Short communication
A Cobalt Nitrate/Hydrogen Peroxide System as an Efficient Reagent for the Synthesis of 2-Aryl Benzimidazoles and Benzothiazoles
Pranav S. Chandrachood,1 Dinesh R. Garud,2 Tushar V. Gadakari,1 Rasika C. Torane,1 Nirmala R. Deshpande1 and Rajashree V. Kashalkar1*
1 T. R. Ingle Research Laboratory, Department of Chemistry, Sir Parashurambhau College, Pune 411030, India. 2 Department of Chemistry, Sir Parashurambhau College, Pune 411030, India. * Corresponding author: E-mail: rvkashalkar@gmail.com Received: 19-12-2010
Abstract
Benzimidazoles and benzothiazoles show significant and promising activities against various viruses such as HIV and HCMV-1. Their synthesis using cobalt nitrate and hydrogen peroxide in N,N-dimethylformamide has been presented in the following study. The cobalt nitrate/H2O2 appears to be a smooth and efficient reagent system for the synthesis of 2-aryl substituted benzimidazoles and benzothiazoles. Simple and convenient reaction procedures and shorter reaction times are the salient features of the presented route.
Keywords: o-phenylenediamine, o-aminothiophenol, aldehyde, cobalt nitrate hexahydrate, hydrogen peroxide.
1. Introduction
Bezimidazole and benzothiazole derivatives show significant activities against various viruses such as human cytomegalovirus (HCMV),1 herpes (HSV-1),2'3 HIV,4'5 influenza etc. Benzothizole nucleus has been a common pharmacophore in various antitumor and anticancer agents.6'7 Consequently, the preparation of benzi-midazole and benzothiazole derivatives with prominent biological activities has attracted tremendous attention nowadays' even though many routes are available for the synthesis of 2-aryl benzimidazoles and benzothiazoles, there are just two commonly used routes. The most commonly used method involves direct condensation of o-phenylenediamine or o-aminothiophenol with aldehyde to afford a Schiff base which then undergoes oxidative cycli-sation to yield corresponding 2-subtituted benzimidazoles or benzothiazoles (Scheme 1). The oxidative cyclisation is catalyzed by various acidic reagents such as p-TsOH,8 Fe-Cl36H2O,9 In(OTf)3,10 Yb(OTf)3,11 or oxidizing agents such as MnO2,1212,13 oxone,14 ceric(IV) ammonium nitrate,15 and silica supported sulfuric acid.16 In another method, strongly acidic conditions are involved in coupling of o-phenylenediamines (or o-aminothiophenol) and car-
boxylic acids (or their derivatives, such as nitriles, orthoesters etc.). This route has a limited scope because of harsh conditions and formation of by-products, whereas milder reaction conditions make the previous route more attractive (Scheme 1). Many published routes use milder reagents, but suffer from disadvantages, such as prolonged reaction times, formation of numerous by-products, usage of toxic solvents etc. Therefore, to overcome these disadvantages, the search for a novel and milder reagent for the synthesis of 2-aryl benzimidazoles and benzothiazoles is the need of the day (Scheme 1).
Scheme 1
2. Experimental
Melting points were measured by using capillary tube method with MP-DS instrument. 1H-NMR spectra
were recorded on a Bruker 400 instrument using TMS as 2-(2-chlorophenyl) benzothiazole (5d): mp 69-71 °C.
m/z = 246, [M+1]+. 1HNMR (400 MHz, CDCl3): 5 8.12-
an internal standard and CDCl3 or DMSO-d6 as a solvent. The IR spectra were recorded on a Shimadzu 1600 instrument using KBr disks.
2. 1. General Procedure for the Synthesis of 2-aryl Substituted Benzimidazoles and Benzothiazoles
Aldehyde (1 mmol) and o-phenylenediamine (or o-aminothiophenol (1 mmol)) were mixed thoroughly in DMF in a round bottom flask. To this solution, cobalt nitrate hexahydrate (0.5 mmol, 146 mg) and aq. H2O2 (30%, 1 mmol, 0.8 mL) were added with continuous stirring. The reaction mixture was then heated to 80 °C using a paraffin oil bath with a magnetic stirrer and formation of product was monitored using TLC with hexane:ethyl acetate (8:2) as the mobile phase. After completion of the reaction, ethyl actate (30 mL) was added to the reaction mixture, and it was extracted with water (2 x 15 mL), brine (1 x 10 mL) and again with water (1 x 15 mL). The organic layer was then dried over anhydrous Na2SO4 and evaporated under vacuum to obtain a crude mass. The solid mass was purified using column chromatography on silica gel (60-120) with hexane:ethyl acetate (8:2) as eluent. The pure compound was then recrystalized from chloroform.
