Molecules 2008, 13, 86-95 molecules ISSN 1420-3049 © 2008 by MDPI www.mdpi.org/molecules Full Paper Substitutions of Fluorine Atoms and Phenoxy Groups in the Synthesis of Quinoxaline 1,4-di-N-oxide Derivatives† Esther Vicente, Raquel Villar, Asunción Burguete, Beatriz Solano, Saioa Ancizu, Silvia Pérez-Silanes, Ignacio Aldana* and Antonio Monge Unidad de Investigación y Desarrollo de Medicamentos, Centro de Investigación en Farmacobiología Aplicada (CIFA), University of Navarra, 31080 Pamplona, Spain † Initial data presented at the 11th International Electronic Conference on Synthetic Organic Chemistry, ECSOC-11, http://www.usc.es/congresos/ecsoc/11/ECSOC11.htm, 1-30 November 2007, paper a035 * Author to whom correspondence should be addressed. E-mail: ialdana@unav.es (for I. Aldana) Received: 18 December 2007; in revised form: 16 January 2008 / Accepted: 16 January 2008 / Published: 18 January 2008 Abstract: The unexpected substitution of fluorine atoms and phenoxy groups attached to quinoxaline or benzofuroxan rings is described. The synthesis of 2-benzyl- and 2-phenoxy3-methylquinoxaline 1,4-di-N-oxide derivatives was based on the classical Beirut reaction. The tendency of fluorine atoms linked to quinoxaline or benzofuroxan rings to be replaced by a methoxy group when dissolved in an ammonia saturated solution of methanol was clearly demonstrated. In addition, 2-phenoxyquinoxaline 1,4-di-N-oxide derivatives became 2-aminoquinoxaline 1,4-di-N-oxide derivatives in the presence of gaseous ammonia. Keywords: Quinoxaline, N-oxides, Beirut reaction, gaseous ammonia. Introduction Quinoxaline and quinoxaline-1,4-di-N-oxide are heterocycles that are frequently used in the synthesis of biologically active compounds [1-4]. The quinoxaline moiety is described as a bioisoster Molecules 2008, 13 87 of the quinoline, naphthyl, benzothienyl and other aromatic rings [5], and the widespread activity of quinoxaline-1,4-di-N-oxide derivatives can be associated with the generation of free radicals [6]. In our continuing efforts to find quinoxaline-1,4-di-N-oxide derivatives with antimycobacterial [7-9] antiprotozoal [10-16] and anti-cancer activity [17, 18], a series of 2-benzyl-3-methylquinoxaline 1,4di-N-oxide derivatives was proposed. With regards to work carried out by our research team, this series involves the analogues of 2-benzoyl-3-methylquinoxaline 1,4-di-N-oxide derivatives in which the carbonyl group has been reduced [7]. In addition, with regards to Carta’s paper [19], this series, together with a series of 2-phenoxy-3-methylquinoxaline 1,4-di-N-oxide derivatives, could complete the bioisosterism replacements based on Grimm’s Hydride Displacement Law (Scheme 1). This law states that the addition of a hydrogen atom with a pair of electrons (i.e. hydride) to an atom belonging to groups 4A, 5A, 6A, 7A on the Periodic Table, produces an isoelectronic pseudoatom, showing the same physical properties as those present in the column immediately behind the initial atom on the Periodic Table of the Elements [5]. The aim of this work was to obtain 2-benzyl- and 2-phenoxy-3methylquinoxaline 1,4-di-N-oxide derivatives as potential antitubercular drug candidates. Scheme 1. Design of new quinoxaline-1,4-di-N-oxide derivatives with antimycobacterial activity. Cart a et al. 2002 R7 R6 O + N Jaso et al. 2003 R7 S + R6 N O O + N O + N O [ reduct