Comparative study of 1 , 3-dibromo-5 , 5-dimethylhydantoin assisted and conventional synthesis of benzimidazole derivatives and the solvent effects on spectroscopic properties

A small library of benzimidazoles with a range of side-chain substituents have been synthesized through the condensation reaction of o-phenylenediamine derivatives and several other commercially available materials. The reactions were catalyzed by either 4M HCl or 1,3-dibromo-5,5dimethylhydantoin (DBDMH). The compounds synthesized using DBDMH as the catalyst required a shorter reaction time, the yield was higher and the workup procedure was not as tedious as those produced using 4M HCl as the catalyst. The structural elucidations of synthesized compounds have been confirmed through spectroscopic analysis. 13 C NMR analysis of some of the synthesized compounds showed that the appearance of carbon signals in the NMR spectrum is affected by the nature of the NMR solvent and temperature.The exchange-induced broadening of the 13 C NMR signal was probably facilitated by the intermolecular proton exchange between the NH of the benzimidazole and the H2O present in the DMSO-d6 solvent.


INTRODUCTION
Benzimidazoles have occupied a prominent place in medicinal chemistry due to their significant effect as therapeutics in clinical applications.In fact, they have a long and rich history in organic chemistry and drug discovery (Grimmett, 1996;Orjales et al., 1997).Benzimidazole derivatives have been called several names in the early chemical literature.Such names include benziminazoles, benzoglyoxalines, o-phenylenediamine, o-phenyleneformamidine and 2(3H)benzimidazolethione derivatives (Wright, 1951).The interest in benzimidazole as a drug molecule began in 1944 when Woolley speculated that benzimidazole, due to its structural resemblance to purine, induced riboflavin deficiency in bacteria (Woolley, 1944).Emerson et al. (1950) identified 5,6dimethylbenzimidazole as the degradation product of E-mail: petersegun2020@yahoo.com.Tel: +2347033637847.
Author(s) agree that this article remain permanently open access under the terms of the Creative Commons Attribution License 4.0 International License cyanocobalamine (vitamin B12) and suggested that this fragment can be considered as the "precursor" of cyanocobalamine.The benzimidazole moiety has been shown to possess several biological activities that includes antiulcer (omeprazole), antifungal (thiabendazole), anti-inflammatory (Benoxaprofen), antihelmintic (albendazole), antifungal (carbendazim), antitumor (bendamustine) and antiviral (enviradine) effects (Pisano et al., 2000).
Three years later, Ladenburg made the same compound by refluxing 3,4-diaminotoluene with acetic acid.
However, the conventional method of benzimidazole synthesis, known as the Phillip's method, involves the reaction of 1,2-diaminobenzenewith carboxylic acid in the presence of a mineral acid catalyst to form the corresponding substituted benzimidazole (Phillips, 1928).Although the Phillip's method is one of the most frequently utilized methods of benzimidazoles synthesis, several variations of this method have been developed (Crotti et al., 1992;Yang et al., 2005;Du and Wang, 2007;Sluiter and Christoffers, 2009;Peng et al., 2010).
In a bid to improve yields and reaction conditions, it is conceivable to develop a series of benzimidazole derivatives using 1,3-dibromo-5,5-dimethylhydantoin (DBDMH) as an efficient homogeneous catalyst and carry out a comparison with the conventional Phillip's synthesis.DBDMH, a five-membered heterocyclic compound that is relatively non-toxic and stable to air and moisture, is a cheap and convenient alternative to Nbromosuccinimide (NBS).It has been used widely in organic synthesis as a brominating and oxidizing agent (Tsuchiya et al., 2013;Sasikumar et al., 2013;Li et al., 2014).Its efficiency as a highly homogeneous catalyst for synthesis of benzimidazoles from orthoesters was described by Hojati et al. (2011); the procedure was optimized in this present study.
All the synthetic compounds were characterized by various spectroscopic analyses and the effect of solvent type on the NMR spectrum of synthesized compounds was investigated.