2. 2. Spectral Data for Selected Compounds
2-(3-nitrophenyl) benzimidazole (4f): mp 198-200 °C. m/z = 240, [M+1]+. 1HNMR (400 MHz, DMSO-d6): 5 12.7 (1H, brs, NH), 9.04 (1H, s, Ar-H), 8.67 (1H, d, Ar-H), 8.24 (1H, d, Ar-H), 7.8-7.59 (3H, m, Ar-H), 7.126 (2H, m, Ar-H).
2-(3-nitrophenyl) benzothiazole (5f): mp 182-184 °C. m/z = 257, [M+1]+. 1HNMR (400 MHz, CDCl3): 5 8.94 (1H, s, Ar-H), 7.3-7.69 (4H, m, Ar-H), 7.93-8.44 (3H, m, Ar-H).
2-(4-chlorophenyl) benzothiazole (5e): mp 118-119 °C. m/z = 246, [M+1]+. 1HNMR (400 MHz, CDCl3): 5 8.087.90 (4H, m, Ar-H), 7.53-7.39 (4H, m, Ar-H).
7.53 (3H, m, ArH), 7.52-7.39 (5H, m, Ar-H).
3. Results and Discussion
The screening of the reagent system was done by carrying out the synthesis of 2-(4-chlorophenyl)benzot-hiazole (5e) using various reagents. The results revealed that when the reaction was carried out using silica as the catalyst, even after prolonged heating in dichloromethane it gave poor yields. When the reaction was carried out using silica in the absence of any solvent under microwave irradiation it gave only 33% yield of the desired product. A solvent free reaction was attempted under heating using silica supported sulfuric acid as a catalyst, which gave poor yields. These results promoted us to use metal nitrates (Co and Ni) for the reaction. The best results were obtained when the reaction was carried out using Co(NO3)2/ H2O2 system in DMF as a solvent (Table 1).
In order to set the optimum reaction conditions in terms of solvent, temperature and reagent quantity, a reaction of o-aminothiophenol and p-chlorobenzaldehyde was carried out at two different temperatures, in various solvents ranging from nonpolar hexane to polar N,N-di-methylformamide (DMF) and by varying reagent quantities (Table 2).
3. 1. Effect of Change of Solvent Media and Temperature
The selection of a proper solvent is an essential condition for synthesis of 2-substituted benzothiazoles and benzimidazoles in quantitative yields. In order to select a proper solvent, the reaction of o-aminothiophenol with p-chlorobenzaldehyde was carried out in various solvents. In nonpolar hexane, the yields were poor with longer reaction times. DMF as the solvent provided quantitative yields with shorter reaction times. To evaluate the effect of change in temperature, the reagent quantity was kept constant. The reaction was carried out at two different temperatures and moderate to excellent yields were obtained at 80 °C.
Table 1. Screening of catalyst for the synthesis of 2-(4-chlorophenyl) benzothiazole.
Entry	Catalyst	Time (Min)	Yield (%)c	Reaction Condition
1	Silicaa	300	29	Dichloromethane/reflux
2	Silicaa	10	33	Solvent free/microwave
3	Silica supported	120	58	Solvent free/heating at 90 °C
	sulfuric acida			
4	Co(NO3)2 6H2Ob	15	93	Dimethyl formamide/80 °C
5	Co(NO3)2 6H2Ob	45	77	Solvent free/room temp.
6	Ni(NO3)2 6H2Ob	90	85	Dimethyl formamide/80 °C
a Reaction conditions: 2 (1 mmol), 3e (1 mmol), catalyst (100 mg). b Reaction conditions: 2 (1 mmol), 3e (1 mmol), Metal nitrate hexahydrate (2 mmol), 30% aq. H2O2 (2 mmol). c Isolated yields.
Table 2. Effect of change in solvent, temperature and reagent quantity on the synthesis of 2-(4-chlorop-henyl)benzothiazolea
aNH2	---
» + "oH>CI
Entry	Solvent	Temperature	Co(NO3)2 6H2O	H2O2	Yield	Time
		(°C)	(Equiv.)	(Equiv.)	(%)	(min)
1	Hexane	25	2	2	49	90
2	Dichloromethane	25	2	2	55	60
3	Acetone	25	2	2	67	60
4	Methanol	25	2	2	70	40
5	DMF	25	2	2	79	30
6	Hexane	Reflux	2	2	54	80
7	Dichloromethane	Reflux	2	2	55	40
8	Acetone	Reflux	2	2	78	30
9	Methanol	Reflux	2	2	81	30
10	DMF	80	2	2	93	15
11	DMF	80	1	1	91	15
12	DMF	80	0	1	30	35
13	DMF	80	0.2	1	52	25
14	DMF	80	0.5	1	93	20
a Reaction conditions: 2 (1 mmol), 3e (1 mmol), Co(NO3)2 6H2O, 30% aq. H2O2, solvent b Isolated yields.
