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

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-carboxymethylbenzimidazoles, condensation products of 2-{2-[1-(3-methylphenyl)-5-oxo-3-pyrrolidinyl]-1H-benzimidazol-1-yl}acetohydrazide with various aromatic aldehydes and aliphatic ketones have been obtained.

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.

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).

Scheme 1

Synthesis of benzimidazole derivatives 2–6

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-arylaminobutanoic 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 γ-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 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 ¹³C 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-benzimidazol-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 aromatic aldehydes or ketones—acetone and ethylmethylketone. Analysis of ¹H NMR spectra of 1-aryl-3-arylidenehydrazinocarbonyl-5-oxopyrrolidines 8–12 showed that a mixture of E/Z rotamers exists in DMSO-d ₆ solutions in which Z isomer predominates due to a hindered rotation around the CO–NH bond [20, 21].

Scheme 2

Synthesis of N-substituted benzimidazole derivatives 7–14

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 (CH₃), 5.65 ppm (=CH), and 11.20 ppm (NH) in ¹H NMR spectra.

Conclusion

1-Phenyl substituted 4-(1H-benzimidazol-2-yl)-2-pyrrolidinones have been synthesized, their properties have been investigated, and it has been determined that during alkaline hydrolysis, the pyrrolidinone cycle cleaves forming sodium 3-(1H-benzimidazol-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 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 δ, ppm relative to TMS. IR spectra (ν, 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 (Büchi, USA) and are uncorrected. TLC was performed using Merck silica gel 60 F254 (Kieselgel 60 F254) plates.

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-d ₆): δ = 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): δ = 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): ν = 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 dimethylformamide); ¹H NMR (300 MHz, DMSO-d ₆): δ = 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-d ₆): δ = 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): ν = 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 dimethylformamide); ¹H NMR (300 MHz, DMSO-d ₆): δ = 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 (m, 7H, ArH) ppm; ¹³C NMR (75 MHz, DMSO-d ₆): δ = 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): ν = 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)

Yield 1.2 g (78 %); m.p.: 187–188 °C; ¹H NMR (300 MHz, DMSO-d ₆): δ = 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-d ₆): δ = 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): ν = 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-d ₆): δ = 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): ν = 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)

Yield 0.82 g (48 %); m.p.: 222 °C (decomp.); ¹H NMR (300 MHz, DMSO-d ₆): δ = 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-d ₆): δ = 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): ν = 3,434 (OH), 2,960 (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-d ₆): δ = 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-d ₆): δ = 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): ν = 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-d ₆): δ = 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-d ₆): δ = 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): ν = 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-d ₆): δ = 1.21 (t, J = 7.1 Hz, 3H, CH₂CH₃), 2.17 (s, 3H, CH₃), 2.90–2.93 (m, 2H, 4-CH₂), 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-d ₆): δ = 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): ν = 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-d ₆): δ = 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-d ₆): δ = 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): ν = 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)

Yield 0.86 g (80 %); m.p.: 240 °C (decomp.); ¹H NMR (300 MHz, DMSO-d ₆): δ = 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-d ₆): δ = 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): ν = 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-d ₆): δ = 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 (m, 1H, 3-CH), 5.51 (s, 2H, NCH₂), 7.36–7.92 (m, 7H, ArH) ppm; ¹³C NMR (75 MHz, DMSO-d ₆): δ = 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): ν = 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-d ₆): δ = 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-d ₆): δ = 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): ν = 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-d ₆): δ = 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-d ₆): δ = 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): ν = 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)

Yield 0.3 g (77 %); m.p.: 216–217 °C; ¹H NMR (300 MHz, DMSO-d ₆): δ = 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-d ₆): δ = 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): ν = 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-d ₆): δ = 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-d ₆): δ = 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): ν = 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-d ₆): δ = 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-d ₆): δ = 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): ν = 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.

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-d ₆): δ = 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-d ₆): δ = 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): ν = 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)

Yield 0.7 g (71 %); m.p.: 210–211 °C; ¹H NMR (300 MHz, DMSO-d ₆): δ = 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-d ₆): δ = 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): ν = 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-d ₆): δ = 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-d ₆): δ = 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), 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): ν = 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-d ₆): δ = 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), ν, 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.: 138–139 °C; ¹H NMR (300 MHz, DMSO-d ₆): δ = 2.00 (6H, s, 3′-CH₃, 5′-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, 4′-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-d ₆): δ = 2.01 (6H, s, 2′-CH₃, 5′-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, 3′-CH, 4′-CH), 6.96–7,66 (8H, m, ArH), 11.2 (1H, s, NH) ppm; ¹³C NMR (75 MHz, DMSO-d ₆): δ = 11.0 (2′-CH₃, 5′-CH₃), 21.2 (CH₃), 28.6 (3-C), 37.6 (4-C), 44.2 (NCH₂CO), 52.1 (2-C), 103.2 (3′-CH, 4′-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 (2′-C, 5′-C), 155.68 (NC), 166.6 (NCH₂CO), 171.7 (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.