Synthesis of some cyclooctane-based pyrazines and quinoxalines

cis , cis -1,5-Cyclooctadiene is the starting point for the synthesis of quinoxaline-and pyrazine-containing heterocycles with three, four or five rings in linear arrays with a central eight-membered carbocyclic ring


Introduction
cis,cis-1,5-Cyclooctadiene is a commercially available and inexpensive starting material.It has been utilised previously in several significant ways, for example as the starting material for the synthesis of 9-borabicyclo[3.3.1]nonane(9-BBN) the important hydroborating reagent, as a ligand (COD) for metal centres, for conversion into 1,3,5-cyclooctatriene (COT) also a widely used ligand, and for the study of transannular interactions involving the two alkene units.Our interest in the synthesis of heterocycles, and pyrazines and quinoxalines in particular, led us to speculate that this eight-membered ring bis-alkene could be made the starting point for the construction of diverse novel heterocycles, but avoiding any transannular processes which would remove the eight-membered feature.

Results and Discussion
cis,cis-Cycloocta-1,5-diene was dihydroxylated, following earlier work, 11 by reaction with a mixture of hydrogen peroxide (33%) and formic acid at 40-45 °C giving 13 in 39% yield.Oxidation of the diol using dimethylsulfoxide activated with acetic anhydride produced the dione 14 (31% yield) and reaction of this with ortho-phenylenediamine in refluxing acetic acid gave the quinoxaline 15 in 88% yield (Scheme 6), these last two steps also having been described previously.

Scheme 7
The hydroxy-ketone 16 was nicely crystalline and we took the opportunity to determine its solid-state structure by an X-ray analysis.Experimental details and atomic co-ordinates are given in the Experimental Section and a Chem3D representation, taken from the atomic co-ordinates, is shown in Figure 1.There are many reported crystal structures of α-hydroxy-ketones (2-hydroxy-ketones) but none of these include this feature in a five-, six-, seven-or eight-membered ring.It is then of considerable interest that in the present structure, the relative orientations of the C-OH and C=O bonds are very nearly completely antiperiplanar -the dihedral angle is 172.0(5)°.This relative orientation is seen in acyclic 2-hydroxy-ketone structures, but it is significant that the steric constraints placed on the hydroxy-ketone unit by the eight-membered ring, and its fusion to an essentially planar quinoxaline, do not perturb a strong tendency for the two carbon-oxygen bonds to orient antiperiplanar, thus minimizing dipole-dipole interaction.
The 1,2-diketone 17 was reacted with ortho-phenylenediamine in refluxing acetic acid producing the pentacycle 18 in 75% yield.A comparable reaction with 2,3-diaminopyridine, again in refluxing acetic acid, produced the five-nitrogen pentacycle 19, in 60% yield.Finally in this series, reaction with diaminomaleonitrile, also in hot acetic acid, gave the dinitrile 20 in a yield of 75% (Scheme 8).In each case, the continued presence of the eight-membered ring was evidenced by signals for eight benzylic-type hydrogens in the range δ 3.77 to 3.96.
The alkene-diol 13 was converted into dione-diacetate 22 (Scheme 9) by first, protection of the hydroxyl groups, forming the diacetate 11 21, and then application of the same oxidising combination as had been successful for the synthesis of 17.
Exposure of the dione-diacetate 22 to the standard conditions we had used for preparing the other quinoxalines -ortho-phenylenediamine in refluxing acetic acid -produced the tricyclic diacetate 23, in 75% yield, without loss of either acetate unit.The structure of product 23 was verified by a single crystal X-ray analysis. 13The dione-diacetate reacted equally well with 2,3diaminopyridine and diaminomaleonitrile to form the cycloocta [

Conclusions
The further chemistry of the eight-membered ring-containing quinoxalines, pyrido[2,3b]pyrazines, and pyrazines described in this paper is the subject of continuing study, particularly of those with functional groups (alcoholic acetates and nitriles) and our further results will be described in due course.

Experimental Section
General Procedures.All substrates were purchased from Merck and used without further purification.Melting points were determined on a digital melting point apparatus (electrothermal) and are uncorrected.Infrared spectra were recorded on a Thermonicolet (Nexus 670) FT-infrared spectrometer, using sodium chloride cells and measured as Nujol mulls or KBr discs. 1 H (300 MHz) and 13 C (75.5 MHz) NMR measurements were recorded on a Bruker 300 spectrometer in CDCl 3 using TMS as the internal reference.High resolution mass spectra were recorded on an Agilent Technology (HP), MS Model: 5973 Network Mass, selective Detector Ion source: Electron Impact (EI) 70 eV, Ion source temperature: 230 ºC Analyzer: quadrupole, Analyzer temperature: 150 ºC and relative abundances of fragments are quoted in parentheses after the m/z values.

2(5)
There are strong H bonding interactions between O(1) and N(1) which link the molecules into chains (Table 3 and Figure 3).In addition, there are weaker C-H … N pairwise interactions between C(2) and N(2) (Table 3,    A mixture of the dione 17 (0.15 g, 0.625 mmol) and o-phenylenediamine (0.07 g, 0.64 mmol) was refluxed in AcOH (10 mL) for 6 h.The product precipitated from the reaction mixture.The mixture was cooled, the product filtered off and washed with water, to give 18 (0.14 g, 75%).Mp > 300 o C.

Figure 1 .
Figure 1.Chem3D representation of hydroxy-ketone 16 taken from the measured atomic coordinates.