A Novel and Simple Synthetic Route for a Piperazine Derivative

Synthetic methods and strategies have been extensively investigated to enable access to piperazine derivatives, particularly the oxo species, due to the importance of this class of compounds in a wide range of biological activities. Also some of these species have been recently probed to be versatile as a probe for crystal structure. For instance, the propensity to form macromolecular arrays in the solid state enables the formation of planar or non-planar type structures. We report herein the synthesis of a novel piperazine derivative obtained from the direct reaction of pyrazine and SO 2 in aqueous solution.


Introduction
][3][4][5][6][7][8][9][10][11] Also some of these species have been recently probed to be versatile as a probe for crystal structure.For instance, the propensity to form macromolecular arrays in the solid state enables the formation of planar or non-planar type structures. 12,13e report herein the synthesis of a novel piperazine derivative obtained from the direct reaction of pyrazine and SO 2 in aqueous solution.

Results and Discussion
5-Oxopiperazinium-3-sulfonate monohydrate was prepared by the direct reaction of pyrazine with SO 2 gas in water.The isolated material crystallizes as pale yellow monoclinic prisms in the space group P1. Figure 1 and Table 1 present, respectively, the ORTEP 14 view of the compound and selected bond lengths and angles.In addition, an illustration of the hydrogen bonds involved in the packing of the water molecule in the crystal is also presented in Figure 1.Bond lengths (Å) and angles (°) of the intermolecular hydrogen bonds are presented in Table 1.The elemental analysis data are consistent with the chemical formulation The distances observed between the carbon atoms are far shorter than those reported for piperazine (1.614 Å), morpholine (1.599 Å), thiomorpholine (1.588 Å), and thioxane (1.575 Å).However, the C(1)-C(2) and C(3)-C(4) bond lengths are higher than those observed for benzene ring (1.40 Å). 16 This result suggests a non-aromatic ring as evidenced by the ORTEP view illustrated in Figure 1.In addition, the conformation of the ring is that of a distorted chair as suggested by the C(4)-N(1)-C(1) and C(3)-N(2)-C(2) angles.This is probably due to the strain induced by the attachment of SO 3 and carbonyl groups.This suggestion is reinforced by the different bond lengths N(1)-C(4) (1.342 Å) and N(1)-C(1) (1.4478 Å) which reflect different withdrawing capability of the SO 3 and CO fragments.
The infrared spectrum of the isolated compound presents signals typically assigned to substituted piperazine.Two absorptions characteristic of the piperazine ring, assigned to the CN stretching vibrational modes, 17,18 are observed at 1130 and 1168 cm -1 .A very sharp and intense band is observed at 1037 cm -1 and is assigned to the ring CH 2 rocking motions.According to Spell,17 this is one of the most useful band for detecting the presence of di-substituted piperazines.The band observed at 1680 cm -1 is assigned 17,18 to the carbonyl stretching frequency thus indicating the presence of this group in the molecule.Two sharp absorptions assigned, 17,18 to SO stretching modes of the SO 3 fragment are observed at 1005 and 957 cm -1 .
1 H and 13 C NMR data of the 5-oxopiperazinium-3sulfonate monohydrate are reported in the experimental section.HMQC spectrum, illustrated in Figure 2, was acquired to undoubtedly assign the protons.
The singlet at 4.06 ppm in the 1 H NMR spectrum is assigned to the H 6a and H 6b protons based on the correlation with the C 6 carbon in the HMQC spectrum.The doublet of doublet at 3.82 ppm is assigned to the geminal ( 2 J 12 Hz), and vicinal ( 3 J = 5 Hz) coupling of the H 2a proton with the H 2b and H 3 protons, respectively.According to the HMQC spectrum, the signals at 3.82 and 4.01 ppm are correlated to the same carbon atom.This assignment is reinforced by the  data obtained from COSY spectrum in which a correlation between the H 2a and H 2b protons and between these protons and the H 3 proton is observed.The signal at 4.77 ppm is assigned to the H 3 proton.Although the COSY spectrum indicates a correlation between this proton and the H 2a and H 2b protons, it is not possible to assign the multiplicity due to the solvent signal.In fact, for piperazine compounds, the exchange between the protons of the amine fragment and deuterium atoms is frequently observed resulting in a single signal in the water region (4.8 ppm). 19he mass spectrum of the 5-oxopiperazinium-3sulfonate monohydrate, illustrated in Figure 3, presents two metastable ions at m/z 197 and 99.The fact that the peak at m/z 99 is more intense than that at m/z 197 is consistent with the current observation that in heteroatom-containing molecules, the amino fragment presents lower abundance.This effect is indeed observed for some diketopiperazine species. 20,21Figure 4 presents a suggestion of a mechanism for the formation of these major ions.
Attempts were made in order to apply the same synthetic approach starting with pyridine, pyrazinamide, and imidazole.However, none of these molecules was reduced as pyrazine, meaning not only that two nitrogen atoms in the ring are required, but also that these atoms should be located trans to each other in order for the process to occur.In addition, the procedure was carried out in dried methanol instead of water.In such condition, no reaction was observed even after 24 h under vigorous stirring and SO 2 flow indicating that water molecules play a fundamental role in the mechanism.Based on these results and as conclusion, the mechanism presented in Figure 5 is suggested.
The reaction was carried out in acidic medium (1.5 < pH < 4.0) saturated with SO 2 gas.In such condition, it is well known that the most stable form of SO 2 molecules is the HSO 3 -bisulphite ion. 22Therefore, a nucleophilic addition is suggested to occur with the attack initiated by HSO 3 -to one of the C=N bond of the ring (I).Then, a positively charged intermediate is formed and experiences successive attacks of water molecules, which act as nucleophiles like in a hydrolysis reaction.The hydrogen ions thus formed are pulled out of the ring by the HSO 3 -ion acting as a Bronsted base.Upon the elimination of water molecule, an enol (compound II) is formed and suffers tautomerism, furnishing compound III.The ORTEP view illustrated in Figure 1 is, indeed, the zwitterionic structure of the final product (III), which is the most stable form in acidic medium.