General experimental methods
All reagents and starting materials were of analytical grade.Melting points were determined in open capillary tubes on a Stuart SMP 11 melting point apparatus and were uncorrected.Thin layer chromatography (TLC) was performed on pre-coated silica gel aluminium sheets.Chromatograms were visualised by UV light (254 and 365 nm).IR spectra were obtained on a Varian 800 FT-IR spectrometer; wavenumbers (ν) are indicated in cm -1 . 1 H and 13 C NMR spectra were determined on AvanceBruker AG 300 and 500 MHz instruments at room temperature (295 K) using DMSO-d6 or CDCl3 as solvent.The chemical shifts (δ) were reported in parts per million (ppm) relative to tetramethylsilane (TMS, δ 0.00 ppm) as the internal standard.All coupling constant (J) values are given in Hertz.The splitting patterns of the 1 H NMR were designated as singlet (s), doublet (d), doublet of doublet (dd), doublet of doublet of doublet (ddd), triplet (t), quartet (q) multiplet (m) and broad (br).Mass spectra were performed on a Waters LCT Premier mass spectrometer.
General procedure for the synthesis of benzimidazole derivatives using DBDMH as catalyst Hojati et al. (2011) described the synthesis of benzimidazoles from orthoesters; the procedure was optimized in this present study.To a 100 mL round-bottom flask equipped with a magnetic stirrer were added diaminobenzene (10 mmol) and ortho-esters (12 mmol) in sequential order.This was followed by the addition of a catalytic amount of 1,3-dibromo-5,5-dimethylhydantoin (3 mol%).A reflux condenser was fitted to the round-bottom flask and the mixture was stirred and refluxed at 85°C.After 10 to 15 min the starting materials were consumed as indicated by thin layer chromatography (eluent: DCM/MeOH 9:1) and the reaction was cooled down to room temperature.The reaction mixture was concentrated via a rotary evaporator to give a dark brown oil.Then n-hexane (20 mL) was added and the resulting solution was stirred at room temperature for 20 min.The crude product precipitated during the stirring and was separated through vacuum filtration.The crude product was purified by recrystallization in distilled H2O to afford the benzimidazole derivatives 1-9 in excellent yields.The structures of the synthesized compounds were confirmed by NMR and EI mass spectroscopy.

General method for the conventional synthesis of benzimidazole derivatives
To a 100 mL round-bottom flask equipped with a magnetic stirrer were added diaminobenzene (10 mmol) and acid (12 mmol) in one portion.The mixture was dissolved in 4M HCl (5 mL).A reflux condenser was fitted to the round-bottomed flask and the resulting solution was refluxed at 100°C and stirred at this temperature for 24 h; by this time thin layer chromatography (eluent: ethyl acetate/ hexane 6:4) indicated that the reaction had gone to completion.After this period, the reaction mixture was allowed to cool down to room temperature and neutralized with aqueous NH3 solution.At the end of the neutralization process, the crude product precipitated and was separated by vacuum filtration.The crude product was recrystallized several times in ethanol-petrol 40/60 mixture to obtain the analytically pure benzimidazole derivatives in good yield.

RESULTS AND DISCUSSION
This present work aimed to study the condensation reaction of o-phenylenediamine derivatives with several other commercially available starting materials to generate a small library of benzimidazoles with a range of side-chain substituents.At the beginning of the work, 4nitro-1,2-diaminobenzene and triethylorthoformate were reacted via a continuous magnetic stirring at 85°C in the presence of catalytic amount of DBDMH for about 15 min.After the completion of the reaction which was monitored by TLC, the crude product precipitated on Scheme 1. Synthesis of benzimidazole derivatives 1-9.Scheme 2.Tautomeric form of Compound 2. addition of n-hexane and this was recrystallized in distilled H 2 O to afford 5-nitrobenzimidazole 1 in good yield (75%).Being motivated by this success, the condensation of other ortho-ester with ophenylenediamine derivatives was carried out to obtain benzimidazole derivatives 2-9 in good to excellent yields (Scheme 1).
In order to elucidate the structural features of compound 1, 1 H and 13 C NMR, IR and Mass spectra were taken.Analysis of the 1 H NMR spectrum of 1 in DMSO-d 6 revealed a vicinal coupling between H-6 and H-7 and a long-range coupling between H-4 and H-6 confirming the presence of the three of the four aromatic protons in 1. H-2 appeared as singlet at the downfield region δ 8.56 ppm while the characteristic NH signal recorded as a broad singlet at δ 13.11 ppm.