ion] Bioisost erism Cart a et al. 2004 R7 R6 O + N + N O O R7 R6 O + N + N O H N R7 R6 O + N + N O Grim m 's Hydride Displacem ent Law: - O- , - NH- , - CH2 - Results and Discussion In a continuing effort to obtain new antitubercular drug candidates, the synthesis of 2-benzyl- and 2-phenoxy-3-methylquinoxaline 1,4-di-N-oxide derivatives was proposed. The synthesis of each of these compounds was based on the classical Beirut reaction and, in this case, methanol and gaseous ammonia were chosen as reaction solvent and catalyst, respectively. After workup, all the compounds obtained were chemically characterized by thin layer chromatography (TLC), infrared (IR) and nuclear magnetic resonance (1H-NMR) spectra, as well as by elemental microanalysis. From these analyses, it was realised that the reaction with phenoxyacetone had failed to give the functionalized 2-phenoxy derivatives; surprisingly, this reaction gave other quinoxaline 1,4-di-N-oxide derivatives 10-12, with an amino group, instead of the phenoxy moiety, linked to C2 of the quinoxaline ring (analytical data in the Experimental section). It is well known that Molecules 2008, 13 88 the phenoxy scaffold is a good leaving group and that the ammonia gas is a potent base; the curious part is that first the quinoxaline is formed and later, the substitution occurs (the events could not have occurred in any other way due to the products obtained) (Scheme 2). Scheme 2. Possible mechanism of reaction for 2-amino-3-methylquinoxaline 1,4-di-N-oxide derivatives. O N O + O H .. H N H exc. NH4+ :N O + - O + N O N R7 R6 R7 R6 O + N R7 + N O R6 O + N O R7 NH R6 NH2 H .. H N H + N O O + N + N O O NH2 O + O N δ+ R7 + N O R6 O The experimental conditions (reaction solvent and catalyst) were explored with the aim of obtaining the target compounds. In an attempt to synthesize the 2-phenoxy derivatives, the catalyst and the solvent were substituted by piperidine and dichloromethane, respectively. In this case, the 2-phenoxy3-methylquinoxaline 1,4-di-N-oxide (13) was obtained (Scheme 3). Scheme 3. Synthesis of 2-benzyl- and 2-phenoxy-3-methylquinoxaline 1,4-di-N-oxide derivatives. R7 R6 O + N O N O NH3 ( g) + CH3 OH R7 R6 O + N + N O ( 1-9) R7 R6 O + N O N O O + NH3 ( g) CH3 OH R7 R6 O + N O + R7 R6 N O O + N + N O ( 10-12) R7 R6 O + N O N O + O piperidine CH2 Cl 2 R7 R6 O + N + N O ( 13) O NH2 Molecules 2008, 13 89 The formation of isomeric quinoxaline 1,4-di-N-oxide was observed in the case of monosubstituted benzofuroxans. According to previous reports [20], we have observed that 7-substituted quinoxaline 1,4-di-N-oxide derivatives prevailed over the 6-isomer, or in the case of the methoxy substituent, only the 7-isomer was formed (NOESY data, not shown). In practice, the workup and purification permitted isolation of the 7-isomer [21]. On the other hand, it was also observed that the reaction of difluorobenzofuroxan with benzylacetone in methanol failed to give 2-benzyl-6,7-difluoro-3-methylquinoxaline 1,4-di-N-oxide (7); the 1H-NMR spectra of the obtained compound showed the presence of a methoxy group in the structure and that it corresponded to a 6,7-disubstituted quinoxaline; we consequently thought that, under these conditions, the fluorine atom in position 6 was being substituted by a methoxy group from the solvent (compound 6). Such a displacement of the fluorine atom in position 6 has