture was diluted with water to 50 ml, then filtered off, and the filtrate was
acidified with acetic acid (30 %) to pH 6. The precipitated product was filtered off,
washed with water, and purified by dissolving the solid in a sodium hydroxide
solution (5 %), filtering, and acidifying the filtrate with acetic acid (30 %).
3-(1H-benzimidazol-2-yl)-4-(3-methylphenylamino)butanoic acid (3a)
1
Yield 1.2 g (78 %); m.p.: 187–188 °C; H NMR (300 MHz, DMSO-d6): d = 2.16
(s, 3H, CH3), 2.67–2.69 (m, 2H, 2-CH2), 3.35–3.48 (m, 2H, 4-CH2), 3.62–3.68 (m,
1H, 3-CH), 5.77 (br. s, 1H, NH), 6.33–7.50 (m, 8H, ArH), 12.74 (br. s, 1H, NH)
ppm; 13C NMR (75 MHz, DMSO-d6): d = 22.0 (CH3), 36.9 (3-C), 38.3 (2-C), 47.5
(4-C), 110.0, 113.3, 115.2, 117.2, 121.6, 121.6, 129.4, 138.5, 139.4, 149.2 (ArC),
158.0 (CN), 175.3 (CO) ppm; IR (KBr): m = 3,289 (OH), 2,852 (NH), 2,515 (NH),
1,551 (CO) cm-1; anal. calcd. for C18H19N3O2, (%): C, 69.88; H, 6.19; N, 13.58;
found, (%): C, 69.79; H, 6.21; N, 13.69.
3-(1H-benzimidazol-2-yl)-4-(2,5-dimethylphenylamino)butanoic acid (3b)
Yield 1.2 g (75 %); m.p.: 240 °C (decomp.); 1H NMR (300 MHz, DMSO-d6):
d = 2.11 (s, 3H, CH3), 2.28 (s, 3H, CH3), 2.90–2.98 (m, 2H, 2-CH2), 3.30–3.48 (m,
2H, 4-CH2), 4.05–4.12 (m, 1H, 3-CH), 5.57 (br. s, 1H, NH), 7.14–7.53 (m, 7H,
ArH), 13.25 (br. s., 1H, NH) ppm; IR (KBr): m = 3,003 (OH), 2,936 (2 NH), 1,579
(CO) cm-1; anal. calcd. for C19H21N3O2, (%): C, 70.57; H, 6.55; N, 12.99; found,
(%): C, 70.49; H, 6.41; N, 13.19.
3-(1H-benzimidazol-2-yl)-4-(5-chloro-2-methylphenylamino)butanoic acid (3c)
1
Yield 0.82 g (48 %); m.p.: 222 °C (decomp.); H NMR (300 MHz, DMSO-d6):
d = 2.14 (s, 3H, CH3), 2.70–2.81 (m, 2H, 2-CH2), 3.32–3.48 (m, 2H, 4-CH2),
3.60–3.65 (m, 1H, 3-CH), 5.98 (br. s, 1H, NH), 6.52–7.48 (m, 7H, ArH), 12.46
(br. s, 1H, NH) ppm; 13C NMR (75 MHz, DMSO-d6): d = 19.1 (CH3), 36.5 (3-C),
38.2 (2-C), 47.4 (4-C), 111.8, 112.4, 112.4, 115.2, 121.7, 121.8, 131.9, 134.3, 139.4,
139.5, 148.6 (ArC), 157.3 (CN), 174.7 (CO) ppm; IR (KBr): m = 3,434 (OH), 2,960
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Synthesis of 1- and 2-carboxyalkyl substituted benzimidazoles
(NH), 2,866 (NH), 1,603 (CO) cm-1; anal. calcd. for C18H18ClN3O2, (%): C, 62.88;
H, 5.28; N, 12.22; found, (%): C, 62.38; H, 5.31; N, 12.42.
