INTRODUCTION:

Benzimidazole is an important heterocyclic organic compound. It is having important pharmacophore and a Privileged structure in medicinal chemistry. Benzimidazole is a Bicyclic in nature which consists of an imidazole ring containing two nitrogen atoms at adjacent position synthesised by Hoebrecker in 1872, who obtained 2,5-(or) 2,6-dimethylbenzimidazole by the using of 2-nitro-4-methylacetanilide^1-2. Benzimidazole is a white to slightly beige solid. Melting at 145-150°c, slightly soluble in water, soluble in ethanol. Benzimidazole derivatives is used in different ways such as antifungal³, antitubaricular⁴, antioxadent⁵, antiallergic⁶, antiparasitic⁷, herbicidal agents⁸,

human and veterinary medicine⁹, antihelmintic, anti-HIV¹⁰, anti-histaminic^11-13, antiulcer^14-15, cardiotonic¹⁶, antihypertensive^17-18, anti-inflammatory^19-20, antiviral^21-22, anti convulsant^23-24, anticancer^25-29, antibacterial^30-31, Benzimidazole nucleus, the isomer of benzofuran, is an essential part of many clinically useful chemotherapeutic agents. Thiabendazol, triclabendazole and mebendazole are more effective anthelmentic agents. Chlormidazole is used in the treatment of fungal infections of the skin. Enviroxime is an effective drug against rhinovirus. Click chemistry is introduced by K.B. Sharpless. Click chemistry is widely used in different areas of science. Such as polymer chemistry, drug discovery, organic chemistry^32-36. We now designed and synthesized a series of 1,4-disubstituted-1H-1,2,3-triazole of benzimidazole derivatives from 2-((prop-2-yn-1-yloxy) methyl)-1H-benzo[d]imidazole. Cu catalyzed version of azide-alkyne cycloaddition with the formation of regioselective product 1,4-disubstituted-1H-1,2,3-triazole and they named the reaction as the ‘Click reaction’ which is also known as ‘Cu-catalyzed azide-alkyne Cycloaddition reaction’(CuAAC)^37-38. Azide-alkyne cycloaddition reaction in the presence of Cu (1) salt has a significant advantage in the synthesis of 1,2,3-triazoles since it has 100% regioselectivity, proceeds under mild reaction conditions, and excellent yields with broad spectrum of substrates. This click reaction is useful to highly yielding, easily remove to the solvents and no need to the column chromatography.

MATERIAL AND METHODS:

All the chemical was used as purchased from Sigma-Aldrich, Avra Laboratories. Solvents and reagents were obtained from commercial sources. Melting Points are uncorrected and were determined using open capillary tubes in sulphuric acid bath. TLC analyses were done on plastic sheets coated with silica gel G and spotting was done using Iodine/UV lamp. IR spectra were recorded on a Perkin Elmer model 1000 instrument in KBr Pellet. ¹H-NMR and ¹³C NMR were recorded in CDCl₃/DMSO-d₆ using 400 MHZ and 100 MHZ Varian Gemini spectrometer and TMS as a reference standard. Mass spectra were recorded on an Agilent-LCMS instrument.

General Procedure for the preparation of (1):

o-Phenylene di amine (10 mmol) was treated with glycolic acid (20mmol) in presence of 4N HCl and refluxed at 80-100°C for 4hr. The progress of reaction was monitored by TLC, reaction mixer is cooled to RT, after that reaction mixer it is poured onto ice and added a small amount of ammonia to obtain 1H-benzo[d]imidizole-2-yl) methanol^39-40 (1).

General procedure for the Preparation of (2):

1H-benzo[d]imidazol-2-yl) methanol (10 mmol) (1) is dissolved in DMF with stirring add quenched with a small amount of TBAB and propargyl bromide (20mmol) at RT condition after 2hr the progress of reaction was monitored by TLC, After the completion of reaction, reaction mixer was poured onto ice. The product 2-((prop-2-yn-1-yloxy) methyl)-1H-benzo[d]imidazole^41-42 (2) was collected by filtration.