been observed on other occasions [22]. In an attempt to obtain the 6,7-difluoro derivative, the solvent was changed but keeping the remainder of the reaction conditions constant. In this case, using dichloromethane as reaction solvent, 2-benzyl-6,7-difluoro-3-methyl-quinoxaline 1,4-di-N-oxide (7) was obtained (Scheme 4). Scheme 4. Synthesis of 2-benzyl-7-fluoro-6-methoxy- and 2-benzyl-6,7-difluoro-3methylquinoxaline 1,4-dioxides. F F F F O + N O N O + N O N O + N O F NH3 ( g) + CH3 OH O + N O F NH3 ( g) + CH2 Cl 2 ( 6) + N O O ( 7) + N O F Finally, we observed another curiosity arising from the use of fluorinated compounds. When we attempted to prepare R7(R6)-fluorobenzofuroxan by oxidation of the corresponding fluoronitroaniline, as previously described [23], the compound obtained was actually R7(R6)-methoxybenzofuroxan. Once again, methanol was present in the reaction as solvent. Therefore R7(R6)-fluorobenzofuroxan was prepared by thermal decomposition as reported [22, 23, 24]. Scheme 5. Synthesis of 5(6)-fluorobenzofuroxan from the corresponding o-nitroaniline. O O + N O N NaOH, NaClO MeOH F NO2 NH2 F NO2 N3 reflux CH3 COOH F O + N O N Conclusions Summarizing, this work clearly demonstrates the tendency of fluorine atoms linked to quinoxaline or benzofuroxan rings to leave their positions and be replaced by a methoxy group when dissolving in an ammonia saturated solution of methanol. In addition, the 2-phenoxyquinoxaline 1,4-di-N-oxide Molecules 2008, 13 90 derivatives, in the presence of gaseous ammonia, become 2-aminoquinoxaline 1,4-di-N-oxide derivatives. Experimental General All the synthesized compounds were chemically characterized by thin layer chromatography (TLC), infrared (IR), nuclear magnetic resonance (1H-NMR), mass spectra (MS) and elemental microanalysis (CHN). Alugram SIL G/UV254 (Layer: 0.2 mm) (Macherey-Nagel GmbH & Co. KG., Düren, Germany) was used for TLC and Silica gel 60 (0.040-0.063 mm, Merck) for Flash Column Chromatography. The 1H-NMR spectra were recorded on a Bruker 400 Ultrashield instrument (400 MHz), using TMS as the internal standard and with DMSO-d6 or CDCl3 as the solvents; the chemical shifts are reported in ppm (δ) and coupling constants (J) values are given in Hertz (Hz). Signal multiplicities are represented by: s (singlet), d (doublet), t (triplet), q (quadruplet), dd (double doublet) and m (multiplet). The IR spectra were recorded on a Nicolet Nexus FTIR (Thermo, Madison, USA) in KBr pellets. Mass spectra were measured on a MSD/DS 5973N mod. G2577A mass spectrometer (Agilent Technologies, Waldbronn, Germany) equipped with a direct insertion probe (DIP) and the ionization method was electron impact (EI, 70 eV). Elemental microanalyses were obtained on an CHN-900 Elemental Analyzer (Leco, Tres Cantos, Spain) from vacuum-dried samples. The analytical results for C, H, and N, were within ± 0.4 of the theoretical values. Chemicals were purchased from Panreac Química S.A. (Barcelona, Spain), Sigma-Aldrich Química, S.A. (Alcobendas, Spain), Acros Organics (Janssen Pharmaceuticalaan, Geel, Belgium) and Lancaster (Bischheim-Strasbourg, France). General synthesis of 2-benzyl-3-methylquinoxaline 1,4-di-N-oxide derivatives 1-9 [11, 19] Equimolar amounts (3.0–10.0 mmol) of the appropriate benzofuroxan and benzylacetone were added to methanol (20 mL) [or dichloromethane (20 mL) for the 6,7-difluoro derivative]. Gaseous ammonia gas was bubbled for 10 minutes through the mixture, which was then stirred at room temperature for 4 hours. After evaporating to dryness under reduced pressure, a crude solid was obtained, which was then washed by adding diethyl ether and purified by recrystallization from a mixture of methanol/dichloromethane. 