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The use of diethylene glycol in the synthesis of 2,2′-bibenzimidazole from o-phenylenediamine and oxalic acid

  • Iwona Mądrzak-Litwa EMAIL logo and Aleksandra Borowiak-Resterna
Published/Copyright: May 12, 2014
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Heterocyclic Communications
From the journal Heterocyclic Communications Volume 20 Issue 3

Abstract

One- and two-step syntheses of 2,2′-bibenzimidazole were compared. Diethylene glycol was used as solvent that provides good solubility of the substrates. The limitation of the one-step preparation is the formation of the by-product, fluoflavine. The two-step synthesis proceeds with the separation of the intermediate product, 1,4-dihydroquinoxaline-2,3-dione, and the final product is only 2,2′-bibenzimidazole. The total yield of the two-step synthesis is above 85%.

Keywords: 2,2′-bibenzimidazole; diethylene glycol; 1,4-dihydroquinoxaline-2,3-dione; o-phenylenediamine; oxalic acid

Introduction

Substituted bibenzimidazoles exhibit anticancer [1, 2], antiviral [3], and antibacterial properties [4] and may form complexes with metal ions, including cobalt, zinc, nickel, iron, and copper [5–11] and as such are used for the recovery of metals from aqueous solutions, mainly in chloride systems [12, 13]. The most common methods for the synthesis of 2,2′-bibenzimidazole (2, Scheme 2) are based on the reactions of o-phenylenediamine (1) with oxalic acid [14, 15] and its derivatives [16, 17], hexachloroacetone [18, 19], and methyl 2,2,2-trichloroacetimidiate [20]. The main disadvantages of these methods are unsatisfactory yields, high cost of substrates, and difficulties in scaling up the synthesis. Related, difficult preparations have been reported [21–27].

Results and discussion

In the present work, we compared two methods for the synthesis of 2,2′-bibenzimidazole (2), namely the one-step synthesis (Scheme 1) and the two-step synthesis, which requires the isolation of the intermediate product, 1,4-dihydroquinoxaline-2,3-dione (4, Scheme 2). The one-step preparation of 2 by the reaction between o-phenylenediamine and oxalic acid has been previously conducted on a small scale only (0.5–2 mmol of o-phenylenediamine) in a melt system (no solvent). A small-scale synthesis of 2, using a two-step melt reaction of o-phenylenediamine (1) and oxalic acid, has been described [14, 15]. Our attempt to repeat this preparation on a hundred-times-larger scale than that described ended in a total failure. The proposed use of tetrafluoroboric acid as the catalyst [14] resulted in the preparation of compound 2 in a yield of 4%. It was decided to conduct the reactions in a suitable solvent that would facilitate the generation of a homogeneous mixture. Low polar solvents, such as toluene, were rejected due to the lyophobic nature of oxalic acid. Based on the analysis of literature, it was suggested that the most suitable solvents for the reactants would be high-boiling polar protic solvents such as glycols. The results of a variety of preparations conducted under different conditions are given in Table 1. When the reaction temperature was varied from 100°C to 210°C in ethylene glycol or propane-1,3-diol as solvents, the formation of 2,2′-bibenzimidazole (2) was observed, but the major product of the reaction was compound 4, but when ethylene glycol was replaced with diethylene glycol and the reaction mixture was heated to about 245°C, the main product was the desired compound 2. However, the by-product fluoflavine (3, 5,12-dihydroquinoxalino[2,3-b]quinoxaline), the isomer of 2, was produced in significant quantities. The by-product 3 is insoluble in diethylene glycol, and therefore, it is possible to purify the crude product 2 by crystallization from diethylene glycol in conjunction with filtration of the hot mixture. After crystallization, pure 2,2′-bibenzimidazole (2) was obtained in a yield of about 66%.

Scheme 1
Scheme 1
Scheme 2
Scheme 2
Table 1

One-step synthesis of 2,2′-bibenzimidazole (2) [o-phenylenediamine (1):oxalic acid=2:1].