General Procedure for the Preparation of 3(a-j):

The mixture of 5mol % of Copper sulphate. Heptahydrate, 10mol% of Na ascorbate was added to t-BuOH-H₂O (6ml) mixture [1:3] this mixture was stirred at RT for 15 min then 2-((prop-2-yn-1-yloxy) methyl)-1H-benzo[d]imidazole and p-Nitro benzyl azide were added to it. The reaction mixture stirred vigorously at RT for 16-20 hr. After completion of the reaction, it is extracted with ethyl acetate (3x10 ml) and washed with brine solution. Concentrate the organic layer, obtained compound purification purpose followed by column chromatography (SiO₂, elution with 20% EtOAc in Hexane) afforded pure 2-(((1-(4-nitrobenzyl)-1H-1,2,3-triazol-4-yl) methoxy) methyl)-1H-benzo[d]imidazole.

2-(((1-(4-nitrobenzyl)-1H-1,2,3-triazol-4-yl) methoxy) methyl)-1H-benzo[d]imidazole:(3a)

¹H NMR (400 MHZ, DMSO-d₆): 7.49 (d, 1H, Ar-H), 7.22 (t, 1H, Ar-H), 7.24 (t, 1H, Ar-H), 7.49 (d, 1H, Ar-H), 5.2 (s, 1H, NH), 4.59 (s, 2H, CH₂), 4.20 (s, 2H, CH₂), 7.69 (s, 1H, Ar-H), 5.32 (s, 2H, CH₂), 7.35 (s, 1H, Ar-H), 8.11 (d, 1H, Ar-H), 8.13 (d, 1H, Ar-H), 7.35(s, 1H, Ar-H):

¹³C NMR (100 MHZ, DMSO-d₆): 113.9, 118.1, 117.9, 113.7, 136.4, 139.2, 136.2, 65.9, 67.0, 141.9, 121.3, 56.1, 141.9, 126.3, 121.0, 142.7, 121.0, 126.3: LC-MS m/z, 365.29 [M+H)⁺.

2-(((1-benzyl-1H-1,2,3-triazol-4-yl) methoxy) methyl)-1H-benzo[d]imidazole: (3b)

¹H NMR (400 MHZ, DMSO-d₆): 7.49 (d, 1H, Ar-H), 7.22 (t, 1H, Ar-H), 7.22 (t, 1H, Ar-H), 7.49 (d, 1H, Ar-H), 5.2 (s, 1H, NH), 4.59 (s, 2H, CH₂), 4.20 (s, 2H, CH₂), 7.69 (s, 1H, Ar-H), 5.32 (s, 2H, CH₂), 7,20 (d, 1H, Ar-H), 7.36 (t, 1H, Ar-H), 7.23 (t, 1H, Ar-H), 7.36 (t, 1H, Ar-H), 7.20 (d, 1H, Ar-H);

¹³C NMR (100 MHZ, DMSO-d₆): 113.29, 118.1, 118.9, 113.9, 136.4, 139.2, 136.4, 65.9, 67.0, 141.9, 121.3, 56.2, 131.9, 125.4, 126.3, 123.1, 126.2, 125.4; LC-MS m/z, 320.19 [M+H]⁺.

4-((4-(((1H-benzo[d]imidazol-2-yl) methoxy) methyl)-1H-1,2,3-triazol-1-yl) methyl) benzonitrile: (3c)

¹H NMR (400 MHZ, DMSO-d₆): 7.49 (d, 1H, Ar-H), 7.22 (t, 1H, Ar-H), 7.22 (t, 1H, Ar-H), 7.49 (d, 1H, Ar-H), 5.20 (s, 1H, NH), 4.59 (s, 2H, CH₂), 4.20 (s, 2H, CH₂), 7.69(s, 1H, Ar-H), 5.32 (s, 2H, CH₂), 7.34(d, 1H, Ar-H), 7.49 (d, 1H, Ar-H), 7.49 (d, 1H, Ar-H), 7.34(d, 1H,Ar-H);