2-Benzyl-3-methylquinoxaline 1,4-di-N-oxide (1). IR ν/cm-1: 1320, 1074, 713; 1H-NMR (CDCl3) δ/ppm: 2.76 (s, 3H, C3-CH3), 4.62 (s, 2H, C2-CH2-Ph), 7.29 (m, 5H, CH2-C6H5), 7.85 (m, 2H, H6+H7), 8.67 (m, 2H, H5+H8). 2-Benzyl-7-fluoro-3-methylquinoxaline 1,4-di-N-oxide (2). IR ν/cm-1: 1321, 1077, 712; 1H-NMR (CDCl3) δ/ppm: 2.75 (s, 3H, C3-CH3), 4.60 (s, 2H, C2-CH2-Ph), 7.30 (m, 5H, CH2-C6H5), 7.58 (ddd, J=2.74, 7.39, 9.52 Hz, 1H, H6), 8.33 (dd, J= 2.69, 8.75 Hz, 1H, H8), 8.68 (dd, J=5.10, 9.48 Hz, 1H, H5). Molecules 2008, 13 91 2-Benzyl-7-chloro-3-methylquinoxaline 1,4-di-N-oxide (3). IR ν/cm-1: 1323, 1076, 713; 1H-NMR (CDCl3) δ/ppm: 2.74 (s, 3H, C3-CH3), 4.59 (s, 2H, C2-CH2-Ph), 7.30 (m, 5H, CH2-C6H5), 7.77 (dd, J=2.21, 9.17 Hz, 1H, H6), 8.60 (d, J=9.16 Hz, 1H, H5), 8.69 (d, J=2.20 Hz, 1H, H8). 2-Benzyl-3,7-dimethylquinoxaline 1,4-di-N-oxide (4). IR ν/cm-1: 1322, 1080, 704; 1H-NMR (CDCl3) δ/ppm: 2.63 (s, 3H, C7-CH3), 2.77 (s, 3H, C3-CH3), 4.62 (s, 2H, C2-CH2-Ph), 7.30 (m, 5H, CH2C6H5), 7.85 (m, 2H, H6+H7), 8.67 (m, 2H, H5+H8), 7.68 (d, J=8.91 Hz, 1H, H6), 8.47 (s, 1H, H8), 8.54 (d, J=8.78 Hz, 1H, H5). 2-Benzyl-7-methoxy-3-methylquinoxaline 1,4-di-N-oxide (5). IR ν/cm-1: 1322, 1071, 707; 1H-NMR (CDCl3). δ/ppm: 2.74 (s, 3H, C3-CH3), 4.02 (s, 3H, C7-OCH3), 4.61 (s, 2H, C2-CH2-Ph), 7.25 (m, 5H, CH2-C6H5), 7.43 (dd, J=2.72, 9.49 Hz, 1H, H6), 7.98 (d, J=2.71 Hz, 1H, H8), 8.54 (d, J=9.46 Hz, 1H, H5). 2-Benzyl-7-fluoro-6-methoxy-3-methylquinoxaline 1,4-di-N-oxide (6). IR ν/cm-1: 1321, 1078, 703; 1HNMR (CDCl3) δ/ppm: 2.75 (s, 3H, C3-CH3), 4.11 (s, 3H, C6-OCH3), 4.58 (s, 2H, C2-CH2-Ph), 7.29 (m, 5H, CH2-C6H5), 8.07 (d, J=7.85 Hz, 1H, H5), 8.33 (d, J=10.72 Hz, 1H, H8). 2-Benzyl-6,7-difluoro-3-methylquinoxaline 1,4-di-N-oxide (7). IR ν/cm-1: 1322, 1080; 1H-NMR (CDCl3) δ/ppm: 2.75 (s, 3H, C3-CH3), 4.58 (s, 2H, C2-CH2-Ph), 7.30 (m, 5H, CH2-C6H5), 8.47 (dd, J=9.28, 16.80 Hz, 2H, H5+H8). 2-Benzyl-6,7-dichloro-3-methylquinoxaline 1,4-di-N-oxide (8). IR ν/cm-1: 1320, 1074, 713; 1H-NMR (CDCl3) δ/ppm: 2.74 (s, 3H, C3-CH3), 4.56 (s, 2H, C2-CH2-Ph), 7.33 (m, 5H, CH2-C6H5), 8.75 (s, 1H, H5); 8.78 (s, 1H, H8). 2-Benzyl-3,6,7-trimethylquinoxaline 1,4-di-N-oxide (9). IR ν/cm-1: 1327, 1082, 706; 1H-NMR (CDCl3) δ/ppm: 2.52 (s, 6H, C6-CH3+C7-CH3), 2.73 (s, 3H, C3-CH3), 4.59 (s, 2H, C2-CH2-Ph), 7.27 (m, 5H, CH2-C6H5), 8.39 (s, 1H, H8), 8.42 (s, 1H, H5). General synthesis of 2-amino-3-methylquinoxaline 1,4-di-N-oxide derivatives 10-12. Equimolar amounts (3.0–10.0 mmol) of the appropriate benzofuroxan and phenoxyacetone were added to methanol (20 mL). Gaseous ammonia was bubbled through the mixture for 10 minutes and then it was stirred at room temperature for 4 hours. After evaporating to dryness under reduced pressure, a crude solid was obtained. This was then washed by adding diethyl ether and purified by recrystallization from a mixture of methanol/dichloromethane. 