#SolventT (°C)Time (h)Yield (%)
1Ethylene glycol10032
2Ethylene glycol12030
3Ethylene glycol19735
4Propane-1,3-diol21035
5Diethylene glycol245140
6diethylene glycol245361

The two-step preparation of 2 is summarized in Scheme 2 and Table 2. The first step, the synthesis of 1,4-dihydroquinoxaline-2,3-dione (4) was conducted according to the efficient method described by Ajani et al. [28], yielding the intermediate product 4 in a 96% yield.

Table 2

The second step of the two-step synthesis of 2,2′-bibenzimidazole (2) from o-phenylenediamine (1) and 1,4-dihydroquinoxaline-2,3-dione (3).

#Molar ratio 1:3SolventT (°C)Time (h)Yield (%)
11:1Ethylene glycol1978a17
21:1Diethylene glycol245883
31.05:1Diethylene glycol245583
41.05:1Diethylene glycol245887
51.05:1Diethylene glycol2451286
61.1:1Diethylene glycol245287
71.1:1Diethylene glycol2452.589
81.1:1Diethylene glycol245589
91.15:1Diethylene glycol245888
101.5:1Diethylene glycol245882

aReaction conditions taken from [17].

In the second step, the reaction of the intermediate product 4 with o-phenylenediamine (1) was initially conducted under the conditions reported by Lane [17] and compound 2 was obtained only in small amounts (Table 2, entry 1). However, when diethylene glycol as the solvent was used, the product 2 was obtained in a high yield. The best yield of 89% for this reaction was obtained with a 10% excess of o-phenylenediamine (1) (Table 2). Additionally, it was observed that the increase in the reaction time has no significant impact on the yield of 2. The total yield of this two-step preparation is higher than 85%.

Conclusion

The efficient two-step procedure for 2,2′-bibenzimidazole (2) synthesis on a large scale was developed.

Experimental

Melting points were determined using a Boetius hot stage apparatus. The low- and high-resolution mass spectra were recorded on a Intectra Mass AMD 402 (ionization method EI, 70 eV) spectrometer. The spectroscopic parameters for compounds 2–4 (IR, 1H NMR, and 13C NMR) were identical to those given in the literature [14, 29, 30].

One-step synthesis of 2,2′-bibenzimidazole (2)

A mixture of o-phenylenediamine (1) (21.6 g, 0.2 mol), oxalic acid dihydrate (12.6 g, 0.1 mol), and diethylene glycol (120 mL) was heated under reflux for 3 h, during which time a light brown solid started to precipitate. After cooling the suspension to 50°C, water (70 mL) was added, and the mixture was stirred for an additional 15 min. The solid product was filtered off and washed with water. Crystallization from diethylene glycol with hot filtration gave pure yellow main product 2 (14.27 g, 61%) and undissolved by-product 3 (4.0 g, 17%).

Two-step synthesis of 2,2′-bibenzimidazole (2)

1,4-Dihydroquinoxaline-2,3-dione (4) was prepared as previously described [28]. Briefly, a heated (100°C) solution of oxalic acid dihydrate (60.0 g, 0.48 mol) in water (400 mL) was treated with concentrated HCl (90 mL) followed by addition of o-phenylenediamine (1) (44.0 g, 0.41 mol) at 100°C for 60 min. The resulting mixture was cooled by addition of crushed ice (200 g) to give white needles, which were collected by filtration, washed with water, and dried. Pure compound 4 (63.45 g, 96%) was obtained without any need for further crystallization.

A solution of 1,4-dihydroquinoxaline-2,3-dione (4, 40.0 g, 0.25 mol) in diethylene glycol (250 mL) was heated under reflux and treated with o-phenylenediamine (1, 29.3 g, 0.27 mol), and the mixture was heated under reflux for an additional 2.5 h, during which time a bright yellow solid started to precipitate. After cooling the suspension to 50°C, water (150 mL) was added, and the mixture was stirred for 15 min. The solid product was filtered off and washed with water. Pure product 2 (51.6 g, 89%) was obtained without any need for further crystallization.

