Synthesis , Crystal and Molecular Structure of Novel Adamantyl Derivatives of N-Aryl Substituted 3-Hydroxy-2-methylpyridine-4-ones

Two novel potentially bioactive compounds, esters 2-methyl-1-phenylpyridine-4-one-3-yl adamantan-1-ylethanoate (1) and 1-(p-methoxyphenyl)-2-methylpyridine-4-one-3-yl adamantan-1ylethanoate (2), were synthesized by esterification of adamantan-1-ylacetic acid with appropriate N-aryl substituted 3-hydroxypyridine-4-one derivatives. Both compounds are fully characterized using standard spectroscopic methods. Crystal and molecular structures of 1 and 2 were determined by the single crystal X-ray diffraction method. The crystal packing of both 1 and 2 shows separation of the hydrophobic and hydrophilic regions. The crystal structure of 1 is characterized by the two-dimensional hydrogen bonding layers parallel to (001). The crystal packing of 2 is characterized by hydrogen-bonded chains extended in the direction [010].(doi: 10.5562/cca2339)


INTRODUCTION
3-Hydroxypyridine-4-ones (3,4-HPOs) are a family of heterocyclic compounds with nitrogen atom in the ring and hydroxyl and keto groups at positions 3 and 4, respectively (Figure 1).−5 In therapeutic applications 3,4-HPOs are primarily used as potential sequesters of metal ions in various diseases that can cause metal overload 6,7 as well as in such conditions that are elicited by metal poisoning. 8Furthermore, it has been shown that these ligands present their highest affinity for metal ions under physiological conditions in which they are quite stable, nontoxic and even resistant to enzyme-catalyzed cleavage.
Variation of substituents at positions 1, 2, 5 and even at position 3 can strongly influence their biological activity.−12 Adamantyl based compounds are used clinically primarily for the treatment of neurological conditions, as antiviral and antitumor agents and potential drugs against type 2 diabetes. 13,14In almost all cases compounds that bear the bulky adamantyl group tend to be more lipophilic than their des-adamantyl analogues.Furthermore, this group can modulate therapeutic activity of many experimental drugs and prodrugs by varying their mechanism of action. 13These are certaintly good enough reasons for its incorporation in any potential or already biologically active compound.
Given the fact that the structure and function are closely related one can only benefit from the obtained X-ray structure data of potential drugs or prodrugs.The detailed structure of such compounds can provide extremely useful information that can be subsequently used in elucidation of their mechanism of action.According to the Cambridge Structural Database, CSDB, 15 a search using the ConQuest Version 1.15, gave only 22 structures containing the adamantan-1-ylacetyl unit yet no structures which contain both adamantan-1-ylacetyl and 3,4-HPO units.
We have prepared two adamantyl modified 3,4-HPOs which are currently used in our ongoing biological study on similar 3,4-HPO derivatives.Preliminary tests have shown that these compounds possess a biological potential. 16Pyridinone esters of adamantan-1ylacetic acid were prepared in Steglich esterification conditions. 17Crystal and molecular structures of both products were determined by the single crystal X-ray diffraction method.

Materials and Methods
The chemical reagents used in syntheses were obtained from Fluka or Aldrich Corp.All solvents were purified using standard procedures.Column chromatography (solvents and proportions are given in the text) of products were performed on Merck silica gel 60 (size 70-230 mesh ASTM) and thin layer chromatography monitoring (TLC) on Fluka silica gel (60 F 254) plates (0.25 mm).Visualization was effected by the use of UV light at 254 nm.Melting points were determined in open capillaries using Büchi B-540 melting point apparatus and are uncorrected.IR spectra were recorded using Perkin Elmer FT-IR Spectrometer Spectrum Two. 1 H and 13 C NMR spectra were recorded with Bruker Avance spectrometer at room temperature at 300.130 MHz and 75.468MHz, respectively.Chemical shifts are given in ppm downfield from TMS as internal standard.Electrospray ionization mass spectrometry (ESI-MS) was performed using Agilent 6410 MS instrument.CHN elemental analyses were carried out by the Analytical Service Laboratory of the Ruđer Bošković Institute.

General Procedure
An appropriate pyridinone derivative (0.5 mmol) was added to a solution of adamantan-1-ylacetic acid (95 mg, 0.5 mmol) in dry CH 2 Cl 2 (3 mL), N,N-dimethylaminopyridine (DMAP; 6 mg, 0.05 mmol).The mixture was cooled down to 0 °C and 1-ethyl-3-(3-dimethyaminopropyl)carbodiimide hydrochloride (EDCHCl; 105 mg, 0.55 mmol) was added next.The solution was stirred for 30 min at 0 °C and subsequently 24 h at room temperature.The reaction was monitored by TLC (ethyl acetate / methanol 5:2).Dichloromethane was added and the or-ganic layer was washed twice with 0.5 M HCl, then with saturated aqueous NaHCO 3 solution and finally dried over MgSO 4 .After filtration, the organic extract was concentrated in vacuo.The residue was purified by column chromatography on silica gel (ethyl acetate / methanol 5:2) giving the corresponding ester, 1 or 2.

