J. Chil. Chem. Soc., 55, Nº 4 (2010) SYNTHESIS, CHARACTERIZATION AND ANTIBACTERIAL EVALUATION OF FEW 2, 3-SUBSTITUTED QUINOXALINES B. JAYACHANDRA REDDY, M.C. SOMASEKHARA REDDY* Department of Sciences, G.P.R. Engg. College (Autonomous), Kurnool -518 002 (A. P.), India. Fax: (91) (8518) 270957; Tel: (91) (8518) 270957 (Received: March 26, 2010 - Accepted: May 13, 2010) ABSTRACT The quinoxaline derivatives (i-v) were synthesized through cyclization-oxidation of α- bromo carbonyl compounds with o-phenyl diamines (7a and 10a) and further coupling at 6-position via Suzuki reaction using PdCl2 (dppf).DCM, ter. BuNH2, Na2CO3 in IPA, H2O refluxed for 16 h. As the results of antibacterial screening tests done by paper disc method, quinoxaline derivatives (i) and (v) revealed significant inhibition zone on Bacillusspericus and quinoxaline derivatives (iii) and (v) on Escherichia coli cultures. Key words: Quinoxaline, Suzuki Coupling, microwave, Bacillus spericus, Escherichia coli 2-bromo-1-(H-imidazo[1,2-a]pyridin-3-yl)propan-1-one (4a): To a INTRODUCTION solution of 1-(H-imidazo[1,2-a]pyridin-3-yl)propan-1-one (3a) (300 mg, 1.72 mmol) in diethyl ether (10 mL) and dichloromethane (2 mL) was added Quinoxaline derivatives are an important class of nitrogen containing bromine (325 mg, 2.06 mmol) drop wise at 0oC. The reaction mixture was heterocyclic in medicinal chemistry, have been reported to show biological, warmed to RT, and further stirred for 30 min. The reaction mixture was diluted including antibacterial activity1. For example, quinoxaline is a part of various with diethyl ether (20 mL). The precipitated solids were filtered and dried by antibiotics such as echinomycin, levomycin, and actinoleutin that are known using vacuum to afford 2-bromo-1-(H-imidazo[1,2-a]pyridin-3-yl)propan-1- to inhibit growth of gram positive bacteria2, and are reactive against various one (4a) (200 mg, 46% yield) as a pale brown solid. MS (e/z): 254 (M+1); IR 3 -1 1 transplantable tumors . These have high activity and a broad spectrum of cm 1665 (C=O); HNMR (200 MHz, CDCl3): δ 9.82 (d, J=6.6 Hz, 1H), 9.24 antibacterial activity. (s, 1H), 8.60 (d, J=9.2 Hz, 1H), 8.15 (t, J=6.8 Hz, 1H), 7.62 (t, J=6.6 Hz, 1H), In addition, the frequency of serious nosocomial bacterial and fungal 5.51-5.59 (q, 1H), 2.01 (d, J=7.4Hz, 3H). infections is rising due to the use of newer and more powerful antimicrobial 6-bromo-3-(H-imidazo[1,2-a]pyridin-3-yl-methylquinoxaline (5a): agents. As additional new antimicrobial agents are being found, microorganisms To a solution of tert-butyl 2-amino-4-bromophenylcarbamate (10a) (150 mg, become more resistant to existing chemotherapies. Thus, there is continuous 0.522 mmol) in acetonitrile (5 mL) were added triethylamine (132 mg, 1.305 need to develop novel antimicrobial compounds that would be effective against mmol) and 2-bromo-1-(H-imidazo[1,2-a]pyridin-3-yl)propan-1-one (4a) (132 these and other pathogens16. mg, 0.522 mmol) slowly at RT. The reaction mixture was further stirred for 12 In recent times, microwave4, 5 syntheses in organic chemistry is quickly h. Trifluoro acetic acid (0.5 mL) was added to the above reaction mixture drop growing. Many organic reactions proceed much faster with higher yields under wise at RT and stirred for 5 h at 85oC. The reaction mixture was concentrated microwave irradiation compared to conventional heating. It has long been by using rotavapour. The residue was diluted with water and adjusted pH ~ 8 know that molecules undergo excitation with electromagnetic radiation is a by using Sat. NaHCO3 solution. The precipitated solids were filtered, washed 6,7 technique for microwave synthesis . In present synthesis, AlCl3 catalyzes the with water and dried under vacuum to afford 6-bromo-3-(H-imidazo[1,2-a] Friedel-Crafts acylation on H-imidazo[1,2-a]pyridine (1a) efficiently under pyridin-3-yl-methylquinoxaline (5a) (101 mg, 56% yield) as a solid. MS (e/z): 1 microwave irradiation in solvent free conditions. We synthesized and studied 340 (M+1). HNMR (200 MHz, DMSO-d6): δ 9.87 (d, J=4.2 Hz, 1H), 8.73- antibacterial activity of few 2, 3- substituted quinoxaline derivatives, including 8.71 (m, 2H), 7.99-7.81 (m, 2H), 7.21 (m, 1H), 7.01 (t, J=6 Hz, 1H), 6.70 (d, those with