2,2′-Bibenzimidazole (2)

Yellow powder: yield 61% (one-step preparation), 89% (two-step preparation); mp >420°C (from diethylene glycol) (lit. mp >300°C (no solvent given) [15]). HRMS (EI). Calcd for C14 H10 N4 (M+): m/z 234.0905. Found: m/z 234.0901.

Fluoflavine (3)

Brown powder: yield 17% (one-step preparation); mp >410°C (mp >310°C (no solvent given) [15]; HRMS (EI). Calcd for C14 H10 N4 (M)+: m/z 234.0905. Found: m/z 234.0914.

1,4-Dihydroquinoxaline-2,3-dione (4)

White needles: yield 96%; mp 386–388°C (from EtOH) (lit. mp 386°C (from ethylene glycol) [17]). HRMS (EI): Calcd for C8 H6 N2 O2 (M)+: m/z 162.0429. Found: m/z 162.0431.

Corresponding author: Iwona Mądrzak-Litwa, Institute of Chemical Technology and Engineering, Poznań University of Technology, 2 Skłodowskiej-Curie Square, 60-965 Poznań, Poland, e-mail:

Acknowledgments

This work was supported by grant no. DS-PB 32-374/2013.

References

[1] Mann, J.; Baron, A.; Opoku-Boahen, Y.; Johansson, E.; Parkinson, G.; Kelland, L. R.; Neidle, S. A new class of symmetric bisbenzimidazole-based DNA minor groove-binding agents showing antitumor activity. J. Med. Chem. 2001, 44, 138–144.Search in Google Scholar

[2] Yang, Y.-H.; Cheng, M.-S.; Wang, Q.-H.; Nie, H.; Liao, N.; Wang, J.; Chen, H. Design, synthesis, and anti-tumor evaluation of novel symmetrical bis-benzimidazoles. Eur. J. Med. Chem. 2009, 44, 1808–1812.Search in Google Scholar

[3] Dai, D.; Hruby, D. E.; Bolken, T. C.; Amberg, S. M.; Warren, T. K. Antiviral drugs for treatment of arenavirus infection. WO Patent 2009123776, 2009.Search in Google Scholar

[4] Agh-Atabay, N. M.; Dulger, B.; Gucin, F. Synthesis and investigation of antimicrobial activity of some bisbenzimidazole-derived chelating agents. Eur. J. Med. Chem. 2003, 38, 875–881.Search in Google Scholar

[5] Mo, H.-J.; Zhong, Y.-R.; Cao, M.-L.; Ou, Y.-C.; Ye, B.-H. Hydrothermal syntheses and structural diversity of cobalt complexes with 2,2’-bibenzimidazole ligand by temperature tuning strategy. Cryst. Growth Des. 2009, 9, 488–496.Search in Google Scholar

[6] Galán-Mascarós, J. R.; Dunbar, K. R. A self-assembled 2D molecule-based magnet: the honeycomb layered material {Co3 Cl4(H2 O)2[Co(Hbbiz)3]2}. Angew. Chem. Int. Ed. 2003, 42, 2289–2293.Search in Google Scholar

[7] Kirchner, C.; Krebs, B. Pentacoordinate zinc complexes of imidazole nitrogen donors as structural models for the active site in enzymes: preparation and crystal structures of (μ-2,2’-biimidazole)tetrakis(2,2’-biimidazole)dizinc(II) tetraperchlorate trihydrate and bis(2,2’-biimidazole)(formato)zinc(II) perchlorate. Inorg. Chem. 1987, 26, 3569–3576.Search in Google Scholar

[8] Zhai, J.; Sang, R.-L.; Xu, L. Supramolecular architectures built of chain-like [PnCl5]2- (Pn=Sb, Bi) and protonated 2,2’-biimidazole: synthesis, crystal structures and characterizations. J. Mol. Struct. 2001, 1006, 553–558.Search in Google Scholar

[9] Liu, G. Di-μ-chlorido-bis[(2,2’-bibenzimidazole)chloridocadmium(II)]. Acta Crystallogr. E. 2009, E65, m37.Search in Google Scholar

