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Indian Journal of Chemistry Vol. 49B, July 2010, pp. 989-993 Note Microwave assisted transformation of benzimidazolyl chalcones into N1-substituted pyrazolines and evaluation of their antimicrobial activities Jayanti Rajora, Janardan Yadav, Ravindra Kumar & Yogendra K Srivastava* Synthetic Organic Chemistry Laboratory, Department of Chemistry, M. P. Govt (PG) College, Chittorgarh 312 001, India E-mail: [email protected] Received 20 April 2009; accepted (revised) 23 April 2010 1-Benzimidazolyl-3-aryl-prop-2-ene-1-ones 2 have been transformed into N1-substituted pyrazoline derivatives by the interaction with phenyl hydrazine, thiosemicarbazide and hydrazine hydrate in the presence of formic acid under solvent free microwave induced protocol. The structure of newly synthesized compounds have been confirmed on the basis of their elemental analysis and spectral data. Newly synthesized compounds have been evaluated for their antimicrobial activity in vitro against E. coli, K. pneumonae, P. aeruginosa and B. subtilis using paper disc method. Some of the compounds have shown significant activity against the pathogens. The diverse nature of chemical reactions require various chemical strategies directed towards environmentally sound and ecofriendly methods and envisages minimum hazards as the performance criteria while designing the new process. One of the thrust areas for achieving this goal is to explore alternative reaction conditions to accomplish desired chemical transformation with elimination of the use of hazardous conventional solvents. Microwave irradiation (MWI) has gained popularity as a powerful non conventional tool for rapid, efficient and ecofriendly synthesis of a variety of compounds, because of selective absorption of microwave energy by polar molecules1. The application of MWI to provide enhanced reaction rate, improved yield and cleaner products2 is proving quite successful in the formation of a variety of carbon-heteroatom bonds. The solvent free solid phase approach involving MWI exposure of neat reactants is applicable to rapid one pot assembly of heterocyclic compounds from in situ generated intermediate3-5. Nitrogen-sulfur containing heterocycles have been exclusively used as important pharmacophores and in drug designing. Benzimidazoles are important group of heterocycles possessing a wide spectrum of pharmacological activities6 such as antifungal7, antihypertensive8, antioxidant9, cardiovascular10, anticonvulsant11, antiviral12, and HIV-IPR inhibitory activity13. Pyrazoline derivatives have been explored extensively due to their versatile biological activities. Antibacterial15, antiamoebic16, antiproliferative17, anticancer18, cox 11SS inhibitory19 and cytoxic activities20-23 have been reported to be associated with pyrazoline nucleus. Besides this, due to easy accessibility and diverse chemical reactivity they are useful synthons. Therefore these two moieties were coupled and an attempt was made to synthesize molecules which may possess enhanced activities. Results and Discussion The required synthon 1-benzimidazolyl-3-aryl-2propen-1-one 2 was prepared by Claisen-Schmidt