General procedure for preparation of ethyl 2-{2-[1-(substituted phenyl)-5-oxo-3-
pyrrolidinyl]-1H-benzimidazol-1-yl}acetates 4a–4c
A mixture of the corresponding 1-aryl-3-(1H-benzimidazol-2-yl)-5-oxopyrrolidine
2a–2c (0.01 mol), potassium carbonate (3.12 g, 20 mmol), potassium hydroxide
powder (1.12 g, 0.02 mol), toluene (40 ml), and tetrabutylammonium iodide (0.1 g)
was heated to boiling, then, during 10 min stirring, chloroacetic acid ethyl ester
(6.6 ml, 60 mmol) was added dropwise. The mixture was refluxed for 5 h, then
filtered hot. After cooling, the precipitated compound was filtered, washed with
toluene, and crystallized from toluene.
Ethyl 2-{2-[1-(3-methylphenyl)-5-oxo-3-pyrrolidinyl]-1H-benzimidazol-1-
yl}acetate (4a)
Yield 2.94 g (78 %); m.p.: 146–147 °C, 1H NMR (300 MHz, DMSO-d6): d = 1.23
(t, J = 7.1 Hz, 3H, CH2CH3), 2.32 (s, 3H, CH3), 2.87–3.05 (m, 2H, 4-C), 4.07–4.27
(m, 5H, 3-CH, 2-CH2, CH2CH3), 5.30 (s, 2H, NCH2), 6.96–7.65 (m, 8H, ArH) ppm;
13C NMR (75 MHz, DMSO-d6): d = 14.7 (OCH2CH3), 21.9 (CH3), 29.1 (3-C),
38.3 (4-C), 45.1 (NCH2CO), 52.8 (2-C), 62.1 (OCH2CH3), 110.8, 117.4, 119.5,
120.7, 122.6, 123.0, 125.5, 129.2, 136.4, 138.7, 139.9, 142.4 (ArC), 156.1 (CN),
169.1 (NCH2CO), 172.4 (CO) ppm; IR (KBr): m = 1,735, 1,692 (CO) cm-1; MS
(25 V): m/z = 378 [M?H]? (100); anal. calcd. for C22H23N3O3, (%): C, 70.01; H,
6.14; N, 11.13; found, (%): C, 70.19; H, 6.21; N, 11.29.
Ethyl 2-{2-[1-(2,5-dimethylphenyl)-5-oxo-3-pyrrolidinyl]-1H-benzimidazol-1-
yl}acetate (4b)
Yield 2.35 g (60 %); m.p.: 160–161 °C; 1H NMR (300 MHz, DMSO-d6): d = 1.21
(t, J = 7.1 Hz, 3H, CH2CH3), 2.13 (s, 3H, CH3), 2.26 (s, 3H, CH3), 2.87–2.91 (m,
2H, 4-C), 3.97–4.25 (m, 5H, 3-CH, 2-CH2, CH2CH3), 5.30 (s, 2H, NCH2),
7.06–7.87 (m, 8H, ArH) ppm; 13C NMR (75 MHz, DMSO-d6): d = 14.7
(OCH2CH3), 17.9 (CH3), 21.0 (CH3), 30.3 (3-C), 36.9 (4-C), 45.0 (NCH2CO),
54.6 (2-C), 62.1 (OCH2CH3), 110.8, 119.5, 122.6, 123.0, 127.7, 128.8, 131.22,
131.5, 132.9, 136.4, 138.0, 142.5 (ArC), 156.4 (CN), 171.9 (NCH2CO), 172.7 (CO)
ppm; IR (KBr): m = 1,731, 1,690 (CO) cm-1; MS (25 V): m/z = 392 [M?H]?
(100); anal. calcd. for C23H25N3O3, (%): C, 70.57; H, 6.44; N, 10.73; found, (%): C,
70.29; H, 6.41; N, 10.59.
