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Acta Cryst. (2008). E64, o839    [ doi:10.1107/S1600536808009136 ]

4-Anilino-1-benzylpiperidine-4-carbonitrile

K. K. Allam, F. R. Fronczek and M. G. H. Vicente

Abstract top

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[triple bond]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.

Comment top

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)°.

Related literature top

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 top

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+).

Refinement top

H atoms on C were placed in idealized positions with C—H distances 0.95 - 0.99 Å and thereafter treated as riding. Coordinates of the N—H hydrogen atom were refined. Uiso for H was assigned as 1.2 times Ueq of the attached atoms.

Computing details top

Data collection: COLLECT (Nonius, 2000); cell refinement: DENZO and SCALEPACK (Otwinowski & Minor, 1997); data reduction: DENZO and SCALEPACK (Otwinowski & Minor, 1997); 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 (Sheldrick, 2008).

Figures top
[Figure 1] Fig. 1. Ellipsoids at the 50% level, with H atoms having arbitrary radius.
4-Anilino-1-benzylpiperidine-4-carbonitrile top
Crystal data top
C19H21N3F000 = 624
Mr = 291.39Dx = 1.240 Mg m−3
Monoclinic, P21/nMo Kα radiation
λ = 0.71073 Å
Hall symbol: -P 2ynCell parameters from 5228 reflections
a = 9.7718 (13) Åθ = 2.5–35.0º
b = 10.0415 (14) ŵ = 0.07 mm−1
c = 15.9519 (15) ÅT = 90 K
β = 94.532 (9)ºFragment, colorless
V = 1560.4 (3) Å30.37 × 0.25 × 0.23 mm
Z = 4
Data collection top
Nonius KappaCCD
diffractometer with an Oxford Cryosystems Cryostream cooler		5189 reflections with I > 2σ(I)
Radiation source: fine-focus sealed tubeRint = 0.025
Monochromator: graphiteθmax = 35.0º
T = 90 Kθmin = 2.5º
ω scans with κ offsetsh = −15→15
Absorption correction: nonek = −12→16
24180 measured reflectionsl = −25→25
6842 independent reflections
Refinement top
Refinement on F2Hydrogen site location: inferred from neighbouring sites
Least-squares matrix: fullH atoms treated by a mixture of
independent and constrained refinement
R[F2 > 2σ(F2)] = 0.044  w = 1/[σ2(Fo2) + (0.0605P)2 + 0.3181P]
where P = (Fo2 + 2Fc2)/3
wR(F2) = 0.124(Δ/σ)max = 0.001
S = 1.04Δρmax = 0.49 e Å−3
6842 reflectionsΔρmin = −0.27 e Å−3
203 parametersExtinction correction: SHELXL97 (Sheldrick, 2008), Fc*=kFc[1+0.001xFc2λ3/sin(2θ)]-1/4
Primary atom site location: structure-invariant direct methodsExtinction coefficient: 0.0081 (18)
Secondary atom site location: difference Fourier map
Crystal data top
C19H21N3V = 1560.4 (3) Å3
Mr = 291.39Z = 4
Monoclinic, P21/nMo Kα
a = 9.7718 (13) ŵ = 0.07 mm−1
b = 10.0415 (14) ÅT = 90 K
c = 15.9519 (15) Å0.37 × 0.25 × 0.23 mm
β = 94.532 (9)º
Data collection top
Nonius KappaCCD
diffractometer with an Oxford Cryosystems Cryostream cooler		6842 independent reflections
Absorption correction: none5189 reflections with I > 2σ(I)
24180 measured reflectionsRint = 0.025
Refinement top
R[F2 > 2σ(F2)] = 0.044203 parameters
wR(F2) = 0.124H atoms treated by a mixture of
independent and constrained refinement
S = 1.04Δρmax = 0.49 e Å−3
6842 reflectionsΔρmin = −0.27 e Å−3
Special details top

Geometry. All e.s.d.'s (except the e.s.d. in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell e.s.d.'s are taken into account individually in the estimation of e.s.d.'s in distances, angles and torsion angles; correlations between e.s.d.'s in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell e.s.d.'s is used for estimating e.s.d.'s involving l.s. planes.

Refinement. Refinement of F2 against ALL reflections. The weighted R-factor wR and goodness of fit S are based on F2, conventional R-factors R are based on F, with F set to zero for negative F2. The threshold expression of F2 > σ(F2) is used only for calculating R-factors(gt) etc. and is not relevant to the choice of reflections for refinement. R-factors based on F2 are statistically about twice as large as those based on F, and R- factors based on ALL data will be even larger.