condensation of 2-acetyl benzimidazole 1 with substituted aromatic aldehydes in the presence of base under MWI by Literature method24. Condensation of 2 with phenyl hydrazine gave N1-phenyl-3-benzimidazolyl-5-aryl-2-pyrazolines 3 in 80-85% yield. The reaction of 2 with hydrazine hydrate in the presence of formic acid afforded 3benzimidazolyl-5-aryl-2-pyarzoline-1-carboxaldehyde 4 where as when 2 was condensed with thiosemicarbazide in the presence of anhydrous K2CO3, gave 3-benzimidazolyl-5-aryl-2-pyrazolinyl-1-thiocarbamides 5 (Scheme I). All these transformations were carried out using solvent less, solid phase neat reactants under microwave irradiation. The reaction was completed with in 4-8 min with 80-85% yield. Above transformation when carried out using conventional heating method under liquid phase, required 6-8 hr of heating and yields were 60-65% indicating the superiority of MWI method over conventional heating. The characterization of newly synthesized compounds was based on their elemental analysis (Table I) and spectral data. IR spectra of newly synthesized compound gave absorption bands at 3420-3380 cm-1 (-NH of benzimidazole ring), 14401385 cm-1 (combined vibrations of C=N and N-N 990 INDIAN J. CHEM., SEC B, JULY 2010 Scheme I grouping), For compounds 4 a sharp peak at 1690 cm-1 for aldehydic group was obtained whereas for compounds 5 absorption band at 1360-1340 cm-1 for C=S linkage was observed. 1 H NMR spectra of these compounds gave signals at δ 3.36-3.38 (double doublet for C4-HA), δ 3.99-4.01 (double doublet C4-HB), and δ 6.18-6.22 (double doublet C5-HX), confirming the presence of typical ABX pattern of pyrazoline system. For compounds 4 a sharp high intensity singlet for aldehyde proton was observed at δ 10.01. Compounds 5 exhibited a sharp singlet at δ 6.75 for proton of amino group. (Table II). The mass spectra of these compounds gave molecular ion peaks corresponding to their molecular mass. Experimental Section The melting points reported were determined in open capillary and are uncorrected. The IR spectra were taken on a Perkin-Elmer spectrometer using KBr pellets (ν cm-1). 1H NMR were recorded on a Brucker DRX-300 spectrometer (Chemical shift δ ppm,CDCl3) and mass spectra (FAB) were recorded on Jeol-Sx102/DA 600 mass spectrometer using m-nitro benzyl alcohol as matrix . The matrix peaks were observed at m/z 136, 137, 154, 289 and 307. The purity of products and progress of reaction was checked by TLC using ethyl acetate:benzene (1:9) as eluent and silica gel G as adsorbent. All the transformation were carried out in domestic microwave oven (Samsung 1630N, output energy 800 watt, frequency 2450 MHz. NOTES 991 Table I ― Physical data of synthesized compounds Compd 3a 3b 3c 3d 3e 3f 4a 4b 4c 4d 4e 4f 5a 5b 5c 5d 5e 5f Ar phenyl 4-OMe phenyl 3,4-diOMe phenyl 3,4,5-triOMe phenyl 4-Cl phenyl 4-NMe2 phenyl phenyl 4-OMe phenyl 3,4-diOMe phenyl 3,4,5-triOMe phenyl 4-Cl phenyl 4-NMe2 phenyl phenyl 4-OMe phenyl 3,4-diOMe phenyl 3,4,5-triOMe phenyl 4-Cl phenyl 4-NMe2 phenyl Mol.Formula (Mol. wt.) C22H18N4 (338) C23H20N4O (368) C24H22N4O2 (398) C25H24N4O3 (428) C22H17N4Cl (372.5) C24H23N5 (381) C17H14N4O (290) C18H16N4O2 (320) C19H18N4O3 (350) C20H20N4O4 (380) C17H13N4OCl (324.5) C19H19N5O (333) C17H15N5S (321) C18H17N5SO (351) C19H19N5SO2 (381) C20H21N5SO3 (411) C17H14N5SCl (355.5) C19H20N6S (364) m.p. ºC 203 260 140 142 283 237 230 210 245 255 204 190 238 175 156 154 190 198 Yield % 80 82 80 84 83 80 85 82 80 84 83 83 85 84 86 82 81 81 Reaction time (min) 4.0 4.0 5.0 4.5 4.0 5.5 4.0 3.5 3.0 4.0 3.0 3.0 6.0 6.0 6.0 6.5 6.5 6.0 %N Calcd (Found) 16.86 (16.80) 15.21 (15.48) 14.07 (14.40) 13.08 (13.00) 15.0 (14.89) 18.37 (18.07) 19.31 (19.22) 17.5 (17.31) 16.0 (15.48) 14.73 (14.56) 17.25 (17.09) 21.02 (20.87) 21.8 (21.66) 19.94 (19.89) 18.37 (18.30) 17.03 (16.88) 19.69 (19.48) 19.23 (19.11) Table II ― Spectral data of synthesized compounds IR (KBr,υ cm-1) 1 MS (FAB, m/z %) 3a 3022-2892 (CH str), 1590-1492 (C=N, N-N combined vib) 338M+(75), 339M+1(100), 227(4) 3b 3058-2837 (CH str), 1594-1498 (C=N, N-N combined vib) 3e 2974-2890 (CH str), 1590-1450 (C=N, N-N combined vib) 5a 3415 (NH), 3252 (NH2), 30572927 (CHstr), 2362 (C=S) 15431468 (C=N, N-N combined vib) 3375 (NH), 3275 (NH2), 29322833 CH str), 2364 (C=S), 15171465 (C=N, N-N combined vib) 3305 (NH), 3252 (NH2), 29332830 (CH, 2360 (C=S), 15991465 (C=N, N-N combined vib) 3061-2960 (CH str), 1596-1495 (C=N, N-N combined vib) 2940-2841 (CH str), 1595-1410 (C=N, N-Ncombined vib) 2932-2893 (CH str), 1596-1490 (C=N, N-N combined vib) 2939-2875 (CHstr), 1510-1434 (C=N, N-N combined vib) 3.14-3.22 (dd, 1H, C4-HA), 4.03-4.10 (dd, 1H, C4-HB) 5.59-5.65 (dd, 1H, C5-HX), 12.88 (s, 1H, NH benzimidazole) 3.35-3.47 (dd, 1H, C4-HA), 3.97-4.07 (dd, 1H, C4-HB), 5.31-5.37 (dd, 1H, C5-HX), 10.20 (s, 1H, NH benzimidazole) 3.33-3.41 (dd, 1H, C4-HA), 4.01-4.11 (dd, 1H, C4-HB), 5.38-5.44 (dd, 1H, C5-HX), 12.35 (s, 1H, NH benzimidazole) 3.46-3.52 (dd, 1H, C4-HA), 4.01-4.05 (dd, 1H, C4-HB), 5.05-5.10 dd, 1H, C5Hx), 7.028.20(m, 9H, Ar), 7.30 (s, 2H, NH2), 12.3 (s, 1H, NH benzimidazole) 3.40-3.50 (dd, 1H, C4-HA), 3.84-3.99 (dd, 1H, C4- HB), 5.99-6.02 (dd, 1H, C5HX), 7.78 (s, 2H, NH2, 11.83 (s, 1H, NH benzimidazole) 3.40-3.52 (dd, 1H, C4-HA), 3.92-4.01 (dd, 1H, C4- HB), 5.99-6.02 (dd, 1H, C5-HX), 7.11-7.71 (m, 6H, Ar), 7.30 (s, 2H, NH2), 12.37 (s, 1H, benzimidazole) 3.29-3.36 (dd, 1H, C4-HA), 3.83-3.93 (dd, 1H, C4- HB), 5.46-5.51 (dd, 1H, C5-HX), 8.90 (s, 1H, CHO), 3.263.34(dd, 1H, CHA), 3.063.95(dd, 1H, C4-HB), 5.435.49(dd, 1H, C5HX), 8.93 (s, 1H, CHO), 3.26-3.34 (dd, 1H, C4-HA), 3.85-3.95 (dd, 1H, C4-HB), 5.44-5.49 (dd, 1H, C5-HX), 8.84 (s, 1H, CHO) 3.30-3.38 (dd, 1H, C4-HA), 3.88- 3.98 (dd, 1H, C4-HB), 5.39-5.45 (dd, 1H, C5-Hx), 8.80 (s, 1H, CHO) Compd 5c 5d 4a 4c 4e 4f H NMR (CDCl3, δ ppm) 368M+(80), 369M+1(100), 261(50) 372M+(85), 373M+1(100), 261(20) 322M+1(90), 321(60) 382M+1(60), 381M+(60), 289(40) 412M+1(90), 411M+ (45), 378(40) 291M+1 (100), 290M+ (79) 237(25) 351M+1(100), 350M+(70), 297(25) 326M+1(100), 325M+(80), 237(25) 334M+1(100), 333M+ (60) 992 INDIAN J. CHEM., SEC B, JULY 2010 General Procedure MWI Process Synthesis of 1-phenyl-3-benzimidazolyl-5-aryl-2pyrazolines, 3a-f Compound (2a-f; 0.01mole) and phenyl hydrazine (0.012 mole) were mixed thoroughly to form an intimate mixture. It was then subjected to microwave irradiation at 300 watt