X-ray Crystallography
The single-crystal X-ray diffraction data of 1 and 2 were collected by -scans on an Oxford Diffraction Xcalibur 3 CCD diffractometer with graphite-monochromated Mo-K  radiation ( = 0.71073 Å).Data reduction was performed using the CrysAlis software package. 18Solution, refinement and analysis of the structures were done using the programs integrated in the WinGX system. 19he structures were solved using SHELXS by direct methods.The refinement procedure was performed by the full-matrix least-squares method based on F 2 against all reflections using SHELXL. 20The non-hydrogen atoms were refined anisotropically.All hydrogen atoms were located in the difference Fourier maps and refined isotropically.Exceptions were hydrogen atoms on atom C18 (methyl group) in 2 which were placed in calculated positions and refined using the riding model.Geometrical calculations were done using PLATON. 21The structure drawings were prepared using the MERCURY program. 22Crystallographic and structure refinement data for 1 and 2 are summarized in Table 1, whereas the selected bond distances and angles are listed in Table 2.

X-ray Crystallography
The molecular geometry, as determined by X-ray analysis, and the atom labelling scheme of 1 and 2 are shown in Figure 2. Differences in the molecular structure of the 1 and 2 are revealed by their overlay (Figure 3), the greatest being at the methoxy group in 2, and by dihedral angles between the pyridinone and phenyl rings.Analysis of the bond lengths revealed only small or insignificant differences in the molecular structure of 1 and 2 (Table 2).The adamantane unit in 1 and 2 consists of four cyclohexanes fused with each other, all approaching the ideal chair conformations.−25 The sixmembered pyridinone and phenyl rings in both 1 and 2   are planar with the dihedral angles between the two planes 78.39(13)  and 60.95(7) , respectively.
In the previously reported structure of 1-(p-methoxyphenyl)-3-hydroxy-2-methyl-4-pyridinone (Hpap) the pyridinone ring is slightly nonplanar and the phenyl ring is planar.The dihedral angle between the two planes is 73.7 , which is quite different than in 2. 26 The pattern of the bond lengths within the pyridinone and phenyl rings in 2 is similar to that observed in the Hpap molecule.Exception is a longer O2C13 bond (1.403(3) Å in 2 and 1.357(2) Å in Hpap).There are no classical hydrogen bonds in the crystal structures of 1 and 2, however weak intermolecular C−H•••O hydrogen bonds are present (Table 3).The Xray structure of 1 also reveals an intramolecular hydrogen bond C18−H18C•••O2 (Table 3).The crystal packing of both 1 and 2 shows separation of the hydrophobic and hydrophilic regions.In 1 the hydrogen bonds connect the molecules into layers parallel to (001) (Figure 4a).Hydrogen bonds in 1 involve double acceptors, the ester carbonyl oxygen atom (O1) and the keto group oxygen atom from the pyridinone moiety (O3).C and H atoms from the phenyl (C20 and C24) and from the pyridinone ring (C15 and C16) serve as hydrogen bond donors (Figure 4b).The crystal packing of 2 is characterized by hydrogen-bonded chains extended in the direction [010] (Figure 5a).Hydrogen bonds in 2 involve a double acceptor function of the keto group oxygen atom O3 and donors from the aromatic C20−H20 and C21−H21 atoms.Additionaly, the ester carbonyl oxygen atom (O1) serves as the hydrogen bond acceptor and C15−H15 from the pyridinone unit as the hydrogen bond donor (Figure 5b).

CONCLUSION
Two pyridinone esters of adamantan-1-ylacetic acid were prepared in satisfactory yields.The procedure involved mild Steglich esterification in which two Naryl substituted 3,4-HPO derivatives were used as the alcohol part.The final pyridinones 1 and 2 bearing the adamantyl moiety were fully characterized by standard spectroscopic methods and also by the X-ray structural analysis.The crystal packing of both 1 and 2 shows separation of the hydrophobic and hydrophilic regions.There are no classical hydrogen bonds in the crystal structures of 1 and 2, however weak intermolecular C−H•••O hydrogen bonds are present.The crystal packing of 1 is characterized by the hydrogen bonds connecting molecules into layers parallel to (001) while the crystal packing of 2 is characterized by hydrogenbonded chains extended in the direction [010].

Figure 2 .
Figure 2. a) The ORTEP drawing of 1. b) The ORTEP drawing of 2. Ellipsoids are shown at the 50% probability and hydrogen atoms are shown as spheres of arbitrary radii.

Figure 3 .
Figure 3. Superposition of the molecules of 1 and 2.

Table 1 .
Crystallographic data and structure refinement details for compounds 1 and 2