13
C NMR spectrum in DMSO-d 6 revealed seven aromatic carbons which was consistent with ChemBioDraw Ultra 14.0 prediction.IR analysis revealed the absorption peaks corresponding to the NH and NO 2 groups at 3101 and 1340 cm -1 respectively.Mass spectrometric analysis confirmed the identity of the synthesized compound by the appearance of MH + at m/z164.The melting point of 1 was within the range of that described in the literature.
The formation of 2 required a shorter time compared to 1 possibly because of the electron-donating group (methyl) present in 2 as against the electron-withdrawing group (NO 2 ) present in 1.The structure of compound 2 was confirmed by spectroscopic analyses.IR spectra showed absorption peaks at 3227 cm -1 (NH) and 3017-2855 cm -1 (C-H str.).The melting point of 2 was within the range of that described in the literature and the mass Segun 199 spectrum showed MH + at m/z 147.
1 H NMR spectrum revealed the characteristic NH signal that recorded as a broad singlet at δ 12.04 ppm and the three aromatic protons that is expected for 2. However, 13 C NMR in DMSO-d 6 (solvent) revealed broadened peaks and the number of the carbon signals observed did not match expectations.Similarly, the heteronuclear single quantum coherence (HSQC) analysis in DMSO-d 6 failed to show the expected correlations between the carbons and the protons, possibly because the carbons were broadened or missing.The broadening of the carbon signals is likely to be due to intramolecular N-H exchange between the two tautomers of 2 (Scheme 2).
This exchange probably happens so fast that the NMR spectrum reveals an average broadened signal of the two tautomers.This exchange-induced broadening is probably facilitated by the intermolecular proton exchange between the NH of 2 and the H 2 O in the DMSO-d 6 solvent, and this is corroborated by the exchange spectroscopy (EXSY) analysis.Although the fast relaxation of the NH proton caused by the quadrupolar 14 N nucleus can lead to broadened 13 C signals, this may not be responsible for the broadening observed here as the 13 C NMR of 2 taken in CDCl 3 gave sharp carbon peaks as expected (Figure 1).This further confirms that the exchange-induced broadening observed when DMSO-d 6 is used as solvent is most likely to be due to the solvent effect.Normally, lowering the temperature of DMSO-d 6 will slow down the proton exchange and allow each carbon to be seen as individual signals, but since DMSO-d 6 has a high freezing point (18.6°C), this experiment is not possible (Williams and Fleming, 2008).
Since compound 2 contains two sets of methyl protons (H-2' and H-5') that gave equal intensity within the same region in the I H NMR spectrum, it was necessary to unambiguously assign the chemical shift of each CH 3 .To achieve this, the heteronuclear multiple bond connectivity (HMBC) analysis was conducted in CDCl 3 and it revealed multiple bond correlation between H-5' and the aromatic carbons (C-4, C-6 and C-7) and this corresponds to the singlet with the chemical shift at 2.38 ppm.The singlet with the chemical shift 2.45 ppm was assigned to the second CH 3 (H-2') since it showed correlation with C-2.The singlet at 7.23 was assigned unequivocally to H-4.The remaining doublet signals at chemical shift 6.92 and 7.32 ppm were unequivocally assigned to H-6 and H-7 respectively following analysis of the HMBC spectrum.On comparison, the aromatic protons of 1 appeared on a more downfield region (7.76 to 8.50 ppm) than the aromatic proton of 2 (6.92 to 7.32 ppm).This is due to the presence of a strong electron-withdrawing group (NO 2 ) on 1 that deshielded the nucleus of the aromatic protons.
