4-Hydroxy-1,1′-bis[(S)-1-phenylethyl]-5,5′,6,6′-tetrahydro-3,4′-bipyridine-2,2′(1H,1′H)-dione

The title bis-piperidine, C26H28N2O3, was unexpectedly obtained via a dimerization mechanism promoted by acetic acid when performing the Dieckmann cyclization of a chiral amido ester. The S,S configuration was assigned by reference to the enantiomerically pure starting material. In the molecule, two core heterocycles are linked by a σ bond. One ring includes a keto–enol group, while the other presents an enone functionality. Both rings present a conformation intermediate between envelope and screw-boat, and the dihedral angle between the mean planes passing through the rings [48.9 (1)°] is large enough to avoid hindrance between ring substituents. The enol tautomeric form in one ring favors the formation of strong intermolecular O—H⋯O=C hydrogen bonds. The resulting one-dimensional supramolecular structure features single-stranded helices running along the 21 screw axis parallel to [100].

The title bis-piperidine, C 26 H 28 N 2 O 3 , was unexpectedly obtained via a dimerization mechanism promoted by acetic acid when performing the Dieckmann cyclization of a chiral amido ester. The S,S configuration was assigned by reference to the enantiomerically pure starting material. In the molecule, two core heterocycles are linked by a bond. One ring includes a keto-enol group, while the other presents an enone functionality. Both rings present a conformation intermediate between envelope and screw-boat, and the dihedral angle between the mean planes passing through the rings [48.9 (1) ] is large enough to avoid hindrance between ring substituents. The enol tautomeric form in one ring favors the formation of strong intermolecular O-HÁ Á ÁO C hydrogen bonds. The resulting one-dimensional supramolecular structure features single-stranded helices running along the 2 1 screw axis parallel to [100].

Related literature
For natural products having a bis-piperidine substructure, see: Gil et al. (1995); Torres et al. (2000); Matsunaga et al. (2004); Smith & Sulikowski (2010). For related structures of monocyclic piperidines, see: Didierjean et al. (2004); Romero et al. (2005). For the application of Dieckmann condensation in organic synthesis, see: Scheiber & Nemes (2008). For an example of self-condensation of a dione similar to that used for the synthesis of the title compound, see: Sugasawa & Oka (1954 Table 1 Hydrogen-bond geometry (Å , ). Data collection: XSCANS (Siemens, 1996); cell refinement: XSCANS; data reduction: XSCANS; program(s) used to solve structure: SHELXS97 (Sheldrick, 2008); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008); molecular graphics: Mercury (Macrae et al., 2008); software used to prepare material for publication: SHELXL97. The title compound is a byproduct of the Dieckmann cyclization carried on the chiral amido ester 3 (Fig. 1). When concentrated acetic acid is used in the fourth synthetic step, a dimerization occurs during the decarboxylation process, affording the title molecule I as the major product, while the expected piperidine-2,4-dione 5 is obtained in low yield.
This synthetic route for the preparation of this kind of piperidone derivatives is known to be successful in many cases (e.g. Scheiber & Nemes, 2008). However, it seems that the possible interference of secondary reactions like dimerization is poorly commented in the literature, probably because these reactions are seen as a trouble for the intended synthetic target. To the best of our knowledge, a single article clearly commented on this problem (Sugasawa & Oka, 1954). In this report, the authors added a note in the galley proofs, which is worth to quote in full: "in the course of the present work, we prepared N-benzyl-2,4-dioxopiperidine [···]. Our attempt to condense this ketone with ethyl cyanoacetate under Cope condition was not effected because this compound was found to undergo bimolecular self-condensation fairly rapidly, at a room temperature [···]. This tendency of the easy intermolecular self-condensation [of N-benzyl-2,4-dioxopiperidine] is so remarkable when compared with the stability of the corresponding 5-ethyl derivatives, which suffer no change when kept in a stoppered bottle at room temperature for a long time".
The synthesis of the title compound in good yield now confirms the observations done by Sugasawa & Oka 59 years ago.
The molecular structure of I is built up from one ring including a keto-enol group (ring N1/C2···C6) bonded to a ring with the enone functionality (ring N1′/C2′···C6′, see Fig. 2). Both rings present a conformation intermediate between envelope and screw-boat, with Cremer parameters being θ = 118.1° and φ = 101.0° for the keto-enol ring, and θ = 60.5° and φ = 278.5° for the enone ring. The dihedral angle between mean planes passing through these heterocycles, 48.9 (1)°, is large enough to avoid hindrance between atoms O2 and O4 in the first ring and H atoms at C3′ and C5′ in the other ring. Heterocycles in I have indeed conformations close to those observed in monocyclic related compounds which were X-ray characterized (e.g. Didierjean et al., 2004;Romero et al., 2005). In the solid state, the enolic tautomer of I seems to be favored over the di-ketone because the presence of a donor OH group allows the formation of stabilizing intermolecular O-H···O═C hydrogen bonds in the crystal. These strong interactions generate a supramolecular structure based on single stranded helices running along the 2 1 crystallographic screw axis in the [100] direction (Fig. 3).
The reported structure may be of interest in the field of natural products. It has been reported that the biosynthesis of some bis-piperidine alkaloids isolated from marine sponges, like halicyclamine A (Gil et al., 1995) or haliclonacyclamine C (Smith & Sulikowski, 2010) could involve the dimerization of dihydropyridines. Other natural products of interest also share the title compound bis-piperidine scaffold, with additional points of cyclization between the piperidine rings (Torres et al., 2000;Matsunaga et al., 2004).