Ethyl 2-{2-[1-(5-chloro-2-methylphenyl)-5-oxo-3-pyrrolidinyl]-1H-
benzimidazol-1-yl}acetate (4c)
Yield 2.14 g (52 %); m.p.: 181–182 °C; 1H NMR (300 MHz, DMSO-d6): d = 1.21
(t, J = 7.1 Hz, 3H, CH2CH3), 2.17 (s, 3H, CH3), 2.90–2.93 (m, 2H, 4-CH2),
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3.98–4.03 (m, 1H, 3-CH), 4.09–4.22 (m, 4H, 2-CH2, CH2CH3), 5.30 (s, 2H, NCH2),
7.21–7.65 (m, 7H, ArH) ppm; 13C NMR (75 MHz, DMSO-d6): d = 14.7
(OCH2CH3), 17.9 (CH3), 30.5 (3-C), 36.8 (4-C), 45.1 (NCH2CO), 54.3 (2-C),
62.1 (OCH2CH3), 110.8, 119.5, 122.2, 123.5, 127.2, 128.0, 130.9, 132.9, 135.4,
136.4, 139.6, 142.5 (ArC), 156.2 (CN), 169.1 (NCH2CO), 172.2 (CO) ppm; IR
(KBr): m = 1,725, 1,694 (CO) cm-1; MS (25 V): m/z = 412 [M?H]? (100), 414
[M?2?H]? (50); anal. calcd. for C22H22ClN3O3, (%): C, 64.15; H, 5.38; N, 10.20;
found, (%): C, 64.38; H, 5.41; N, 10.32.
General procedure for preparation of benzimidazolium chlorides 5a–5c
A mixture of the corresponding ethyl ester 4a–4c (2.7 mmol) and concentrated
hydrochloric acid (10 ml) was refluxed for 4 h. The reaction mixture was cooled,
and the residue was filtered and washed with water.
1-(Carboxymethyl)-2-[1-(3-methylphenyl)-5-oxo-3-pyrrolidinyl]-1H-
benzimidazol-1-ium chloride (5a)
Yield 0.71 g (68 %); m.p.: 158–159 °C; 1H NMR (300 MHz, DMSO-d6): d = 2.32
(s, 3H, CH3), 2.98–3.20 (m, 2H, 4-CH2), 4.22–4.38 (m, 2H, 2-CH2), 4.42–4.52 (m,
1H, 3-CH), 5.57 (s, 2H, NCH2CO), 7.22–7.98 (m, 8H, ArH) ppm; 13C NMR
(75 MHz, DMSO-d6): d = 21.9 (CH3), 28.8 (3-C), 38.0 (4-C), 46.4 (NCH2CO),
52.3 (3-C), 112.9, 116.0, 117.8, 121.1, 125.9, 126.0, 126.1, 129.3, 129.3, 133.6,
138.8, 139.5 (ArC), 155.2 (CN), 169.2 (NCH2CO), 171.2 (CO) ppm; IR (KBr):
m = 3,333 (OH), 2,792 (=N?H–), 1,734, 1,696 (CO) cm-1; anal. calcd. for
C20H20ClN3O3, (%): C, 62.26; H, 5.22; N, 10.89; found, (%): C, 62.29; H, 5.31; N,
10.69.
1-(Carboxymethyl)-2-[1-(2,5-dimethylphenyl)-5-oxo-3-pyrrolidinyl]-1H-
benzimidazol-1-ium chloride (5b)
1
Yield 0.86 g (80 %); m.p.: 240 °C (decomp.); H NMR (300 MHz, DMSO-d6):
d = 2.15 (s, 3H, CH3), 2.29 (s, 3H, CH3), 2.91–2.94 (m, 2H, 4-CH2), 3.98–4.10 (m,
2H, 2-CH2), 4.18–4.27 (m, 1H, 3-CH), 5.24 (s, 2H, NCH2CO), 7.08–7.29 (m, 7H,
ArH), 13.41 (br. s, 1H, COOH) ppm; 13C NMR (75 MHz, DMSO-d6): d = 17.9
(CH3), 21.0 (CH3), 30.2 (3-C), 36.8 (2-C), 45.2 (NCH2CO), 54.5 (2-C), 111.0,
119.1, 123.2, 123.3, 127.7, 128.89, 131.2, 132.9, 133.5, 136.5, 137.9 (ArC), 156.2
(CN), 170.4 (NCH2CO), 171.8 (CO) ppm; IR (KBr): m = 3,379 (OH), 2,922
(=N?H–), 1,715, 1,692 (CO) cm-1; anal. calcd. for C21H22ClN3O3, (%): C, 63.08;
H, 5.55; N, 10.51; found, (%): C, 63.29; H, 5.31; N, 10.69.