With the proton assignments of 2 in hand, the HSQC and HMBC analyses were used to assign all the carbon signals displayed on the 13 C NMR spectrum.C-2', C-5', C-4, C-5, C-6 and C-7 were easily assigned by observing the correlation with their corresponding protons.The quaternary and sp 2 hybridized C-2 was assigned to the most downfield signal of 151.18 ppm on the basis of its unique environment; it is surrounded by two electronegative nitrogen atoms.This assignment was confirmed by the presence of a 2 J HMBC connectivity between the H-2' resonance and the signal at 151.18 ppm.The two remaining quaternary carbon were tentatively assigned as C-8 (136.77ppm) and C-9 (138.22 ppm).
Success in the synthesis of 1 and 2 which has electronwithdrawing and electron-donating side chain respectively led to the synthesis of 3 which contains both electron donating and electron-withdrawing groups.The information revealed in the 1 H NMR spectrum of 3 was sufficient to unambiguously assign each chemical shift to the corresponding proton.The melting point of 3 was within the range described in the literature.IR analysis revealed the absorption peaks corresponding to the NH and NO 2 groups at 3561 and 1334 cm -1 respectively.Mass spectrometric analysis confirmed the identity of the synthesized compound by the appearance of MH + at m/z 178 and MNa + at m/z 200.
Compounds 4-9 were characterised by various spectroscopic methods.IR absorption spectra showed a sharp peak at 1654 and 1651 cm -1 for 6 and 7 respectively and this corresponds to the ketone carbonyl group present in these compounds.The melting point and spectroscopic data for 7 could not be found in the Scifinder® and Reaxys® database; these data is included in the experimental section of this report.1 H NMR analysis of 8 and 9, the signals displayed by the aromatic protons showed patterns different from those observed in previously synthesized compounds; especially a doublet of doublet of doublet signal which is probably due to the strong coupling between hydrogen and fluorine.
Following success with the synthetic route described above, compound 10 and 11 were made from the conventional Phillips method which involves condensation reaction of 4-methyl-1,2-diaminobenzene and the respective acid using 4M HCl as the catalyst (Scheme 3).In comparing the methods used in the synthesis of the benzimidazole derivatives, the compounds synthesized using DBDMH as the catalyst required a shorter reaction time, the yield was higher and the workup procedure was not as tedious as those produced using 4M HCl as the catalyst.In fact, within the same period, the Phillips method of benzimidazole synthesis could only afford two pure products while the DBDMH catalysed process generated nine pure compounds.Similarly, the DBDMH catalyzed reaction is an environmentally friendly reaction as it is solvent free and does not generate hazardous waste materials.

Conclusions
Eleven benzimidazole derivatives have been prepared using different starting materials and the synthetic procedure has been described in this work.The compounds synthesized using DBDMH as the catalyst required a shorter reaction time, the yield was higher and the workup procedure was not as tedious as those produced using 4 M HCl as the catalyst (Phillip's method).The structural elucidations of all synthesized compounds have been confirmed through spectroscopic analysis.This present study also revealed that the appearance of carbon signals in the 13 C NMR analysis of some of the synthesized compounds was affected by the nature of the NMR solvent and temperature.

Figure 1 .Figure 1 .
Figure 1.Expansion of 13 C NMR spectrum of compound 2 taken in DMSO-d6 and CDCl 3 used to elucidate the structure of 10 and 11.It is worth mentioning that the OH proton (H-3') in the 1 H NMR spectrum of 10 was observed as a broad singlet (δ= 5.83 ppm) which disappeared after D 2 O shake.The mass spectrum revealed MH + expected for 10 and 11.