Chemoselective Oxidation of Benzophenazines by m-CPBA : N-Oxidation vs . Oxidative Cleavage

Quimiosseletividade é observada, após reação de oxidação, utilizando-se m-CPBA, a partir da piranobenzo[a]fenazina e da furanobenzo[a]fenazina, derivadas, respectivamente da β-lapachona e da nor-β-lapachona. A fenazina pirânica forneceu macrolactonas, principalmente, enquanto a fenazina furânica conduziu a um único produto: o N-8 óxido da fenazina. Objetivando entender essa diferença de reatividade, uma nova fenazina furânica foi sintetizada, tendo como característica principal, a presença da ligação dupla em um sítio menos encoberto estericamente do que aquele presente no derivado nor-beta-lapachônico. Essa furanofenazina, após oxidação com m-CPBA, forneceu, principalmente, a macrolactona esperada. Esses resultados experimentais, aliados a cálculos mecânico-moleculares do estado fundamental dos substratos, permitiram sugerir que a quimiosseletividade observada pode ter controle estérico, relacionado à presença dos grupos substituintes metila geminados, que dificultam a aproximação do oxidante. Muitos dos compostos sintetizados são relatados, pela primeira vez, no presente artigo.


Introduction
In previous communication, 1 we reported the unexpected reactivity of β-lapachone phenazine 1 upon oxidation by m-CPBA.The oxidative cleavage of the aromatic double bond at the site of ring junction was observed, leading to the formation of a 10-membered macrolactone 2 (27%) and its N-oxide 3 (13%), together with an α-hydroxy-dihydrobenzophenazinone derivative 4 (35%), resultant from the pyranic ring cleavage (Figure 1). 1 Hydroxy and bromo derivatives of 1, respectively, 5 and 6, were also submitted to oxidation in the same conditions and furnished substituted 10 membered macrolactones: 7 from 5 and 8 from 6. 2 Based on that initial study, 1 some papers dealing with modifications of the methodology and a more general view Chemoselective Oxidation of Benzophenazines by m-CPBA J. Braz.Chem.Soc.
of the synthetic aspects have appeared in the literature, showing the large potential of this macrolide synthetic approach. 3,4acrolides are an attractive class of compounds that have shown a wide variety of bioactivities, 5 especially recognized as antibiotics. 6The presence of diaza heterocyclic groups close to the ion-binding macrolactone moiety constitutes attractive molecular features. 3On the other hand, N-oxides were also designed and synthesized to behave as bioreducible drugs, being the anticancer hypoxic agent tirapazamine, one of the most successful example. 7hese results and the relevance of the synthesized compounds led us to perform a more detailed study of this reaction.Two furan phenazines, 9 (Figure 2) and 10 (Figure 3), were synthesized and submitted to m-CPBA oxidation in an attempt to obtain 9-membered macrolactones.
It is worth mentioning that medium-sized heterocycles (with 8 to 10-membered rings) are often pharmaceutically important compounds and the production of such rings remains challenging. 1,8
The product characterization was based on data from spectroscopic methods, mainly IR, 1 H NMR and 13 C NMR and by comparison with spectra of similar compounds. 1-4, 10, 14gure 1.m-CPBA oxidation of selected pyran phenazines.The differences in reactivity of these phenazines toward m-CPBA oxidation (1, 5, 6, and 9, Figures 1 and  2, which produced the corresponding macrolactones, versus 10, Figure 3, which led only to N-8 oxide product) has prompted us to perform some preliminary theoretical calculations on these substrates.
Firstly, considering that the different reactivity might have an electronic origin, we performed electronic structure calculations at B3LYP/6-31G(d,p) level of theory, [15][16][17] on compounds 1, 9, and 10.At this level, no appreciable differences were detected between the values of these compounds, either in charge distribution around the reactive double bond site or in HOMO and/or LUMO energy levels (Table 1) 18 which could have been responsible for such a dramatic difference in reactivity.
Nevertheless, during the theoretical conformational analysis of these compounds, we observed that while one of methyl groups in the half-chair pyranic ring of 1 occupied a pseudo-equatorial position, leaving a relatively accessible surface for m-CPBA approach, both faces of the planar furanic ring of phenazine 10 were sterically hindered by its methyl groups (Figure 4).On the other hand, phenazine 9 assumed a envelop conformation with one of its dihydrofurane faces relatively free for m-CPBA approach (Figure 4).So, it seems reasonable to suppose that a steric approach control based on the proposed spiro transition structure for epoxidation of double bonds with m-CPBA [19][20][21] could be responsible for the dramatic effect observed on reactivity.The two methyl groups in 10 would preclude the attack of m-CPBA on the enol double bond shared by aromatic and heterocyclic rings, leading exclusively to the N-8 oxidation and the production of 13.
As a conclusion, both experimental results and theoretical evidences seem to indicate that the steric approach control would explain the different reactivities, especially if we consider that the attack of m-CPBA tends to be perpendicular to the plane of the rings (spirotransition-structure).Additional theoretical study is currently being performed in order to find transition structures and barrier heights for these oxidations and to corroborate this initial guess.
This rationale could now be extended to reactions with other phenazines, with the goal of preparing 9-or 10membered macrolactones or N-oxides.The phenazine 9, the N-oxide 13 and the oxidized products from 10 are reported, herein, for the first time.

Experimental
NMR experiments were performed in deuteriochloroform with TMS as the internal standard with Gemini-200 MHz instrument: chemical shifts are given in δ (ppm), and J values are given in Hz.For elemental analysis, IR spectra and mass spectra we used Perkin-Elmer CHN 2400, Perkin-Elmer 783 and a Shimadzu GCMS-QP 5050-A, respectively.

Figure 4 .
Figure 4. Proposed spiro transition structure for epoxidation of double bonds with m-CPBA.