1-(Carboxymethyl)-2-[1-(5-chloro-2-methylphenyl)-5-oxo-3-pyrrolidinyl]-1H-
benzimidazol-1-ium chloride (5c)
Yield 0.58 g (51 %); m.p.: 162–163 °C; 1H NMR (300 MHz, DMSO-d6): d = 2.23
(s, 3H, CH3), 2.91–3.21 (m, 2H, 4-CH2), 4.08–4.27 (m, 2H, 2-CH2), 4.56–4.62
123

Synthesis of 1- and 2-carboxyalkyl substituted benzimidazoles
(m, 1H, 3-CH), 5.51 (s, 2H, NCH2), 7.36–7.92 (m, 7H, ArH) ppm; 13C NMR
(75 MHz, DMSO-d6): d = 17.9 (CH3), 29.9 (3-C), 36.7 (4-C), 46.3 (NCH2CO),
53.9 (2-C), 112.8, 116.1, 125.8, 126.0, 127.4, 128.3, 130.9, 132.9, 133.7, 135.6,
139.2 (ArC), 155.3 (CN), 169.3 (NCH2CO), 171.1 (CO) ppm; IR (KBr): m = 3,364
(OH), 2,924 (=N?H–), 1,735, 1,694 (CO) cm-1; anal. calcd. for C20H19Cl2N3O3,
(%): C, 57.16; H, 4.56; N, 10.00; found, (%): C, 57.28; H, 4.51; N, 10.12.
General procedure for preparation of acids 6a–6c
Benzimidazolium chloride 5a–5c (1 mmol) and sodium hydroxide solution (5 %,
10 ml) were heated under reflux for 1 min. The hot reaction mixture was acidified
with acetic acid (10 %) to pH 6 and left to cool. The residue was filtered off, washed
with water, and purified by dissolving the solid in a sodium hydroxide solution
(5 %), filtering the solution, and acidifying the filtrate with 10 % acetic acid to pH
6.
2-{2-[1-(3-Methylphenyl)-5-oxo-3-pyrrolidinyl]-1H-benzimidazol-1-yl}acetic
acid (6a)
Yield 0.21 g (61 %); m.p.: 278–279 °C; 1H NMR (300 MHz, DMSO-d6): d = 2.32
(s, 3H, CH3), 2.99–3.01 (m, 2H, 4-CH2), 4.00–4.05 (m, 1H, 3-CH), 4.21–4.24 (m,
2H, 2-CH2), 4.64 (s, 2H, NCH2), 6.96–7.58 (m, 8H, ArH) ppm; 13C NMR (75 MHz,
DMSO-d6): d = 21.9 (CH3), 29.3 (3-C), 38.3 (4-C), 52.9 (2-C), 110.8, 117.4, 119.0,
120.7, 121.6, 122.0, 125.3, 129.2, 136.9, 138.6, 139.9, 142.4 (ArC), 156.4 (CN),
172.9 (CO) ppm; IR (KBr): m = 3,374 (OH), 1,684, 1,607 (CO) cm-1; MS (25 V):
m/z = 350 [M?H]? (100); anal. calcd. for C20H19N3O3, (%): C, 68.75; H, 5.48; N,
12.03; found, (%): C, 68.59; H, 5.41; N, 12.09.
2-{2-[1-(2,5-Dimethylphenyl)-5-oxo-3-pyrrolidinyl]-1H-benzimidazol-1-
yl}acetic acid (6b)
Yield 0.22 g (61 %); m.p.: 278–279 °C; 1H NMR (300 MHz, DMSO-d6): d = 2.14
(s, 3H, CH3), 2.29 (s, 3H, CH3), 2.91–2.96 (m, 2H, 4-CH2), 4.00–4.12 (m, 3H,
3-CH, 2-CH2), 4.57 (s, 2H, NCH2), 7.09–7.61 (m, 7H, ArH) ppm; 13C NMR
(75 MHz, DMSO-d6): d = 17.9 (CH3), 21.0 (CH3), 30.6 (3-C), 36.8 (4-C), 54.7
(2-C), 110.8, 119.0, 121.5, 122.0, 127.7, 128.7, 131.1, 132.9, 136.4, 137.0, 138.1,
142.5 (ArC), 156.5 (CN), 172.3 (CO) ppm; IR (KBr): m = 3,347 (OH), 1,679, 1,605
(CO) cm-1; MS (25 V): m/z = 350 [M?H]? (100); anal. calcd. for C21H21N3O3,
(%): C, 69.41; H, 5.82; N, 11.56; found, (%): C, 69.69; H, 5.61; N, 11.49.