¹³C NMR (100 MHZ, DMSO-d₆): 113.9, 118.1, 118.7, 113.9, 136.4, 139.2, 136.4, 65.9, 67.0, 141.9, 121.3, 56.5, 132.7, 121.6, 124.7, 105.3, 113.4, 124.1, 121.5, LC-MS m/z, 345.29 [M+H]⁺

2-(((1-(4-bromobenzyl)-1H-1,2,3-triazol-4-yl) methoxy) methyl)-1H-benzo[d]imidazole:3d

¹H NMR (400 MHZ, DMSO-d₆): 7.49 (d, 1H, Ar-H), 7.22 (t, 1H, Ar-H), 7.22 (t, 1H, Ar-H), 7.49 (d, 1H, Ar-H), 5.21 (s, 1H, NH), 4.59 (s, 2H, CH₂), 4.20 (s, 2H, CH₂), 7.69(s, 1H, Ar-H), 5.32 (s, 2H, CH₂), 7.06 (d, 1H, Ar-H), 7.78 (d, 1H, Ar-H), 7.78 (d, 1H, Ar-H), 7.06 (d, 1H, Ar-H);

¹³C NMR (100 MHZ, DMSO-d₆): 113.9, 118.1, 118.3, 113.2, 136.4, 139.2, 136.5, 65.9, 67.2, 141.9, 121.3, 56.3, 132.7, 129.1, 130.7, 118.1, 129.3, 130.2: LC-MS m/z, 398.59 [M+H]⁺.

2-(((1-(4-chlorobenzyl)-1H-1,2,3-triazol-4-yl) methoxy) methyl)-1H-benzo[d]imidazole: 3e

¹H NMR (400 MHZ, DMSO-d₆): 7.49 (d, 1H, Ar-H), 7.22 (t, 1H, Ar-H), 7.22 (t, 1H, Ar-H), 7.49 (d, 1H, Ar-H), 5.2 (s, 1H, NH), 4.59 (s, 2H, CH₂), 4.21 (s, 2H, CH₂), 7.69 (s, 1H, Ar-H), 5.32 (s, 2H, CH₂), 7.14 (d, 1H, Ar-H), 7.39 (d, 1H, Ar-H), 7.39 (d, 1H, Ar-H), 7.14 (d, 1H, Ar-H);

¹³C NMR (100 MHZ, DMSO-d₆): 113.9, 118.1, 118.9, 113.5, 136.4, 139.2, 136.8, 65.9, 67.0, 141.2, 122.3, 56.3, 131.2, 125.6, 126.8, 133.4, 126.1, 125.9; LC-MS m/z, 354.28 [M+H]⁺.

2-(((1-(4-fluorobenzyl)-1H-1,2,3-triazol-4-yl) methoxy) methyl)-1H-benzo[d]imidazole: 3f

¹H NMR (400 MHZ, DMSO-d₆): 7.49 (d, 1H, Ar-H), 7.21 (t, 1H, Ar-H), 7.22 (t, 1H, Ar-H), 7.49(d, 1H, Ar-H), 5.2 (s, 1H, NH), 4.59 (s, 2H, CH₂), 4.20 (s, 2H, CH₂), 7.69 (s, 1H, Ar-H), 5.32 (s, 2H, CH₂), 7.18 (d, 1H, Ar-H), 7.06 (d, 1H, Ar-H), 7.09 (d, 1H, Ar-H), 7.18 (d, 1H, Ar-H);

¹³C NMR (100 MHZ, DMSO-d₆): 113.9, 118.1, 118.1, 113.9, 136.4, 139.2, 136.4, 65.9, 67.0, 141.9, 121.3, 56.1, 130.4, 127.2, 113.9, 161.2, 113.9, 127.2; LC-MS m/z, 338.79 [M+H]⁺.

2-(((1-(4-methoxybenzyl)-1H-1,2,3-triazol-4-yl) methoxy) methyl)-1H-benzo[d]imidazole: (3g)

¹³C NMR (100 MHZ, DMSO-d₆): 113.9, 118.1, 118.1, 113.9, 136.4, 139.2, 136.4, 65.9, 67.0, 141.9, 121.3, 56.1, 126.7, 129.4, 116.3, 160.8,116.3, 129.4, 53.4: LC-MS, m/z, 350.34 [M+H]⁺.

