Crystal structures of two chiral piperidine derivatives: 1-[(1R)-2-hydroxy-1-phenylethyl]piperidin-4-one and 8-[(1S)-1-phenylethyl]-1,4-dioxa-8-azaspiro[4.5]decane-7-thione

The conformation of the piperidine ring is modified by the hybridization state of the C atom in the α-position to the piperidinic N atom.

The crystal structures of the two title piperidine derivatives show different conformations for the six-membered heterocycle. The N-substituted 4-piperidinone 1-[(1R)-2-hydroxy-1-phenylethyl]piperidin-4-one, C 13 H 17 NO 2 , (I), has a chair conformation, while the piperidine substituted in position 2 with a thiocarbonyl group, 8-[(1S)-1-phenylethyl]-1,4-dioxa-8-azaspiro[4.5]decane-7-thione, C 15 H 19 NO 2 S, (II), features a half-chair conformation. Comparison of the two structures, and data retrieved from the literature, suggests that the conformational flexibility is mainly related to the hybridization state of the C atom to the piperidinic N atom: a Csp 3 atom favours the chair conformer, while a Csp 2 atom distorts the ring towards a half-chair conformer. In the crystal structure of (I), weak C-HÁ Á ÁO hydrogen bonds link the molecules into supramolecular chains propagating along the b-axis direction. In the crystal of (II), the molecules are linked by weak C-HÁ Á ÁS contacts into supramolecular chains propagating along the b-axis direction.

Chemical context
The 4-piperidone scaffold has been used as a building block for the synthesis of more complex heterocyclic compounds. An example is the one-pot three-step synthesis of fentanyl [N-(1-phenethyl-4-piperidyl) propionanilide], a strong agonist of -opioid receptors, used for its potent analgesic activity. This industrial synthesis, patented by Janssen Pharmaceutica (Gupta et al., 2010) employs 4-piperidone hydrochloride monohydrate as the starting material. The range of biological activity for 4-piperidone derivatives is quite broad, including anti-inflammatory, anticancer, antibacterial and antifungal properties. For this reason, new synthetic methods are being sought proactively in this field (e.g. Tortolani & Poss, 1999;Davis et al., 2001;Das et al., 2010). For our part, our emphasis is on the synthesis of chiral N-substituted piperidone derivatives (e.g. Romero et al., 2007). ISSN 2056-9890 In this context, X-ray crystallography is a potent tool to assess the conformational modifications experienced by the piperidine heterocycle while its substitution pattern is altered along a synthetic route. The pair of structures reported here illustrates such conformational flexibility in this chemistry.

Structural commentary
The first piperidin-4-one derivative [(I), Fig. 1] is a nonsterically hindered molecule, and thus adopts the most stable chair conformation for the six-membered heterocycle. The total puckering amplitude is Q = 0.553 (3) Å , and the Cremer parameters are = 168.8 (3) and ' = 171.8 (18) . The deviation from the ideal conformation, = 180 , may be related to the heterocyclic nature of the ring, with short C-N bond lengths and longer C-C bond lengths, as expected. Moreover, atom C4 has a geometry consistent with its sp 2 hybridization state, while N1 is essentially tetrahedral, with the lone pair occupying the axial position. The equatorial group substituting this N atom is rigid, as a result of its chiral character. However, the spatial orientation of this group allows the hydroxyl group to interact with the nitrogen lone pair, stabilizing the observed molecular conformation.
The chair conformation for the piperidone in (I) was previously observed in related compounds based on the same heterocycle Rajesh et al., 2010aRajesh et al., , 2012. Apparently, the only significant variation allowed for this system is for the N atom, which may approach a planartrigonal geometry (Shahani et al., 2010;Rajesh et al., 2010b).
The chair conformation of (I) is, however, different from that observed for (II), derived from piperidine-2-thione (Fig. 2). In that case, the half-chair form is found in the crystal structure, characterized by a puckering amplitude Q = 0.513 (3) Å , and Cremer parameters = 127.5 (3) and ' = 29.29 (5) (ideal values: = 129.2 and ' = 30 ). The N atom has a planar environment, the sum of angles about this center being 360 . This conformer is identical to one of the stable forms reported for piperidin-2-one (known as -valerolatcam): microwave spectroscopy indicated that for -valerolatcam, two conformers are stabilized in the gas phase, the half-chair form and the twist form (Kuze et al., 1999). -Valerolatcam is actually comparable to (II), because in both molecules C4 has the same sp 3 hybridization. In (II), the spiro atom C4 is part of the 1,3-dioxolane ring. The slightly twisted half-chair conformation for this ring is common. The two rings are almost perpendicular, as reflected in the dihedral angle between their mean-planes of 76.4 (2) .

Effect of hybridization on ring conformation
Since the ring conformation in (II) seems not to be related to any intramolecular strong interaction nor the hybridization modification from sp 2 to sp 3 at C4, it should be a consequence of the presence of the thiocarbonyl functionality at C2. This center is in a state very close to pure sp 2 hybridization. This is reflected in the bond length for the C S group, 1.677 (3) Å , close to the mean value of 1.669 Å computed from almost 10000 thiocarbonyl bonds retrieved from the organics subset of the CSD (Version 5.36 with all updates; Groom & Allen, 2014. The restriction to sp 2 -C centers is applied by requiring the C atom to be linked to exactly three atoms and the S atom to be linked to exactly one atom). Indeed, long C S bonds, above 1.75 Å , are found in compounds including molecules having a propensity to form hydrogen bonds, like thiourea (Weber, 1984)  The molecular structure of (I), with displacement ellipsoids for non-H atoms at the 30% probability level.