Experimental
The synthesis is described in Fig. 1. A solution of 1 (41.2 mmol, 1 eq.) and methyl acrylate (49.6 mmol, 1.2 eq.) was stirred overnight at 298 K. The reaction mixture was concentrated under reduced pressure, and the crude purified by column chromatography (SiO 2 , CH 2 Cl 2 :MeOH, 97:3), to afford 2 as a colourless oil (98%). An amount of 2 (40.6 mmol, 1 eq.) was dissolved in diethyl malonate (40 ml) and the mixture refluxed until the reaction was complete (6 h). After concentration, the crude was chromatographed (Al 2 O 3 , n-hexane:AcOEt, 1:1), to afford 3, as a colourless oil (75%). A suspension of NaH (34.2 mmol, 2.5 eq.) in cyclohexane (100 ml) was refluxed for 20 min, and then, a solution of 3 (13.7 mmol, 1.1 eq. in 30 ml of anhydrous toluene) was added dropwise. After refluxing the mixture for 5 h, a solid was obtained, 4, which was filtered and dried in air. This solid was treated with acetic acid:water (30%, v/v) for the decarboxylation process. The mixture was refluxed until gas evolution stopped. After cooling down to 298 K, pH was adjusted to 7 with NaHCO 3 , and the mixture was washed with CH 2 Cl 2 (3 × 50 ml). The organic phase was dried over Na 2 SO 4 , and concentrated. Compounds 5 and I were separated by column chromatography, (SiO 2 , CH 2 Cl 2 :MeOH, 95:5).

Refinement
All C-bound H atoms were placed in idealized positions and refined as riding to their carrier atoms, with bond lengths fixed to 0.93 (aromatic CH), 0.96 (methyl CH 3 ), 0.97 (methylene CH 2 ) or 0.98 Å (methine CH). Isotropic displacement parameters were calculated as U iso (H) = xU eq (carrier atom), with x = 1.5 (methyl groups) or x = 1.2 (other H atoms). H4 (hydroxyl group) was found in a difference map and refined with free coordinates and U iso (H4) = 1.5U eq (O4). The absolute configuration for C7 and C7′ is based on the known configuration of the enantiomerically pure starting material, (S)-(-)-1-phenylethylamine, and 621 measured Friedel pairs were merged for refinement.