2-(((1-(4-methylbenzyl)-1H-1,2,3-triazol-4-yl) methoxy) methyl)-1H-benzo[d]imidazole: (3h)

¹H NMR (400 MHZ, DMSO-d₆): 7.49 (d, 1H, Ar-H), 7.22 (t, 1H, Ar-H), 7.22 (t, 1H, Ar-H), 7.49 (d, 1H, Ar-H), 5.26 (s, 1H, NH), 4.59 (s, 2H, CH₂), 4.20 (s, 2H, CH₂), 7.69(s, 1H, Ar-H), 5.32 (s, 2H, CH₂), 7.06 (s, 1H, Ar-H), 7.10 (d, 1H, Ar-H), 7.10 (d, 1H, Ar-H), 7.06(s, 1H, Ar-H):

¹³C NMR (100 MHZ, DMSO-d₆): 113.9, 118.5, 118.7, 113.2, 136.4, 139.2, 136.4, 65.9, 67.0, 141.9, 121.3, 56.1, 131.6, 125.3, 126.9, 137.2, 126.9, 125.3, 20.9: LC-MS m/z, 334.26 [M+H]⁺.

2-(((1-(3-bromobenzyl)-1H-1,2,3-triazol-4-yl) methoxy) methyl)-1H-benzo[d]imidazole: 3i

¹H NMR (400 MHZ, DMSO-d₆): 7.49 (d, 1H, Ar-H), 7.22 (t, 1H, Ar-H), 7.22 (t, 1H, Ar-H), 7.49 (d, 1H, Ar-H), 5.2 (s, 1H, NH), 4.59 (s, 2H, CH₂), 4.20 (s, 2H, CH₂), 7.69 (s, 1H, Ar-H), 5.32 (s, 2H, CH₂), 7.01 (d, 1H, Ar-H), 7.38 (t, 1H, Ar-H), 7.01 (d, 1H, Ar-H), 7.13 (s, 1H, Ar-H):

¹³C NMR (100 MHZ, DMSO-d₆): 113.9, 118.5, 118.5, 113.9, 136.4, 139.2, 136.4, 65.9, 67.0, 141.9, 121.3, 56.1, 139.3, 125.7, 129.1, 127.0, 136.4, 130.1: LC-MS m/z, 398.32 [M+H]⁺.

2-(((1-(3-chlorobenzyl)-1H-1,2,3-triazol-4-yl) methoxy) methyl)-1H-benzo[d]imidazole: 3j

¹H NMR (400 MHZ, DMSO-d₆); 7.49 (d, 1H, Ar-H), 7.22 (t, 1H, Ar-H), 7.22 (t, 1H, Ar-H), 7.49 (d, 1H, Ar-H), 5.2 (s, 1H, NH), 4.59 (s, 2H, CH₂), 4.20 (s, 2H, CH₂), 7.69 (s, 1H, Ar-H), 5.32 (s, 2H, CH₂), 7.06 (s, 1H, Ar-H), 7.17 (d, 1H, Ar-H), 7.24 (d, 1H, Ar-H), 7.39 (s, 1H, Ar-H);

¹³C NMR (100 MHZ, DMSO-d₆): 113.9, 118.1, 118.1, 113.9, 136.4, 139.2, 136.4, 65.9, 67.0, 141.9, 121.3, 55.9, 138.2, 126.5, 131.2, 126.8, 135.7, 129.8; LC-MS m/z, 354.56 [M+H]⁺.

RESULTS AND DISCUSSION:

o-Phenylene diamine was treated with glycolic acid in presence of 4N HCl at reflux condition for 4hr to obtain 1H-benzo[d]imidizole-2-yl) methanol^39-40 (1). Then (1H-benzo[d]imidazol-2-yl) treated with Propargyl bromide and quinch amount of TBAB in presence of DMF and obtain Product is already reported 2-((Prop-2-yn-1-yloxy) methyl)-1H-benzo[d]imidazole^41-42(2).

