Substitutions of Fluorine Atoms and Phenoxy Groups in the Synthesis of Quinoxaline 1,4-di-N-oxide Derivatives†

The unexpected substitution of fluorine atoms and phenoxy groups attached to quinoxaline or benzofuroxan rings is described. The synthesis of 2-benzyl- and 2-phenoxy-3-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.


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 ( 1 H-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 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. 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-phenoxy-3-methylquinoxaline 1,4-di-N-oxide (13) was obtained (Scheme 3).
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 1 H-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).
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].

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 derivatives, in the presence of gaseous ammonia, become 2-aminoquinoxaline 1,4-di-N-oxide derivatives.
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