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

Nancy Romero; Dino Gnecco; Joel Terán; Sylvain Bernès

doi:10.1107/S1600536813004017

. 2013 Feb 20;69(Pt 3):o408–o409. doi: 10.1107/S1600536813004017

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

Nancy Romero ^a, Dino Gnecco ^b, Joel Terán ^b, Sylvain Bernès ^c,^*

PMCID: PMC3588428 PMID: 23476588

Abstract

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].

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 ▶). graphic file with name e-69-0o408-scheme1.jpg

Experimental

Crystal data

C₂₆H₂₈N₂O₃
M _r = 416.50
Orthorhombic,
a = 9.6647 (13) Å
b = 9.7281 (10) Å
c = 23.684 (3) Å
V = 2226.7 (5) Å³
Z = 4
Mo Kα radiation
μ = 0.08 mm⁻¹
T = 296 K
0.60 × 0.60 × 0.08 mm

Data collection

Bruker P4 diffractometer
3173 measured reflections
2250 independent reflections
1843 reflections with I > 2σ(I)
R _int = 0.019
3 standard reflections every 97 reflections intensity decay: 1.5%

Refinement

R[F ² > 2σ(F ²)] = 0.039
wR(F ²) = 0.095
S = 1.04
2250 reflections
286 parameters
H atoms treated by a mixture of independent and constrained refinement
Δρ_max = 0.19 e Å⁻³
Δρ_min = −0.15 e Å⁻³

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.

Supplementary Material

Click here for additional data file.^{(31.8KB, cif)}

Crystal structure: contains datablock(s) I, global. DOI: 10.1107/S1600536813004017/nr2039sup1.cif

e-69-0o408-sup1.cif^{(31.8KB, cif)}

Click here for additional data file.^{(110.7KB, hkl)}

Structure factors: contains datablock(s) I. DOI: 10.1107/S1600536813004017/nr2039Isup2.hkl

e-69-0o408-Isup2.hkl^{(110.7KB, hkl)}

Click here for additional data file.^{(8.7KB, cml)}

Supplementary material file. DOI: 10.1107/S1600536813004017/nr2039Isup3.cml

Additional supplementary materials: crystallographic information; 3D view; checkCIF report

Table 1. Hydrogen-bond geometry (Å, °).

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A
O4—H4⋯O2′ⁱ	0.97 (4)	1.67 (4)	2.637 (3)	177 (4)

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Symmetry code: (i) Inline graphic .

Acknowledgments

The authors wish to acknowledge CONACyT–Gobierno del Estado Tabasco and the Universidad Juárez Autónoma de Tabasco for financial support via projects TAB-2009-C18–122141 and UJAT-2009-C05–02, respectively.

supplementary crystallographic information

Comment

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 2₁ 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 (SiO₂, CH₂Cl₂: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 (Al₂O₃, 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 NaHCO₃, and the mixture was washed with CH₂Cl₂ (3 × 50 ml). The organic phase was dried over Na₂SO₄, and concentrated. Compounds 5 and I were separated by column chromatography, (SiO₂, CH₂Cl₂:MeOH, 95:5). The title compound I was obtained in 80% yield, and was recrystallized from AcOEt:n-hexane (1:1). m.p. = 444 K, [α]²⁰_D = -172.5 (c=1, CH₂Cl₂). Compound 5, a colourless oil, was isolated in low yield (< 20%). Key NMR and IR data are given in the archived CIF.