Table-1:2-((Prop-2-yn-1-yloxy) methyl)-1H-benzo[d]imidazole compound cyclo addition with different types of Benzyl azide derivatives in presence of t-BuOH-H₂O solvent system^a

Entry

Starting

compound

Azide

Product

Time/hr

Yield^b (%)

^a1eq, 2-((Prop-2-yn-1-yloxy)-1H-benzo[d]imidazole, 1.2eq, Benzyl azide, 5mol% CopperSulphate Heptahydride, 10 mol% Na Ascorbate. [1:3] t-BuOH-H₂O.

^bIsolated yields

Table-2: Optimization of reaction conditions^a.

Entry	Na ascorbate(mol%)	[Cu] 1(mol%)	Ligand(2 mol%)	Time(hr)	Yield^b (%)
1	10	Cu(OAc)_2.2H₂O	Urea	2 hr	92%
2	10	CuCl_2.2H₂O	Urea	2 hr	90%
3	-	CuCl	Urea	2 hr	94%
4	-	CuI	Urea	2 hr	94%
5	10	CuSO_4.7H₂O	Urea	2 hr	98%

^a1eq 2-((Prop-2-yn-1-yloxy)-1H-benzo[d]imidazole, 1.2eq Benzyl azide, 5mol% Copper Sulphate Heptahydrade, 10mol% Na ascorbate, 2mol% Urea. [1:3] t-BuOH-H₂o

^bIsolated yields.

In this reaction ligand, free condition reaction takes more time. In ligand present it is play an important role in the rate of reaction. very less time reaction complet. because of we are take different ligands and optimize that reaction condition.

Table-3: 2-((prop-2-yn-1-yloxy) methyl)-1H-benzo[d]imidazole compound cycloaddition with different types of benzyl azide derivatives in presence of ligand just like urea in t-BuOH-H₂O solvent system^a.

Entry

Starting

compound

Azide

Products

Time/hr

Yield(%)

^a1eq, 2-((prop-2-yn-1-yloxy) methyl)-1H-benzo[d]imidazole. 1.2eq, Benzyl azide, 5 mol% CuSO_4.7H₂O. 10 mol% Na Ascorbate, 2mol% Urea. Isolated yields^b

Biological Activity:

Newly synthesized compounds were screened forantibacterial activity study purpose micro organisams employed were Gram positive (Bacillussubstillis, Streptococcusaureus), Gram negative (Escherichia coli, Pseudomonasvulgaris).

Table-4: Determination of MICs Microgram/ml.

S.no.	Product	*Bacillus substillis*	*S. aureus*	*E. coli*	*P.vulgaris*
1	3a	31.25	62.50	31.25	>100
2	3b	62.50	31.25	15.62	31.25
3	3c	31.25	62.50	31.25	>100
4	3d	62.50	31.25	15.62	>100
5	3e	62.50	31.25	15.62	31.25
6	3f	31.25	15.62	31.25	>100

CONCLUSION:

In conclusion, we have developed a simple, effective, novel, stable and inexpensive methodology. Urea ligand, Copper Sulphate.Heptahydride, NaAscorbate catalized azide alkyne cycloaddition reaction complet and obtained 1,2,3-triazole contain benzimidazole compounds. The structures of all the new products obtained in the present work are supported by spectral and analytical data (IR, ¹H NMR, and Mass spectroscopy) and this compound showed good activity against the tested bacterial strains. so finally, we believe this process give highly yield substrates.

ACKNOWLEDGEMENTS:

The Authors are thankful to Dr.Deepak Biradar, Vinay Chamla, Unisynaxis Laboratory, Hyderabad for providing necessary facilities and I am thankful to Chaithanya Degree and P.G. College, Warangal, Department of Chemistry, JNTU Hyderabad for their encouragement.

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Received on 27.05.2017 Modified on 11.06.2017

Asian J. Research Chem. 2017; 10(4):546-552.

DOI:10.5958/0974-4150.2017.00090.6