2-{2-[1-(5-Choro-2-methylphenyl)-5-oxo-3-pyrrolidinyl]-1H-benzimidazol-1-
yl}acetic acid (6c)
1
Yield 0.3 g (77 %); m.p.: 216–217 °C; H NMR (300 MHz, DMSO-d6): d = 2.16
(s, 3H, CH3), 2.86–3.02 (m, 2H, 4-CH2), 4.03–4.13 (m, 3H, 3-CH, 2-CH2), 4.78 (s,
2H, NCH2), 7.16–7.62 (m, 7H, ArH) ppm; 13C NMR (75 MHz, DMSO-d6):
123

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K. Mickeviciene et al.
d = 17.9 (CH3), 30.7 (3-C), 36.7 (4-C), 54.4 (2-C), 110.8, 119.1, 121.8, 122.3,
127.2, 127.9, 130.9, 132.8, 135.4, 136.8, 139.7, 142.5 (ArC), 156.3 (CN), 172.5
(CO) ppm; IR (KBr): m = 3,386 (OH), 1,684, 1,614 (CO) cm-1; MS (25 eV):
m/z = 384[M?H]? (100), 386 [M?2?H]? (50); anal. calcd. for C20H18ClN3O3,
(%): C, 62.58; H, 4.73; N, 10.95; found, (%): C, 62.28; H, 4.51; N, 10.82.
2-{2-[1-(3-Methylphenyl)-5-oxo-3-pyrrolidinyl]-1H-benzimidazol-1-
yl}acetohydrazide (7)
A mixture of ethyl ester 4a (3.77 g, 0.01 mol), hydrazine hydrate (3.4 g, 0.07 mol),
and 2-propanol (60 ml) was refluxed for 2 h. After cooling the reaction mixture to
the ambient temperature, the precipitate was filtered off, washed with 2-propanol,
and crystallized from dimethylformamide. Yield 2.28 g (63 %); m.p.: 216–217 °C;
1H NMR (300 MHz, DMSO-d6): d = 2.34 (3H, s, CH3), 2.92–3.05 (2H, m, 4-CH2),
4.12-4.14 (1H, m, 3-CH), 4.22–4.28 (2H, m, 2-CH2), 4.63 (2H, s, NCH2), 4.94 (2H,
s, NH2), 6.96–7.52 (8H, m, ArH), 9.64 (1H, s, NH) ppm; 13C NMR (75 MHz,
DMSO-d6): d = 21.9 (CH3), 29.2 (3-C), 30.9 (4-C), 45.1 (NCH2CO), 52.9 (2-C),
110.7, 117.4, 119.4, 120.7, 122.4, 125.4, 129.2, 136.4, 138.6, 139.9, 142.4 (ArC),
156.5 (CN), 166.7 (NCH2CO), 172.6 (CO) ppm; IR (KBr): m = 3,299 (NH), 3,049
(NH2), 1,698, 1,669 (CO) cm-1; MS (25 V): m/z = 364 [M?H]? (100); anal. calcd.
for C20H21N5O2, (%): C, 66.10; H, 5.82; N, 19.27; found, (%): C, 66.59; H, 5.61; N,
19.09.
General procedure for the synthesis of hydrazones 8–10
A mixture of hydrazide 7 (0.73 g, 2 mmol), the corresponding aromatic aldehyde
(3 mmol), and ethanol (30 ml) was refluxed for 5 h. After cooling the reaction
mixture to the ambient temperature, the precipitate was filtered off, washed with
ethanol, and crystallized from dimethylformamide.