Figure 2
The molecular structure of (II), with displacement ellipsoids for non-H atoms at the 30% probability level. Chumakov et al., 2006), and trithiocarbonic acid (Krebs & Gattow, 1965), among others. In the case of a single C-S bond based on a sp 3 -hybridized C atom, the bond length is sharply distributed around 1.81 Å .
The other factor contributing to the ring conformation in (II) is the absence of the hydroxyl group in the chiral moiety, making the heterocyclic N atom inert towards potential interactions. The lone pair should thus be oriented randomly above and below the piperidine mean plane, through nitrogen inversion, characterized by a low energy barrier in the gas and solution phases. Both features, the planar N atom and the neighboring sp 2 -C atom, generate the half-chair conformation observed for the piperidine-2-thione core. In the present case, it is difficult to determine whether one feature dominates, or both are of importance for stabilizing the half-chair conformation. However, for the 25 hits corresponding to piperidine-2-ones deposited in the CSD, 21 of them present the same conformation as in (II), with C4 as the flap atom for the halfchair. In three cases, the puckering amplitude of the half-chair is close to 0 Å (Woydt et al., 1991;Bolla et al., 2014), and in one case, the ring presents a twist-boat conformation (Sanfilippo et al., 1992). In contrast, piperidine derivatives are stabilized almost universally in the chair conformation, with very few exceptions in some disordered structures (Thirumaran et al., 2009). These rules hold regardless of the substituent on the N atom. Applying these general rules to compounds (I) and (II), we thus infer that the ring conformation is mainly determined by the hybridization state of the C atom in position to the piperidinic N atom.

Supramolecular features
In the crystal of (I), weak C-HÁ Á ÁO hydrogen bonds link the molecules into supramolecular chains propagating along the b-axis direction ( Table 1).
The crystal structure of (II) is based on weak intermolecular C-HÁ Á ÁS contacts involving one methylene group of the dioxolane ring and the thiocarbonyl functionality (Table 2), which forms chains along the 2 1 symmetry axis parallel to [010].

Synthesis and crystallization
Compound (I). The synthesis is illustrated in Fig. 3. A solution of compound (1), (R)-(À)-2-phenylglycinol (5.65 g, 41.2 mmol) with an excess of ethyl acrylate in methanol (60 mL), was stirred overnight at 298 K. The reaction mixture was concentrated, and the crude purified by column chromatography (SiO 2 , CH 2 Cl 2 :MeOH, 97:3), to afford (2) as a colorless oil (98%). An amount of (2) (40.6 mmol) was added to a mixture of MeONa in anh. benzene. After refluxing the mixture for 5 h, a solid was obtained, which was filtered and dried in air. This solid was treated with AcOH:water (30%, v/v) until pH = 1, initiating 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 Â 50 ml). The organic phase was dried over Na 2 SO 4 , and concentrated. Compound (I) was purified by column chromatography (SiO 2 , CH 2 Cl 2 :MeOH, 95:5). Compound (I) was obtained in 80% yield, and was recrystallized from an AcOEt:n-hexane mixture (1:1).
Compound (II). The synthesis is illustrated in Fig. 4. The synthesis of compound (3), (S)-(À)-phenylethylpiperi-2,4dione, has been reported previously (Romero et al., 2013; see compound 5 in Fig. 1 of this report). To a solution of (3) in 50 mL of dry benzene, was added ethylene glycol (0.2 mL, 3.4 mmol) and a catalytic amount of p-TSA. The mixture was refluxed until water formation, collected with a Dean-Stark trap, stopped. Then, the reaction mixture was cooled down to room temperature, treated with brine, and washed with CH 2 Cl 2 (3 Â 50 mL). The organic phase was dried over Table 1 Hydrogen-bond geometry (Å , ) for (I).

Refinement
Crystal data, data collection and structure refinement details are summarized in Table 3. All C-bound H atoms were placed in calculated positions, and refined as riding on their carrier atoms, and with C-H bond lengths fixed at 0.93 (aromatic CH), 0.96 (methyl CH 3 ), 0.97 (methylene CH 2 ), or 0.98 Å (methine CH). For (I), the hydroxyl H atom, H2, was first found in a difference map. Its position was fixed in the last least-squares cycles, with O2-H2 = 0.91 Å . For all H atoms, the isotropic displacement parameters were calculated as U iso (H) = xU eq (carrier atom), where x = 1.5 for methyl and hydroxyl H atoms, and x = 1.2 otherwise. The absolute configuration for chiral centers C7 in (I) and (II) was assumed from the chirality of starting materials used for the synthesis (see previous section). In the case of (II), which contains one site producing anomalous scattering, the expected enantiomer was confirmed by the refinement of the Flack parameter (Parsons et al., 2013).