4-Anilino-1-benzyl­piperidine-4-carbo­nitrile

Kiran K Allam; Frank R Fronczek; M Graça H Vicente

doi:10.1107/S1600536808009136

. 2008 Apr 16;64(Pt 5):o839. doi: 10.1107/S1600536808009136

4-Anilino-1-benzylpiperidine-4-carbonitrile

Kiran K Allam ^a,^‡, Frank R Fronczek ^a,^*, M Graça H Vicente ^a

PMCID: PMC2961292 PMID: 21202327

Abstract

The title molecule, C₁₉H₂₁N₃, an important precursor in the synthesis of porphyrin–fentanyl conjugates, has its piperidine ring in the chair conformation, with endocyclic torsion-angle magnitudes in the range 53.26 (8)–60.63 (9)°. The C N group is axial, while the CH₂Ph and NHPh groups are equatorial. The NH group does not engage in strong hydrogen bonding, but forms an intermolecular N—H⋯N interaction.

Related literature

For background literature, see: Barth et al. (2005 ▶); Deguchi et al. (2004 ▶); Henriksen et al. (2005 ▶); Terasaki et al. (2003 ▶); Vicente, (2001 ▶). For a related structure, see: Brine et al. (1994 ▶).

Experimental

Crystal data

C₁₉H₂₁N₃
M _r = 291.39
Monoclinic,
a = 9.7718 (13) Å
b = 10.0415 (14) Å
c = 15.9519 (15) Å
β = 94.532 (9)°
V = 1560.4 (3) Å³
Z = 4
Mo Kα radiation
μ = 0.07 mm⁻¹
T = 90 K
0.37 × 0.25 × 0.23 mm

Data collection

Nonius KappaCCD diffractometer with an Oxford Cryosystems Cryostream cooler
Absorption correction: none
24180 measured reflections
6842 independent reflections
5189 reflections with I > 2σ(I)
R _int = 0.025

Refinement

R[F ² > 2σ(F ²)] = 0.044
wR(F ²) = 0.124
S = 1.03
6842 reflections
203 parameters
H atoms treated by a mixture of independent and constrained refinement
Δρ_max = 0.49 e Å⁻³
Δρ_min = −0.27 e Å⁻³

Data collection: COLLECT (Nonius, 2000 ▶); cell refinement: DENZO and SCALEPACK (Otwinowski & Minor, 1997 ▶); data reduction: DENZO and SCALEPACK; program(s) used to solve structure: SIR97 (Altomare et al., 1999 ▶); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008 ▶); molecular graphics: ORTEP-3 for Windows (Farrugia, 1997 ▶); software used to prepare material for publication: SHELXL97.

Supplementary Material

Crystal structure: contains datablocks global, I. DOI: 10.1107/S1600536808009136/om2222sup1.cif

e-64-0o839-sup1.cif^{(19.3KB, cif)}

Structure factors: contains datablocks I. DOI: 10.1107/S1600536808009136/om2222Isup2.hkl

e-64-0o839-Isup2.hkl^{(334.8KB, hkl)}

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
N2—H2N⋯N3ⁱ	0.847 (14)	2.756 (13)	3.5044 (12)	148.2 (11)

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Symmetry code: (i) Inline graphic .

Acknowledgments

The purchase of the diffractometer was made possible by grant No. LEQSF(1999–2000)-ENH-TR-13, administered by the Louisiana Board of Regents.

supplementary crystallographic information

Comment

1-Benzyl-4-phenylamino-4-piperidinecarbonitrile is an important precursor in the synthesis of porphyrin-fentanyl conjugates that might be used as sensitizers in photodynamic therapy (PDT) (Vicente, 2001) and/or in boron neutron capture therapy (BNCT) (Barth et al., 2005) of brain tumors. One of the obstacles for treating brain tumors using chemotherapy is the presence of the blood brain barrier (BBB), which protects the central nervous system from drugs and endogenous molecules (Terasaki et al., 2003). Porphyrin-fentanyl conjugates could potentially cross the BBB due to the affinity of fentanyl derivatives for the opioid receptors highly expressed in the BBB (Deguchi et al., 2004), and thus selectively accumulate within brain tumors.

The structure of the title compound is shown in Fig 1. The piperidine ring is in the chair conformation, with the C≡N group axial and the CH₂Ph and NHPh groups equatorial. The conformation of the CH₂Ph group with respect to the piperidine is described by torsion angles C5—N1—C6—C7 - 168.52 (6) and N1—C6—C7—C8 62.28 (10)°. The conformation of the NHPh group with respect to the piperidine is described by torsion angles C2—C3—N2—C13 179.19 (8) and C3—N2—C13—C18 172.56 (8)°. The pyramidal nature of N1 can be seen by the near-tetrahedral C—N1—C angles, which all fall within the narrow range 110.18 (6) - 110.76 (7)°, such that N1 lies 0.465 (1) Å from the plane defined by C1, C5, and C6.

Despite the presence of both a potential hydrogen-bond donor and potential hydrogen-bond acceptors, the compound exhibits no strong hydrogen bonding, nor any short C—H···N interactions. The nearest distance of the N—H group to a hydrogen-bond acceptor is to nitrile N3ⁱ (at i = 3/2 - x, 1/2 + y, 3/2 - z), having N2···N3ⁱ distance 3.5044 (12) Å, H2N··· N3ⁱ distance 2.756 (13) Å, and angle about H2N 148.2 (11)°.

Experimental

The title compound was prepared in 89.5% yield from N-benzyl-4-piperidone, using an optimized procedure from that previously published (Henriksen et al., 2005), as follows. To a 100 ml round-bottom flask under an argon atmosphere were added N-benzyl-4-piperidone (1.89 g, 10 mmol), aniline (3.7 g, 40 mmol), KCN (2.6 g, 40 mmol) and dry dichloromethane (40 ml). The reaction mixture was cooled to 0° C and stirred under argon for 20 minutes. Acetic acid (1.8 g, 30 mmol) was added to the reaction mixture over a period of 10 minutes and the final mixture heated at 50° C for 24 h. After cooling to room temperature the reaction mixture was poured into crushed ice (50 g), neutralized with 25% aqueous NaOH and the pH of the mixture was adjusted to about 10 using 40% aqueous K₂CO₃. The organic phase was collected and the water layer was extracted with dichloromethane (2 x 25 ml). The organic extracts were dried over anhydrous sodium bicarbonate and concentrated under reduced pressure to give a yellow solid. The yellow crystals were purified by re-crystallization from dichloromethane/hexane to give 2.6 g (89.5%) yield of colorless crystals. Spectroscopic analysis, ¹H NMR (250 MHz, CDCl₃): 1.92 (td, J₁= 3.6 Hz, J₂ = 10.8 Hz, 2H, CH₂), 2.29–2.53 (m, 4H, CH₂), 2.79–2.85 (m, 2H, CH₂), 3.56 (s, 2H, CH₂Ph), 3.64 (s, 1H, NH), 6.88–6.95 (m, 3H, ArH), 7.20–7.33 (m, 7H, ArH). ¹³C NMR (CDCl₃): 36.09, 49.27, 59.06, 62.58, 117.78, 120.93, 127.26, 128.96, 129.00, 129.31, 134.02, 138.00, 143.29. MS MALDI-TOF m/z 290.9 (M⁺).