substituted phenyl ring by replacing halide at 6- position. J=7.8 Hz, 1H), 2.99 (s, 3H). EXPERIMENTAL 6-(4-flurophenyl)-3-(H-imidazo[1,2-a]pyridin-3-yl)-2- methylquinoxaline (i): 6-bromo-3-(H-imidazo[1,2-a]pyridin-3-yl- All reagents and solvents were purchased from Srinivasa traders, methylquinoxaline (5a) (75 mg, 0.221 mmol) was dissolved in iPrOH-H2O ( Hyderabad, India. Microwave reactions were carried out using monomode and mL, 1:1) and de-oxygenated by bubbling with N2 for 5 min. Then PdCl2 (dppf). multi-power biotage sixty microwave instrument. TLC (Pre-coated silica gel DCM (cat), tert-BuNH2 (1.8 mL), Na2CO3 (47 mg, 0.442) were added to the 60 F254, Merck) was performed with visualization by UV-light. Melting points reaction mixture at RT. After being stirred for 15 min, 4-fluoro phenylboronic were taken in open capillary tubes and corrected with reference to benzoic acid (6a) (31 mg, 0.221mmol) was added to the reaction mixture and heated at 1 acid. IR spectra in KBr pellets were recorded. H NMR recorded in CDCl3 and 100°C for 16 h. After the completion, the volatiles were concentrated by using DMSO-d6 with 200 MHz instrument as TMS was used as an internal standard. rotavapour. The residue was diluted with water and extracted with EtOAc (3 MS spectra were recorded on Agilent 6310 Ion Trap and Shimadzu LCMS (e/z x 50 mL). The combined organic extracts were dried over anhy.Na2SO4 and and relative intensity). concentrated by using rotavapour. The obtained crude material was purified by 1-(H-imidazo[1,2-a]pyridin-3-yl)propan-1-one (3a): The mixture of column chromatography, eluted product by using 1% MeOH/DCM to afford H-imidazo[1,2-a]pyridine (1a) (500 mg, 4.23 mmol), propanoic anhydride 6-(4-flurophenyl)-3-(H-imidazo[1,2-a]pyridin-3-yl)-2-methylquinoxaline (i) 1 (2a) (2.75 g, 21.18 mmol) and AlCl3 (1.12 g, 8.46 mmol) were irradiated in (32 mg, 40% yield) as a solid. MS (e/z): 355 (M+1). HNMR (200 MHz, o microwave for 20 min at 100 C. The reaction mixture was neutralized by DMSO-d6): δ 9.64 (d, J=7 Hz, 1 H), 8.86 (s, 1H), 8.36 (s, 1H), 8.24 (s, 2H), using sat. Na2CO3 and extracted product into ethyl acetate (25 mL), dried 8.09-7.95 (m, 4H), 7.53 (t, J=6.6 Hz, 1H), 7.40 (t, J=8.8 Hz, 2H), 2.98 (s, 3H). (anhy. Na2SO4) and concentrated by using rotavapour. The crude material was 1,2-dihydro-3-(H-imidazo[1,2-a]pyridine-3-yl)-2-methylquinoxaline purified through silica gel column chromatography, eluted product by using (ii): To a solution of 2-bromo-1-(H-imidazo[1,2-a]pyridin-3-yl)propan-1-one 2% MeOH/DCM to afford 1-(H-imidazo[1,2-a]pyridin-3-yl)propan-1-one (3a) (4a) (100 mg, 0.395 mmol) in acetonitrile (10 mL) was added benzene-1,2- (352 mg, 47.7% yield) as a solid. MS (e/z): 175 (M+1); IR cm-1 1632 (C=O); diamine (7a) (43 mg, 0.395 mmol) at RT, and further stirred for 4 h. The 1 HNMR (200 MHz, CDCl3): δ 8.56 (d, J=6.6 Hz, 1H), 8.63 (s, 1H), 7.84 (d, reaction mixture was concentrated by using rotavapour. The residue was J=9.2 Hz, 1H), 7.63 (t, J=6.8 Hz, 1H), 7.26 (t, J=6.6 Hz, 1H), 3.04-2.93 (q, diluted with water and pH of the solution was adjusted to ~8 by using sat. 2H), 1.15 (t, J=7.4 Hz, 3H). NaHCO3. The precipitated solids were filtered, washed with water and dried e-mail: [email protected]; [email protected]* 483 J. Chil. Chem. Soc., 55, Nº 4 (2010) under vacuum to afford 1,2-dihydro-3-(H-imidazo[1,2-a]pyridine-3-yl)-2- 1H), 7.19 (d, J=7 Hz, 1H), 6.96 (t, J=6.2 Hz, 1H), 6.68 (t, J=6 Hz, 2H), 6.23 methylquinoxaline (ii) (40 mg, 39% yield) as a solid. MS (e/z): 263 (M+1); (brs, 1H), 4.37 (s, 2H), 2.68 (s, 3H). -1 1 IR cm 3375 (-NH); HNMR (200 MHz, DMSO-d6): δ 10.26 (d, J=7.2 Hz, 1 H), 8.71 (s, 1H), 7.96-7.81 (m, 3H), 7.46-7.43 (m, 1H), 7.32 (d, J=6.8 Hz, 1H), RESULTS AND DISCUSSION 7.01 (t, J=7.8 Hz, 1H), 6.70 (d, J=7.8 Hz, 2H), 6.58 (brs, 1H), 4.78-4.73 (q, 1H), 1.17 (d, J=6.6 Hz, 3H). All the Quinoxaline derivatives (i-v) in this report were synthesized tert-butyl 4-bromo-2-nitrophenylcarbamate (9a): To a solution of through cyclization-oxidation with o-phenyl diamine analogs, then further 4-bromo-2-nitrobenzenamine (8a) (2.5 g, 11.5 mmol) in DMF (20 mL) was synthesized quinoxaline-phenyl substituted compounds (i and iii) were added NaH (60%) (690 mg, 17.25 mmol) portion wise at 0oC.