Experimental
The water used throughout was purified by a Milli-Q system (Millipore Co.).
Pyrazine, pyridine, pyrazinamide, and imidazole, from Aldrich, were used as received.Pure SO 2 (purity > 99.9%) delivered in a bottle as liquefied gas, was purchased from White Martins Praxair Inc..All other chemicals and solvents were of analytical grade.
Elemental analyses were performed by on a FISIONS CHNS, mod.EA 1108 micro analyzer at the Microanalytical Laboratory at Universidade Federal de São Carlos in São Carlos, SP.LCMS (liquid chromatography mass spectrometry) analyses were conducted using isocratic elution (water/methanol, 90:10 v/v) with a Shimadzu C18 column (250×2.0mm, 4.6 mm).The general synthetic procedure was followed using pyrazine (150 mg, 0.83 mmol) in water (2 mL), at room temperature, in a Schlenk flask.A flow of SO 2 was bubbled for 30 s at each 30 min of reaction.According to SO 2 equilibrium, 22 in the acidic condition (1.5 < pH < 7.0) in which the reaction was carried out, the HSO 3 -form is favored.Just after the beginning of SO 2 addition, a color change is observed.After 1 h of reaction, pale yellow crystals start to be produced.The mixture was kept under stirring and SO 2 addition for 3 h when it seems that the precipitate was no longer formed thus suggesting the complete consumption of the starting material.Calc

Table 1 .Figure 1 .
Figure 1.(A) ORTEP 14 view showing the atoms labelling and the 50% probability ellipsoids and (B) illustration of the hydrogen bonds involved in the packing of the solvated water molecule of the 5-oxopiperazinium-3-sulfonate monohydrate.

Figure 4 .
Figure 4. Suggested mechanism for the formation of the major ions from the fragmentation of the 5-oxopiperazinium-3-sulfonate monohydrate in water/methanol solution.

Figure 5 .
Figure 5. Mechanism suggested for the formation of the 5-oxopiperazinium-3-sulfonate monohydrate as consequence of the pyrazine reduction in acidic medium.

Table 2 .
Crystal data and structure refinement parameters