Efficient Synthesis of Some New 2,3-Dimethylquinoxaline-1-oxides Using Bis(acetoxy)phenyl-λ 3-iodane as an Oxidant

Abstract A series of 2-(arylimino)-3-(hydroxyimino)butanes 3a–g, easily accessed by the condensation of variously substituted anilines 1a–g with biacetyl monoxime 2, were efficiently cyclized to afford 2,3-dimethylquinoxaline-1-oxides 4a–g using bis(acetoxy)phenyl-λ 3-iodane as an oxidant. This methodology utilizes a commercially available and environmental benign oxidant to achieve the title compounds in excellent yields under mild conditions. [Supplementary materials are available for this article. Go to the publisher's online edition of Synthetic Communications® for the following free supplemental resource(s): Full experimental and spectral details.] GRAPHICAL ABSTRACT


INTRODUCTION
Heterocycles are ubiquitous scaffolds in pharmacologically active compounds, agrochemicals, and natural products. Quinoxaline systems, in particular, constitute a privileged substructure and are present in a large number of compounds with diverse biological activities such as cytotoxic agents and CB2 receptor agonists. [1] The quinoxaline ring system represents the core skeleton of various antibiotics, for example, triostin A, quinomycin, levomycin, and actinoleutin. Interestingly, quinoxaline N-oxide and its derivatives also exhibit antileishmanial, antimalarial, anti-inflammatory, trypanocidal, anticancer, antituberculosis, and antimycobacterial activities. [2] Methyl-3-[(2-quinoxalinyl)methylene]carbazate-N,N 0 -dioxide, commercially known as carbadox, [3] has proven to be an efficient antibacterial and growth-promoting material. Penicillin derivatives of quinoxaline N,N 0 -dioxide carboxylic acids [4] exhibit remarkable activity against Salmonella and Proteus species. [5] Because of the broad biological properties, a variety of approaches have been developed for the preparation of quinoxaline-N-oxides. The most common method for the synthesis of quinoxaline N-oxides involves the N-oxidation of quinoxaline by using different oxidizing reagents such as hydrogen peroxide, peracetic acid, peroxyformic acid, m-chloroperbenzoic acid, monoperphthalic acid, permaleic acid, and peroxy sulfuric acid in sulfuric acid. [6] Even though this strategy for synthesis of quinoxaline N-oxides has proven to be efficient and general, all of these synthetic routes share several drawbacks such as drastic reaction conditions, tedious workup, the use of toxic and corrosive reagents, long reaction times, and poor selectivity. For example, treatment of 2,3-diphenylquinoxaline with excess of aqueous H 2 O 2 in acetic acid gives expected 1,4-dioxide along with N,N 0 -dibenzoyl-ophenylenediamine. [7] Quinoxaline-N-oxides have been synthesized successfully by the reaction of benzofurazan-1-oxide with enones and amines. [8] Maroulis et al. also have reported the synthesis of some quinoxaline-N-oxides by the oxidative cyclization of benzil-a-arylimino oximes using lead tetraacetate (LTA). [9] This reaction was regioselective but the choice of reagent was inappropriate because of highly toxic nature of LTA. To overcome these difficulties, development of a convenient protocol for the synthesis of quinxaline-N-oxides is still of paramount importance.
In recent years, hypervalent iodine compounds, referred as k 3 -iodanes, are gaining the attention of a number of organic chemists because of their mild and highly selective oxidizing properties. These reagents have emerged as reagents of choice for various synthetically useful transformations. The reactivity pattern of k 3 -iodane reagents closely resembles with those of organometallic compounds such as salts of Pd, Pt, Hg(II), Ni(IV), Pb(IV), and Tl(III) as oxidizing agents. k 3 -Iodane reagents are commercially available and they do not have undesirable toxic, hazardous, and harmful effects. Inspired from applications of hypervalent iodine reagents and in continuation of our previous work on the synthesis of 2,3-diphenylquinoxaline-1oxides, [10] we report herein the synthesis of 2-(arylimino)-3-(hydroxyimino)butanes 3 and their oxidation to some new 2,3-dimethylquinoxaline-1-oxides 4 using bis (acetoxy)phenyl-k 3 -iodane.