2-{2-[1-(3-Methylphenyl)-5-oxo-3-pyrrolidinyl]-1H-benzimidazol-1-yl}-N’-
(phenylmethylidene)acetohydrazide (8)
Yield 0.69 g (76 %); m.p.: 272–273 °C; 1H NMR (300 MHz, DMSO-d6): d = 2.31
(3H, s, CH3), 2.73–2.99 (2H, m, 4-CH2), 4.12–4.14 (1H, m, 3-CH), 4.21–4.27 (2H,
m, 2-CH2), 5.15, 5.62 (2H, 2 s, NCH2), 6.96–7.83 (13H, m, ArH), 8.11, 8.30 (1H,
2 s, NCH), 11.90, 12.01 (1H, 2 s, NH) ppm; 13C NMR (75 MHz, DMSO-d6):
d = 21.9 (CH3), 29.2 (3-C), 36.5 (4-C (Z)), 38.4 (4-C (E)) 44.9 (NCH2CO), 52.9
(2-C), 110.8, 117.4, 119.4, 120.7, 122.3, 122.8, 125.4, 127.8, 127.9, 129.2, 129.5,
130.8, 134.6, 136.9, 138.6, 139.9, 142.5 (ArC), 145.1 (NCH), 156.7 (CN), 169.2
(NCH2CO), 172.5 (CO) ppm; IR (KBr): m = 3,099 (NH), 1,694, 1,661 (CO) cm-1
;
MS (25 V): m/z = 452 [M?H]? (100); anal. calcd. for C27H25N5O2, (%): C, 71.82;
H, 5.58; N, 15.51; found, (%): C, 71.59; H, 5.61; N, 15.49.
123

Synthesis of 1- and 2-carboxyalkyl substituted benzimidazoles
N’-[(4-methoxyphenyl)methylidene]-2-{2-[1-(3-methylphenyl)-5-oxo-3-
pyrrolidinyl]-1H-benzimidazol-1-yl}acetohydrazide (9)
Yield 0.71 g (73 %); m.p.: 236–237 °C; 1H NMR (300 MHz, DMSO-d6): d = 2.31
(3H, s, CH3), 2.93–3.04 (2H, m, 4-CH2), 3.81 (3H, s, OCH3), 4.09–4.14 (1H, m,
3-CH), 4.19–4.27 (2H, m, 2-CH2), 5.12, 5.59 (2H, 2 s, NCH2), 6.93–7.95 (12H, m,
ArH), 8.05, 8.23 (1H, 2 s, NCH), 11.76, 11.88 (1H, 2 s, NH) ppm; 13C NMR
(75 MHz, DMSO-d6): d = 21.9 (CH3), 29.2 (3-C, (Z)), 31.4 (3-C, (E)) 36.5 (4-C
(Z)), 38.4 (4-C (E)) 44.8 (NCH2CO), 52.9 (2-C), 56.0 (OCH3), 110.8, 115.0, 115.0,
117.4, 117.4, 120.7, 122.3, 122.8, 125.4, 127.2, 129.2, 129.4, 129.5, 136.9, 138.6,
139.9, 142.5, 161.5 (ArC), 145.0 (NCH), 156.7 (CN), 163.0 (NCH2CO (Z)), 168.9
(NCH2CO (E)), 172.5 (CO) ppm; IR (KBr): m = 3,124 (NH), 1,706, 1,689 (CO)
cm-1; MS (25 V): m/z = 482 [M?H]? (100); anal. calcd. for C28H27N5O3, (%): C,
69.84; H, 5.65; N, 14.54; found, (%): C, 69.59; H, 5.61; N, 14.48.
