Synthesis of Quinoxaline 1,4-di-N-Oxide Analogues and Crystal Structure of 2-Carbomethoxy-3-hydroxyquinoxaline-di-N-oxide

A series of quinoxaline 1,4-di-N-oxide analogues were prepared from benzofurazan N-oxide derivatives and β-diketone ester compounds by the improved Beirut reaction. The structures of the target products were characterized by NMR, MS, IR and elemental analysis measurements, and that of 2-carbomethoxy-3-hydroxyquinoxaline- di-N-oxide was further confirmed by single-crystal X-ray diffraction. Its crystal structure belongs to the monoclinic system, space group C2/c with a = 14.4320 (12) Å, b = 10.7514 (9) Å, c = 13.2728 (11) Å, V = 1958.5 (3) Å 3, Z = 8. The X-ray crystallographic analysis reveals that quinoxaline 1,4-di-N-oxide displays acyloin-endiol tautomerism.


Introduction
Some quinoxaline 1,4-di-N-oxides and their derivatives are useful materials that possess a wide range of antimicrobial activities and animal growth promotion effects [1][2][3][4]. Benzofurazan N-oxide derivatives can react with enamines [5], β-diketone esters [6], or any aldehyde or ketone containing two α-H [7,8] to form quinoxaline 1,4-di-N-oxides. This reaction, which has been referred to as the Beirut reaction, is an excellent method for preparing these heterocyclic compounds. The applicable reaction systems include triethylamine [9], triethylamine/methanol [10], and KOH/methanol [11], with long reaction times (8 h-2 d) and 50%-80% yield. When we first set out to discover novel and OPEN ACCESS biologically active compounds, we managed to synthesize a series of quinoxaline 1,4-di-N-oxide analogues with the NaH/THF reaction system, which offered shorter reaction times and gave higher yields.

Results and Discussion
We synthesized a series of quinoxaline 1,4-di-N-oxide analogues 1-10 by the NaH/THF reaction system, which allows the reaction times to be shortened to 2-4 h with yields ranging from 60% to 80%. All these analogues are new compounds and have not been previously reported. Scheme 1. Synthesis of quinoxaline 1,4-di-N-oxide analogues.
The configurations of the products were determined by IR, NMR, MS and elemental analysis. By those measurements, it can be clearly confirmed that these molecules had a quinoxaline di-N-oxide skeleton and the corresponding side chains such as carboalkyl. And on account of this, we believe that our synthesis method was feasible. However, NMR could not differentiate the absolute configurations of C-OH and C=O. Therefore, to obtain deeper insights into these compounds, the absolute configuration of analog 1 was determined by X-ray diffraction. The geometry of 1 is illustrated in Figure 1, and selected bond lengths are given in Table 1.   (14) The crystal structure belongs to monoclinic system, space group C2/c with a = 14.4320 (12) Å, b = 10.7514 (9) Å, c = 13.2728 (11) Å, V = 1958.5 (3) Å 3 , Z = 8. The X-ray crystallographic analyses revealed that the quinoxaline 1,4-di-N-oxide has an acyloin-endiol tautomerism. As shown in Table 1 19 Å) bonds and much more close to the C=O length, so we believe the O(2)-C(2) bond was a C=O bone. As shown in Scheme 2, we hold that there is an acyloin-endiol tautomerism, and as the keto form can provide a conjugate structure, it is more stable than the enol form.

General
All reagents were of high purity, purchased from either Aldrich or TCI, and used without further purification. Analytical grade tetrahydrofuran, dichloromethane, methanol, ethyl acetate, and petroleum ether were obtained from Shanghai Chemicals, China. Yields were not optimized. Melting points were measured in capillary tubes using a WRS-1B apparatus and remained uncorrected. Elemental analyses were performed by a Vario EL III elemental analyser. Nuclear magnetic resonance (NMR) spectra were determined in methanol-d 4 or CDCl 3 solutions using a Bruker 500 MHz spectrometer (operating at 500 MHz for 1 H and 125.75 MHz for 13 C). Chemical shifts are reported in parts per million (ppm, δ) downfield from tetramethylsilane. Splitting patterns are described as singlet (s), doublet (d), triplet (t), quartet (q), multiplet (m), and broad (br). Infrared (IR) spectra were determined using a Bruker IFS-48 FT-IR IR spectrometer. Window material was prepared with potassium bromide (KBr) powder, and the results are reported in wavenumbers (cm −1 ). Mass spectra (MS) were obtained with electric or chemical ionization (ESI) on a MAT-95 spectrometer.

Crystal structure determination
Single crystals of 1 suitable for X-ray crystal structure analysis were obtained by growth under slow evaporation at 5 °C from a methanol/water mixture (1:1 v/v). Crystal data and structure solutions at T = 293 (2)  The intensity data were collected on a Bruker Smart CCD diffractometer with graphite monochromated MoKα radiation and the ω-2θ scan technique [2θ max = 54.00°]. The structures were determined by direct methods using SHELXS-97 [13] and expanded using Fourier techniques [14]. The non-hydrogen atoms were refined anisotropically. The final cycle of full-matrix least-squares refinement was based on 1859 observed reflections [I > 2σ(I)] and 160 variable parameters and converged with unweighted and weighted factors of 1 (R 1 = 0.0439 and R w2 = 0.1220). Neutral atom scattering factors were taken from Cromer and Waber [15]. Anomalous dispersion effects were included in F calc [16]. The values used for Δf´ and Δf″ were those of Creagh and McAuley [17], while