[10] Lin, S.; Chen, L.-J.; Xu, H.-H.; Su, J.-B.; Huang, H. Two 2D metal–organic frameworks based on 2,2′-bibenzimidazole ligand with (6,3) net topology. Inorg. Chem. Commun. 2010, 13, 1347–1349.Search in Google Scholar

[11] Zhong, Y.-R.; Cao, M.-L.; Mo, H.-J.; Ye, B.-H. Syntheses and crystal structures of metal complexes with 2,2′-biimidazole-like ligand and chloride: investigation of X-H···Cl (X=N, O, and C) hydrogen bonding and Cl-π (imidazolyl) interactions. Cryst. Growth Des. 2008, 8, 2282–2290.Search in Google Scholar

[12] Devonald, D. P.; Nelson, A. J.; Quan, P. M.; Stewart, D. Process for the extraction of metal values and novel metal extractants. EP Patent 0196153, 1989.Search in Google Scholar

[13] Cote, G.; Jakubiak, A. Modelling of extraction equilibrium for zinc(II) extraction by a bibenzimidazole type reagent (ACORGA ZNX 50) from chloride solutions. Hydrometallurgy. 1996, 43, 277–286.Search in Google Scholar

[14] Mukhopadhyay, C.; Ghosh, S.; Butcher, R. J. An efficient and versatile synthesis of 2,2’-(alkanediyl)-bis-1H-benzimidazoles employing aqueous fluoroboric acid as catalyst: Density Functional Theory calculations and fluorescence studies. ARKIVOC. 2010, 9, 75–96.Search in Google Scholar

[15] Kaupp, G.; Naimi-Jamal, M. R. Quantitative cascade condensations between o-phenylenediamines and 1,2-dicarbonyl compounds without production of wastes. Eur. J. Org. Chem. 2002, 2002, 1368–1373.Search in Google Scholar

[16] Fieselmann, B. F.; Hendrickson, D. N.; Stucky, G. D. Synthesis, electron paramagnetic resonance, and magnetic studies of binuclear bis(η5-cyclopentadienyl) titanium(III) vompounds with bridging pyrazolate, biimidazolate, and bibenzimidazolate anions. Inorg. Chem. 1978, 17, 2078–2084.Search in Google Scholar

[17] Lane, E. S. A modified benziminazole synthesis. Part II. A route to unsymmetrically substituted 2:2’-dibenziminazolyls and methylenebis-2-benziminazoles. J. Chem. Soc. 1955, 1079–1081.10.1039/JR9550001079Search in Google Scholar

[18] Rezende, M. C.; Dall’Oglio, E. L.; Zucco, C. Puzzling formation of bisimidazole derivatives from hexachloroacetone and diamines. Tetrahedron Lett. 1996, 37, 5265–5268.Search in Google Scholar

[19] Huang, W.-K.; Cheng, C.-W.; Chang, S.-M.; Lee, Y.-P.; Diau, E. W.-G. Synthesis and electron-transfer properties of benzimidazole-functionalized ruthenium complexes for highly efficient dye-sensitized solar cells. Chem. Commun. 2010, 46, 8992–8994.Search in Google Scholar

[20] Holan, G.; Samuel, E. L.; Ennis, B. C.; Hinde, R. W. 2-Trihalogenomethylbenzazoles. Part I. Formation. J. Chem. Soc. (C). 1967, 20–25.10.1039/j39670000020Search in Google Scholar

[21] Li, Y.; Jin, J.; Qian, W.; Bao, W. An efficient and convenient Cu(OAc)2/air mediated oxidative coupling of azoles via C–H activation. Org. Biomol. Chem. 2010, 8, 326–330.Search in Google Scholar

[22] Monguchi, D.; Yamamura, A.; Fujiwara, T.; Somete, T.; Mori, A. Oxidative dimerization of azoles via copper(II)/silver(I)-catalyzed CH homocoupling. Tetrahedron Lett. 2010, 51, 850–852.Search in Google Scholar