power for 4-6 min. After completion of reaction as indicated by TLC, the reaction-mixture was cooled to RT and extracted with ethanol. The solid separated on standing was filtered and crystallized from benzene, petroleum ether to get analytical sample of 3a-f. Synthesis of 3-benzimidazolyl-5-aryl-2-pyrazolinyl-1-carboxaldehydes, 4a-f An intimate mixture of compound (2a-f; 0.01 mole) hydrazine hydrate (0.015 mole) and formic acid (15 mL) was subjected to MWI for 4-6 min at 240 watt power. After completion of reaction the separated solid was washed thoroughly with water, dried and crystallized from benzene-ethyl acetate to get analytical sample of 4a-f. Synthesis of-1-thiocarbamido-3-benzimidazolyl-5aryl-pyrazolines, 5a-f An intimate mixture of compound (2a-f; 0.01 mole), thiosemicarbazides (0.015 mole) and anhydrous K2CO3 (4 g) was subjected to MWI at 300 watt for 3-5 min. After completion of reaction the reactionmixture after cooling at RT, was extracted with water and filtered. The residue obtained was washed again with water and dried. It was crystallized from ethanol to get analytical sample of 5a-f. Table III ― Biological screening results of compounds 3 and 4 (Zone of inhibition in mm) Compd K. pneumonae E. coli P. aeruginosa B. subtilis 12 14 10 12 3a 10 12 11 11 3b 14 13 12 10 3c 12 11 10 3d 08 10 10 08 3e 12 16 14 3f 16 18 12 12 4a 13 16 10 11 4b 15 17 14 12 4c 14 19 12 09 4d 11 17 14 09 4e 20 23 12 24 Ciproflaxange std.drug Synthesis of 3-benzymidazolyl-5-aryl-2-pyrazolinyl-1-carboxaldehyde, 4a-f Compound (2a-f; 0.01 mole) was taken in formic acid (50 mL). To it, hydrazine hydrate (0.015 mole) was added. The reaction-mixture was refluxed for about 6 hr and then left overnight at RT. The separated solid was filtered, washed with water and crystallized to get analyzed sample of 4a-f. Synthesis of 1-thiocarbamido-3-benzimidazolyl-5aryl-2-pyrazolines, 5a-f Compound (2a-f; 0.01mole) was dissolved in dry benzene (50 mL). To it, thiosemicarbazide (0.015 mole) and anhydrous. K2CO3 (4 g) was added. The reaction-mixture was refluxed for about 7-8 hr. It was then left at RT. The solid separated was filtered, washed with little benzene, dried and crystallized to get analytical sample of 5a-f. Conventional Process Antibacterial activity Synthesis of 1-phenyl-3-benimidazolyl-5-aryl-2pyrazoline, 3a-f The newly prepared pyrazoline derivatives were screened for their antibacterial activity using paper disc method in vitro against E. coli, K. pneumonae B. subtilis and P. aeruginosa at a maximum concentration 250 ppm. The results were compared with standard drug ciproflaxange. All the compounds were found to possess moderate to good activity against gram +ve and gram –ve strains. (Table III) Compound (2a-f; 0.01 mole) and phenyl hydrazine (0.012 mole) were dissolved in absolute alcohol and reaction-mixture was refluxed for 6-8 hr on water bath. After cooling at RT the solid separated out was filtered, dried and crystallized to get analytical sample 3a-f. NOTES Acknowledgement Authors are grateful to Dr. B. L. Verma (Retd. Prof, M L S University, Udaipur) for guidance, encouragement and useful discussions. 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