2-Amino-3-methylquinoxaline 1,4-di-N-oxide (10). IR ν/cm-1: 3400, 3290, 1616, 1329; 1H-NMR (DMSO-d6) δ/ppm: 2.57 (s, 3H, C3-CH3), 7.61 (m, 3H, NH2+H6), 7.81 (t, J=7.78 Hz, 1H, H7), 8.31 (dd, J=0.72, 8.53 Hz, 1H, H5), 8.37 (dd, J=0.73, 8.53 Hz, 1H, H8). Molecules 2008, 13 92 2-Amino-7-chloro-3-methylquinoxaline 1,4-di-N-oxide (11). IR ν/cm-1: 3385, 3262, 1623, 1327; 1HNMR (DMSO-d6). δ/ppm: 2.55 (s, 3H, C3-CH3), 7.61 (dd, J=1.58, 9.07 Hz, 1H, H6), 7.77 (s, 2H, NH2), 8.26 (d, J=2.23 Hz, 1H, H8), 8.36 (d, J=9.12 Hz, 1H, H5). 2-Amino-6,7-dichloro-3-methylquinoxaline 1,4-di-N-oxide (12). IR ν/cm-1: 3416, 3299, 1617, 1325; 1 H-NMR (DMSO-d6). δ/ppm: 2.55 (s, 3H, C3-CH3), 7.86 (s, 2H, NH2), 8.42 (s, 1H, H5), 8.50 (s, 1H, H8) Synthesis of 3-methyl-2-phenoxyquinoxaline 1,4-di-N-oxide (13). An equimolar amount of phenoxyacetone was added to a solution of the appropriate benzofuroxan (3.0-10.0 mmol) in dry dichloromethane (35 mL). The mixture was allowed to stand at 0 ºC. Piperidine (1 mL) was added dropwise and the reaction mixture was stirred at room temperature in darkness for 4 hours. After evaporating to dryness under reduced pressure, a crude solid was obtained, which was then washed by adding diethyl ether (or n-hexane), affording the target compound. The precipitate obtained was purified by recrystallization from a mixture of methanol/dichloromethane. IR ν/cm-1: 1326, 1093, 760; 1H-NMR (CDCl3) δ/ppm: 2.72 (s, 3H, C3-CH3), 6.98 (d, J=7.72 Hz, 2H, H2’+H6’), 7.19 (t, J= 7.42 Hz, 1H, H4’), 7.39 (dd, J=7.57 Hz, 2H, H3’+H5’); 7.87 (m, 2H, H6+H7); 8.63 (m, 1H, H5); 8.69 (m, 1H, H8). Table 1. Structure, analytical data (C, H, N) and MS of the synthesized compounds R7 R6 ID 1 R2 CH2-Ph O + N + N O R6 R7 Formula MW H H C16H14N2O2 266.30 2 CH2-Ph H F C16H13FN2O2 284.29 3 CH2-Ph H Cl C16H13ClN2O2 300.75 4 CH2-Ph H CH3 C17H16N2O2 280.33 5 CH2-Ph H OCH3 C17H16N2O3 296.33 6 CH2-Ph F OCH3 C17H15FN2O3 314.32 7 CH2-Ph F F C16H12F2N2O2 302.28 R2 CH3 Calc. C Calc. H Calc. N MS (EI, 70 (found) (found) (found) eV): m/z 72.17 5.30 10.52 (71.78) (5.27) (10.24) 67.60 4.61 9.85 (67.34) (4.52) (10.19) 63.90 4.36 9.31 (64.01) (4.30) (9.42) 72.84 5.75 9.99 (72.45) (5.66) (10.30) 68.91 5.44 9.45 (68.59) (5.34) (9.58) 64.96 4.81 8.91 (65.01) (4.83) (8.69) 63.58 4.00 9.27 (63.61) (3.70) (9.00) 266 ([M·]+), 249, 232 284 ([M·]+), 267, 250 300 ([M·]+), 283, 266 280 ([M·]+), 263, 246, 230 296 ([M·]+), 279, 262, 247, 219 314 ([M·]+), 297, 280, 265, 237 302 ([M·]+), 285, 268 Molecules 2008, 13 93 Table 1. Cont. 8 CH2-Ph Cl Cl 9 CH2-Ph CH3 CH3 C16H12Cl2N2O4 335.19 C18H18N2O2 294.36 10 NH2 H H C9H9N3O2·H2O 191.19+18.02 11 NH2 H Cl C9H8ClN3O2·½H2O 225.64+9.01 12 NH2 Cl Cl C9H7Cl2N3O2 260.08 13 O-Ph H H C15H12N2O3 268.27 334 ([M·]+), 317, 57.33 3.61 8.36 (57.04) (3.52) (7.99) 73.45 6.16 9.52 (73.16) (6.16) (9.41) 260, 245 51.67 5.30 20.09 191 ([M·]+), 173, (51.61) (5.52) (19.77) 46.03 3.83 17.90 (46.40) (3.63) (17.51) 41.56 2.71 16.16 (41.90) (2.72) (15.78) 67.16 4.51 10.44 (66.81) (4.52) (10.05) 300, 285 294 ([M·]+), 277, 145 225 ([M·]+), 208, 191 259 ([M·]+), 243, 226 268 ([M·]+), 251, 234, 175 Acknowledgements This work has been carried out with the financial support of the FIS project (1051005, October 2005), the Instituto de Salud Carlos III: Red de centros de cancer RTICCC (C03/10) and the PiUNA project (University of Navarra). We also thank the Ministerio de Educación y Ciencia for the grant (AP2003-2175) to Esther Vicente. References and Notes 1. 2. 3. 4. 5. 6. 7. 8. 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