[23] Komarov, I. V.; Strizhak, A. V.; Kornilov, M. Yu. Direct phosphorylation of N-protected imidazoles and benzoimidazoles-a route to 1H-imidazol(benzoimidazol)-2-yl phosphonic and phosphinic acids and their derivatives. Synthetic Commun. 1998, 28, 2355–2370.Search in Google Scholar

[24] Bergman, J.; Koch, E.; Pelcman, B. 2,2’-Biindolyl revisited. Synthesis and reactions. Tetrahedron. 1995, 51, 5631–5642.Search in Google Scholar

[25] Hudkins, R. L.; Diebold, J. L.; Marsh, F. D. Synthesis of 2-aryl- and 2-vinyl-1H-indoles via palladium-catalyzed cross-coupling of aryl and vinyl halides with 1-carboxy-2-(tributylstannyl)indole. J. Org. Chem. 1995, 60, 6218–6220.Search in Google Scholar

[26] Dupeyre, G.; Lemoine, P.; Ainseba, N.; Michel, S.; Cachet, X. A one-pot synthesis of 7-phenylindolo[3,2-a]carbazoles from indoles and β-nitrostyrenes, via an unprecedented reaction sequence. Org. Biomol. Chem. 2011, 9, 7780–7790.Search in Google Scholar

[27] Fuhrhop, J.-H.; Li, G. Organic Synthesis. Concepts and Methods; Wiley-VCH Verlag GmbH & Co. KGaA: Weinheim, 2003.Search in Google Scholar

[28] Ajani, O. O.; Obafemi, C. A.; Ikpo, C. O.; Ogunniran, K. O.; Nwinyi, O. C. Microwave-assisted synthesis and antibacterial activity of some pyrazol-1-ylquinoxalin-2(1H)-one derivatives. Chem. Heterocycl. Comp. 2009, 45, 1370–1378.Search in Google Scholar

[29] Armand, J.; Boulares, L. Electrochemical reduction of quinoxalino[2,3-b]quinoxaline. Can. J. Chem. 1982, 60, 2797–2803.Search in Google Scholar

[30] Oxtoby, N. S.; Blake, A. J.; Champness, N. R.; Wilson, C. Water superstructures within organic arrays; hydrogen-bonded water sheets, chains and clusters. Chem. Eur. J. 2005, 11, 4643–4654.Search in Google Scholar

Received: 2013-12-20
Accepted: 2014-3-30
Published Online: 2014-5-12
Published in Print: 2014-6-1

©2014 by Walter de Gruyter Berlin/Boston

This article is distributed under the terms of the Creative Commons Attribution Non-Commercial License, which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

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https://doi.org/10.1515/hc-2013-0241
Keywords for this article
2,2′-bibenzimidazole; diethylene glycol; 1,4-dihydroquinoxaline-2,3-dione; o-phenylenediamine; oxalic acid
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BY-NC-ND 3.0

Articles in the same Issue

  1. Frontmatter
  2. Review
  3. Synthesis and reactivity of heterocyclic hydroxylamine-O-sulfonates
  4. Preliminary Communication
  5. Synthesis of pyridine derivatives as potential antagonists of chemokine receptor type 4
  6. Research Articles
  7. Design and synthesis of novel active phosphonate esters and their application in preparation of ceftriaxone
  8. Synthesis of novel oxepine-containing polycyclic-fused quinoline systems
  9. Crystal structure of 2-aminobenzothiazolinium nitrate and theoretical study of the amino-imino tautomerism of 2-aminobenzothiazole
  10. Short and efficient synthesis of 5-aminothiazole-4-carboxamide
  11. The use of diethylene glycol in the synthesis of 2,2′-bibenzimidazole from o-phenylenediamine and oxalic acid
  12. Facile one-pot synthesis of chromeno[4,3-b]quinoline derivatives catalyzed by Cu(II)-Schiff base/SBA-15
  13. 5-(2,2-Dimethyl-4H-1,3-benzodioxin)methanol: the synthetic precursor to o-formyl-m-hydroxycinnamic acid, the most oxidized salicylaldehyde-type phytotoxin isolated from rice blast fungus, Magnaporthe grisea
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