Optimum reaction conditions were obtained when reaction was carried out at 80 °C and DMF as a solvent (Table 2).
3. 2. Effect of Change in Reagent Quantity
In order to optimize the reagent quantity, the reaction was carried out at 80 °C in DMF by varying the concentrations of cobalt nitrate hexahydrate and H2O2. Initially, 2 equiv. of cobalt nitrate were used along with equi-molar proportion of H2O2. The yields were quantitative with shorter reaction times. Next, in order to find out optimal reagent concentration, it was gradually decreased from 2 equiv. to 1 equiv. and so on. In the absence of cobalt nitrate the yields were very poor (only 30% of the desired product was isolated). This confirms the essentiality of the cobalt nitrate in the synthesis of benzothiazole. The yields were only slightly increased when 0.2 equiv. of cobalt nitrate was used along with 2 equiv. of H2O2. To get the more satisfactory results, the quantity of cobalt nitrate was increased to 0.5 equiv. keeping the concentration of H2O2 constant. The best results were obtained when 0.5 equiv. of cobalt nitrate was used along with 1 equiv. of H2O2 as reported (Table 2).
The reagent system was tested by carrying out the reaction using aromatic aldehydes with varying substi-tuents on the aromatic ring for generalization of reaction route. It was a delight to observe that the reaction of o-phenylenediamine (or o-aminothiophenol) worked well with a variety of the substituents on the aromatic ring ranging from electron withdrawing NO2 to electron donating
OMe. The above mentioned reagent system tolerated different substituents such as NO2, Cl, Br, CH3 and OMe. From the results can be concluded that compounds containing electron withdrawing substituents reacted relatively faster than those with electron donating substituents. This can be attributed to higher electrophilicity of the carbonyl carbon in the presence of electron withdrawing nitro substituent which is an essential condition for the first condensation step to take place. As expected, ophenylenedia-mine reacted faster with increased yields than o-aminot-hiophenol due to the higher nucleophilicity of nitrogen than sulfur (Table 3).
4. Conclusions
The Co(NO3)2/H2O2 presents a novel and efficient reagent system for the synthesis of 2-aryl benzimidazoles and benzothiazoles in moderate to excellent yields. Simple reaction conditions, simple workup procedures and easy availability of the reagents make this route more attractive and economically viable. Aliphatic aldehydes do not work well with this reagent.
5. Acknowledgements
The authors are grateful to The Principal, Sir Paras-hurambhau College, Pune, India, for providing necessary facilities and place of work.
Table 3. Synthesis of 2-aryl benzimidazoles and benzthiazoles using Co(NO3)2/H2O2 systema
Entry	X	Aldehyde	Ar	Product	Time (min)	Yield (%)b	m.p. Lit Ref	(°C) Observed
1	NH	3a	o	4a	30	87	290-29317	288-291
2	NH	3b	-o»	4b	35	85	165-16717	168-169
3	NH	3c		4c	30	84	264-26518	260-261
4	NH	3d	-p	4d	30	89	234-23519	229-231
5	NH	3e		4e	30	90	292-29419	290-291
6	NH	3f		4f	25	89	201-20320	198-200
7	NH	3g		4g	35	88	246-24821	244-245
8	NH	3h		4h	30	89	262-26422	258-260
9	NH	3i		4i	40	Trace	168-17023	170-171
10	S	3a	-o	5a	35	88	112-11424	110-111
11	S	3b		5b	30	86	120-12125	120-122
12	S	3c	-o».	5c	25	87	84-8626	82-83
13	S	3d	iP	5d	25	92	72-7427	69-71
14	S	3e		5e	15	93	115-11728	115-117
15	S	3f		5f	15	91	180-18229	182-184
a Reaction conditions: Amino compound (1 mmol), aldehyde (1 mmol), Co(NO3)2 6H2O (0.5 mmol), H2O2 (1 mmol) in DMF at 80 °C.
' Isolated yields.
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Povzetek
Benzimidazoli in benzotiazoli kažejo opazno in obetavno aktivnost proti različnim virusom, kot sta npr. HIV in HCMV-1. V tej študiji predstavljamo njihovo sintezo z uporabo kobaltovega nitrata in vodikovega peroksida v A,A-dimetilforma-midu. Kobaltov nitrat/H2O2 se je izkazal kot učinkovit sistem reagentov za sintezo 2-aril substituiranih benzimidazolov in benzotiazolov. Enostavna in priročna izvedba reakcije ter kratki reakcijski časi so bistvene prednosti predstavljene sinteze.