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R. AGGARWAL, C. RANI, AND G. SUMRAN The structures of all the newly synthesized compounds 3c-g and 4a-g were characterized on the basis of infrared (IR), NMR ( 1 H and 13 C) spectral data, and elemental analyses. The known compounds 3a and 3b were identified by the comparison of their 1 H NMR with those reported in the literature. [11] The IR spectra of compounds 3c-g displayed characteristic absorption bands ranging from 3117 to 3142 cm À1 (¼ N-OH). The 1 H NMR spectra of 3c-g displayed two singlets of three proton intensity each at d 2.02-2.05 ppm and d 2.18-2.21 ppm corresponding to C 1 and C 4 methyl groups, respectively. It may be noted that methyl adjacent to hydroxyl imino group (¼ N-OH) is more deshielded than the other methyl group adjacent to ¼N-Ar due to high electronegativity associated with oxygen. One broad singlet of one proton intensity has also been observed at d 7.95-8.25 ppm due to the hydroxy imino (¼N-OH) group. The IR spectrum of 4a-g showed the disappearance of the absorption band in the range 3117-3142 cm À1 (¼N-OH), indicating the conversion of 3 to 4. The 1 H NMR spectra of 4a-g exhibited signals at d 2.69-2.71 ppm and d 2.74-2.77 ppm corresponding to C 3 -CH 3 and C 2 -CH 3 , respectively. Protons in the aromatic region resonated in the range d 7.36-8.75 ppm confirmed formation of quinoxaline nucleus. Further, disappearance of broad singlet at d 7.95-8.25 ppm (¼N-OH) also confirmed the oxidation of 2-(arylimino)-3-(hydroxyimino)butanes (3) to 2,3-dimethylquinoxaline-1-oxides (4). The 13 C NMR spectra of 3c-g and 4a-g are given in the experimental part.
A plausible mechanism for the conversion of 3 to 4 is outlined in Scheme 2. It is assumed that generation of a new I(III) intermediate (5) in the initial step takes place by the electrophilic attack of bis(acetoxy)phenyl-k 3 -iodane on the 2-aryliminoximes (3). This is followed by reductive elimination of iodobenzene and acetic acid to give 2-nitroso-3 (phenylimino)butan-2-ylacetate (6), which undergoes entropy-favored electrophilic cyclization to afford intermediate 7. Loss of another mole of acetic acid and spontaneous aromatization leads to the formation of 2,3-dimethylquinoxaline-1oxide (4). Scheme 1. Synthesis of 2,3-dimethylquinoxaline-1-oxides.

EXPERIMENTAL
Melting points were determined in open capillaries in electrical apparatus and are uncorrected. Infrared spectra were recorded on IR M-500 spectrophotometer (Buck Scientific Inc, Norwalk, CT) in KBr pellets (n max in cm À1 ). 1 H (300 MHz) and 13 C NMR (75 MHz) spectra were measured on a Bruker instrument (Billerica, MA) by using CDCl 3 as solvent and tetramethylsilane (TMS) as an internal standard. Chemical shifts are expressed as d in parts per million (ppm). Coupling constants (J) are given in hertz (Hz). Elemental analysis was performed at CDRI and the compounds gave satisfactory results (within AE0.05 of the calculated values).
General Procedure for the Synthesis of 2-(Arylimino)-3-(hydroxyimino)butane 3 A solution of biacetyl monoxime 1 (10.1 g, 0.1 mol) and an appropriately substituted aniline 2 (0.1 mol) in toluene (20 ml) was refluxed for 4-5 h. The progress of the reaction was monitored by thin-layer chromatography (TLC). On completion of the reaction, excess solvent was distilled off in a vaccum. The solid thus obtained was recrystallized from ethanol to give 3.
Complete experimental details and 1 H and 13 C NMR spectra are given in the Supporting Information, available online.