Quinoxaline 1, 4-Dioxides. A Mechanistic Study of Their Formation and the Structural Assignment of 6(7) Isomeric Products

Two ty-pes of reactions were used to study the effect of substituents (CH3, OCH3 ) on the condensation of 5(6) ~substi­ t1Jted benzofurazan 1-oxides C1) with {methyl thio ) -2-·propanone (BFO Reaction, A), and 4substituted o-quinone dioximes (2) l'1../ vrith pyru.vald~hyde (OQD Reaction, B). The nitrogen atom is an electrophile in reaction A and nucleophile in reaction B .. ro:· ~N\ R · , 0 ~ ---~1 ~ oR-

The general Gharactet of this method has allowed the preparation of a large number of quinoxaline 1, 4-dioxides20 and phenazine 5,10-diaxides 2 1. The method is especially useful for the preparation of 2,3-substituted compounds where such substituents inhibit and/or retard the peracid oxidation of the parent quinoxaline. o- Another, but inferior, method for the preparation of quinoxaline

1,4-Dioxides
A low-temperature nmr study of BFO he.lped explain the above prediction~ This study established the structure of BFO to be a rapidly equilibrating system between two tautomers ~ and h_9 with Q-dini trosobenzene ( 'J;!) as a plausib~e intermediate. 24...:.27 The activation energy for the equilibration has been estimated to be about 15 kcal./mole .28 The tautomerism of a number of 5(6)-substituted BFO's has been studied by low-temperature. nmr by Boulton et al. 2

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Although a first supposition would be that both electron donor and electron acceptor groups would show a preference for conjugation with the N-oxide group rather than with the other nitrogen atom, this is not the general rule. Boulton's data indicate either that conjugative infiuences of the substituents are small, or that opposing influences are fairly evenly balanced. The stability of one tautomer over the other was also indicated and the findings are summari zed i n Figure 3.
7~ is more stable than _Lb when R = OCH 3 , Cl, Br 7~b i s more stable than z._ a when R = N0 2 , co 2 R t a and l? are of equal stability when R = ctt 3 The r~sults showed · _ _ that 5(6)-methyl BFO exists in equal proportions between the 5and the 6--methyl isomers, whi ch demonstrates t hat the methyl group has no stabilizing effect on either isomeric form. In contrast, 5(6) -carboxy BFO exists in a 7 to 3 ratio of the 6-carboxy (:lE, R = co 2 H) to the 5-carboxy (~, R = co 2 H) isom_ er. In this case the substituent effect can be explained by stabilization through conjugation of the carboxy group in the 6-position with the N-oxide (20).

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In ~he present work a rigorous study of isomer formation was made in which the electronic effects of a 5(6)substi tuent (R = OCH 3 , CH 3 ) on the course of the reaction of BFO with (methylthio)-2-propanone was examined, and the isomer ratios were determined by examining nrnr spectra of suitable derivatives where first order analysis is possible.
The aromatic region in the nrnr spectrum of a 2,3dialkyl-6(7)-substututed quinoxaline 1,4-dioxide consists of two one-proton doublets with ortho and meta spin-spin coupling constants both coupled to a third proton appearing as a quartet. The two doublets arise from H-5 and H-8 resonances but chemical shift assignments of these protons is not possible since the position of the substituent at either C-6 or C-7 affects both the chemical shift as well as the coupl ing constants of these two protons. If substutution is at C-6 then H-5 will appear as a doublet meta coupled to H-7 while H-8 will appear as a doublet with ortho coupling to H-7. Should the substituent be at C-7, following the above rationalization, assignments to H-5 and H-8 should be interchanged and the full structure determination of the compound by nrnr spectral analysis becomes very difficult.
(   to 60%. Their Ilt~r spectral data are summar±zed in Table 1. In Order to minimize chances for the loss of minor isomers, careful column chromatography was conducted on the mother liquors of these reactions. As a result, additional compounds were isolated and characterized by chemical and spectral methods (see Experimental).
Initial elution of· the column with benzene gave benzfurazan and the starting BFO. Further elution of the column With more polar solvents gave additional quinoxaline proqucts Table 1 Chemical Shifts of the 6(7)-Substituted     ./"l_ ~ The above finding suggested that base hydrolysis of 3-(methythio )~· quinoxaline 1, 4-dioxides should proceed to give the corresponding hydroxamic acids. This proved to be the case and the highly insoluble products were obtai ned in excellent yields.. The hydroxamic acids whose nmr spectral data are summarized in Table 2 were quantitatively esterified with either diazomethane or dimethyl sulfate to the chloroform-soluble methyl esters (37), which were subjected ·-v to nmr analysis. The nmr data for those compounds are in

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The aromatic regions -of the nmr spectra of the hydroxamic acid esters (37a and 37b) obtained from BFO reactions ,. ....,,. rJ are shown in Figures 7 and 8 for that region to obtain the ratios of isomers. The percentages of 7:6 isomers are summarized in Table 4. As was pre~ dieted earlier, a major isomer in the BFO reaction became the minor one in the OQD reaction. -Table 4. Cor r e ct elemental a.rialyses of t he isomi~ri c mixtures prove that t he "extra peaks" seen in the nmr spe ctra are really due to isomers rather than i!!lpurities. Pure isomers were obtained by repeated fractional crystallizations of the· iso·rneric rnixtures. The nmr spectra of the 7and 6-methyl isomers are shown in Figure 9 (A and B). Superimposing these two spectra produces an nmr spectrum (Figure 9,G) which is similar to that obtained for the mixture of the isomers ( se· e Anal·. Calcd for c 11 H 1 2N202S: C, 55 . . 92;H,5.11;N,11.85. Found: C,56.04;H,4.92;N,11.71. 3, (6) . Anal. Calcd for C1c)H11N302: C, 58.74;H,5.37;N,20.37. Found: C,58.67;H,5.38;N,20.48c. showed the presence of both the 3,6-dimethyl and 3,7-dime t hyl isomers. Anal. Calcd f or c 10 H 10 N20 3 : C, 58.26;H,4.89;N,13 . 58. Found : C,57.95;H,5.07;N,13.35.
. After drying over magnesium sulfate, the solution was filtered and allowed to evaporate giving the crude product (1.0 g, 94%), m.p. 160° (dee); nmr data indicated the ·presence· of