N’-{[4-(dimethylamino)phenyl]methylidene}-2-{2-[1-(3-methylphenyl)-5-oxo-
3-pyrrolidinyl]-1H-benzimidazol-1-yl}acetohydrazide (10)
1
Yield 0.7 g (71 %); m.p.: 210–211 °C; H NMR (300 MHz, DMSO-d6): d = 2.31
(3H, s, CH3), 2.95–3.01 (8H, m, 4-CH2 ? N(CH3)2), 4.11–4.15 (1H, m, 3-CH),
4.21–4.25 (2H, m, 2-CH2), 5.09, 5.55 (2H (0,29:0,71), 2 s, NCH2), 6.74–7.62 (12H,
m, ArH), 7.98, 8.14 (1H, 2 s, NCH), 11.61, 11.72 (1H, 2 s, NH) ppm; 13C NMR
(75 MHz, DMSO-d6): d = 21.9 (CH3), 29.2 (3-C, (Z)), 31.4 (3-C, (E)) 36.5 (4-C
(Z)), 38.4 (4-C (E)), 39.7 (N(CH3)2), 44.8 (NCH2CO), 52.9 (2-C), 110.8, 112.4,
112.4, 117.4, 119.4, 120.7, 121.9, 122.3, 122.8, 125.4, 129.1, 129.2, 136.9, 138.6,
139.9, 139.95, 142.5, 151.4 (ArC), 146.0 (NCH), 156.7 (CN), 163.0 (NCH2CO (Z)),
168.5 (NCH2CO (E)), 172.6 (CO) ppm; IR (KBr): m = 3,210 (NH), 1,689, 1,672
(CO) cm-1; MS (25 V): m/z = 364 [M?H]? (100); anal. calcd. for C29H30N6O2,
(%): C, 70.43; H, 6.11; N, 16.99; found, (%): C, 70.59; H, 6.21; N, 16.89.
General procedure for the synthesis of hydrazones 11, 12
A mixture of hydrazide 7 (0.73 g, 2 mmol), acetone or methyl ethyl ketone (30 ml)
was refluxed for 7 h. After cooling the reaction mixture to the ambient temperature,
the precipitate was filtered off, washed with ethanol, and crystallized from the
appropriate solvent.
N’-(1-methylethylidene)-2-{2-[1-(3-methylphenyl)-5-oxo-3-pyrrolidinyl]-1H-
benzimidazol-1-yl}acetohydrazide (11)
Yield 0.55 g (68 %) m.p.: 210–211 °C (from acetone); 1H NMR (300 MHz,
DMSO-d6): d = 1.93, 1.95, 1.96, 2.01 (6H, 4 s, (CH3)2), 2.31 (3H, s, CH3),
2.95–3.01 (2H, m, 4-CH2), 4.06–4.10 (1H, m, 3-CH), 4.18–4.25 (2H, m, 2-CH2),
5.14, 5.41 (2H (0.36:0.64), 2 s, NCH2), 6.97–7.62 (8H, m, ArH), 10.60, 10.70 (1H
(0,36:0,64), 2 s, NH) ppm; 13C NMR (75 MHz, DMSO-d6): d = 17.2, 17.7 (cis (Z,
E), C(CH3)2), 21.2 (CH3), 24.9, 25.2 (trans (Z, E), C(CH3)2), 28.4 (3-C), 37.6 (4-C),
123

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K. Mickeviciene et al.
44.4, 44.5 (NCH2CO), 52.2 (2-C), 109.9, 116.6, 118.8, 120.0, 121.5, 122.0, 124.7,
128.5, 136.1, 137.9, 139.2, 141.8 (ArC), 152.1 (C(CH3)2), 156.0 (CN), 163.2, 168.4
(NCH2CO), 171.8 (CO) ppm; IR (KBr): m = 3,192 (NH), 1,699, 1,677 (CO) cm-1
;
MS (25 V): m/z = 404 [M?H]? (100); anal. calcd. for C23H25N5O2, (%): C, 68.47;
H, 6.25; N, 17.36; found, (%): C, 68.59; H, 6.21; N, 17.39.
2-{2-[1-(3-Methylphenyl)-5-oxo-3-pyrrolidinyl]-1H-benzimidazol-1-yl}-N’-(1-
methylpropylidene)acetohydrazide (12)
Yield 0.54 g (65 %); m.p.: 194–195 °C (from methyl ethyl ketone); 1H NMR
(300 MHz, DMSO-d6): d = 0.90, 1.03, 1.08, 1.12 (3H (E cis, Z trans, Z cis, E trans),
4t, J = 7.4 Hz, CCH2CH3), 1.91, 1.94, 1.95, 2.07 (3H (E cis, Z trans, Z cis, E trans),
4 s, CCH3), 2.22–2.44 (5H, m, CH3 ? CCH2CH3), 2.95–3.08 (2H, m, 4-CH2),
4.02–4.29 (3H, m, 3-CH ? 2-CH2), 5.15, 5.43 (2H (0.34:0.66), 2 s, NCH2),
6.96–7.64 (8H, m, ArH), 10.58, 10.64, 10.78, 10.80 (1H (0.24:0.08:0.52:0.16), 4 s,
(Z cis, Z trans, E cis, E trans) NH) ppm; IR (KBr), m, cm-1: 3,207 (NH), 1,684, 1,662
(CO) cm-1; MS (25 V): m/z = 418 [M?H]? (100); anal. calcd. for C24H27N5O2,
(%): C, 69.04; H, 6.52; N, 16.77; found, (%): C, 69.29; H, 6.21; N, 16.79.
4-{1-[2-(3,5-Dimethyl-1H-pyrazol-1-yl)-2-oxoethyl]-1H-benzimidazol-2-yl}-1-
(3-methylphenyl)-2-pyrrolidinone (13)
A mixture of hydrazide 7 (0.73 g, 2 mmol), 2,4-pentanedione (0.8 g, 8 mmol),
2-propanol (20 ml), and HCl (2 drops) was refluxed for 5 h. After cooling the
reaction mixture to the ambient temperature, the precipitate was filtered off, washed
with 2-propanol, and crystallized from 1,4-dioxane. Yield 0.46 g (53 %); m.p.:
1
138–139 °C; H NMR (300 MHz, DMSO-d6): d = 2.00 (6H, s, 30-CH3, 50-CH3),
2.33 (3H, s, CH3), 2.91–3.11 (2H, m, 3-CH2), 4.13–4.29 (3H, m, 4-CH ? 5-CH2),
5.26, 5.32 (2H, 2 s, NCH2), 6.01 (H, s, 40-CH), 6.99–7.69 (8H, m, ArH) ppm; MS
(25 V): m/z = 428 [M?H]? (100); anal. calcd. for C25H25N5O2, (%): C, 70.24; H,
5.89; N, 16.38; found, (%): C, 70.29; H, 5.71; N, 16.49.
N-(2,5-dimethyl-1H-pyrrol-1-yl)-2-{2-[1-(3-methylphenyl)-5-oxo-3-
pyrrolidinyl]-1H-benzimidazol-1-yl}acetamide (14)
A mixture of hydrazide 7 (0.73 g, 2 mmol), 2,5-hexanedione (1.14 g, 10 mmol),
2-propanol (20 ml), and conc. acetic acid (10 ml) was heated under reflux for 4 h.
The precipitate formed after cooling the reaction mixture to the ambient temperature
was filtered off, washed with 2-propanol and crystallized from 2-propanol. Yield
0.59 g (67 %); m.p.: 204 °C (decomp.); 1H NMR (300 MHz, DMSO-d6): d = 2.01
(6H, s, 20-CH3, 50-CH3), 2.31 (3H, s, CH3), 2.91–3.11 (2H, m, 4-CH2), 4.14–4.32
(3H, m, 3-CH ? 2-CH2), 5.29 (2H, s, NCH2), 5.65 (2H, s, 30-CH, 40-CH), 6.96–7,66
(8H, m, ArH), 11.2 (1H, s, NH) ppm; 13C NMR (75 MHz, DMSO-d6): d = 11.0
(20-CH3, 50-CH3), 21.2 (CH3), 28.6 (3-C), 37.6 (4-C), 44.2 (NCH2CO), 52.1 (2-C),
103.2 (30-CH, 40-CH), 109.7, 116.7, 118.9, 120.0, 121.9, 122.3, 124.7, 128.5, 135.7,
137.9, 139.1, 141.8 (ArC), 126.7 (20-C, 50-C), 155.68 (NC), 166.6 (NCH2CO), 171.7
123

Synthesis of 1- and 2-carboxyalkyl substituted benzimidazoles
(CO) ppm; MS (25 V): m/z = 442 [M?H]? (100); anal. calcd. for C26H27N5O2,
(%): C, 70.73; H, 6.16; N, 15.86; found, (%): C, 70.69; H, 6.11; N, 15.79.
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140, 1513 (2009)
123