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å2) top
xyzUiso*/Ueq
N10.43216 (7)0.37118 (8)0.73394 (4)0.01247 (13)
N20.68233 (8)0.66885 (8)0.63306 (4)0.01659 (14)
H2N0.6447 (13)0.7350 (14)0.6548 (8)0.020*
N30.86941 (8)0.40176 (9)0.70892 (5)0.01981 (15)
C10.53227 (8)0.44146 (9)0.79097 (4)0.01280 (14)
H1A0.61240.38300.80500.015*
H1B0.49030.46280.84380.015*
C20.57970 (8)0.56932 (9)0.75123 (5)0.01372 (14)
H2A0.64750.61440.79100.016*
H2B0.50020.62980.74030.016*
C30.64507 (8)0.54198 (8)0.66810 (5)0.01146 (13)
C40.54095 (8)0.45965 (9)0.61165 (5)0.01336 (14)
H4A0.46020.51580.59470.016*
H4B0.58370.43280.56000.016*
C50.49370 (8)0.33556 (9)0.65622 (5)0.01364 (15)
H5A0.42560.28690.61850.016*
H5B0.57310.27590.66950.016*
C60.38149 (8)0.25204 (9)0.77503 (5)0.01443 (14)
H6A0.46040.19820.79830.017*
H6B0.32730.19710.73290.017*
C70.29300 (8)0.28909 (9)0.84504 (5)0.01256 (14)
C80.17137 (8)0.35979 (9)0.82626 (5)0.01463 (15)
H80.14580.38520.76980.018*
C90.08730 (9)0.39339 (9)0.88947 (5)0.01645 (16)
H90.00470.44140.87600.020*
C100.12395 (9)0.35679 (10)0.97276 (5)0.01752 (16)
H100.06550.37771.01570.021*
C110.24640 (10)0.28969 (9)0.99214 (5)0.01758 (16)
H110.27300.26651.04880.021*
C120.33101 (9)0.25597 (9)0.92851 (5)0.01539 (15)
H120.41490.21020.94230.018*
C130.74564 (8)0.68867 (8)0.55887 (5)0.01178 (14)
C140.80105 (8)0.58537 (8)0.51281 (5)0.01315 (14)
H140.79350.49570.53080.016*
C150.86740 (8)0.61438 (9)0.44045 (5)0.01405 (14)
H150.90370.54370.40940.017*
C160.88109 (8)0.74472 (9)0.41323 (5)0.01466 (15)
H160.92730.76360.36440.018*
C170.82588 (8)0.84752 (9)0.45882 (5)0.01452 (15)
H170.83440.93710.44080.017*
C180.75859 (8)0.82007 (9)0.53034 (5)0.01298 (14)
H180.72080.89110.56040.016*
C190.77255 (8)0.46283 (9)0.68964 (5)0.01285 (14)
Atomic displacement parameters (Å2) top
U11U22U33U12U13U23
N10.0132 (3)0.0145 (3)0.0100 (2)−0.0015 (2)0.0032 (2)−0.0008 (2)
N20.0258 (4)0.0095 (3)0.0161 (3)0.0039 (3)0.0115 (3)0.0025 (2)
N30.0166 (3)0.0209 (4)0.0217 (3)0.0027 (3)0.0001 (2)0.0017 (3)
C10.0158 (3)0.0133 (3)0.0096 (3)−0.0012 (3)0.0027 (2)0.0001 (3)
C20.0178 (3)0.0127 (3)0.0113 (3)0.0002 (3)0.0056 (2)−0.0002 (3)
C30.0131 (3)0.0106 (3)0.0111 (3)0.0017 (3)0.0034 (2)0.0015 (2)
C40.0125 (3)0.0182 (4)0.0095 (3)0.0011 (3)0.0016 (2)0.0012 (3)
C50.0137 (3)0.0168 (4)0.0106 (3)−0.0015 (3)0.0024 (2)−0.0024 (3)
C60.0155 (3)0.0131 (3)0.0152 (3)−0.0009 (3)0.0050 (2)−0.0007 (3)
C70.0133 (3)0.0121 (3)0.0126 (3)−0.0022 (3)0.0032 (2)−0.0003 (3)
C80.0135 (3)0.0170 (4)0.0134 (3)−0.0017 (3)0.0016 (2)−0.0013 (3)
C90.0132 (3)0.0178 (4)0.0187 (3)−0.0017 (3)0.0036 (3)−0.0033 (3)
C100.0200 (4)0.0168 (4)0.0167 (3)−0.0048 (3)0.0080 (3)−0.0025 (3)
C110.0250 (4)0.0146 (4)0.0136 (3)−0.0030 (3)0.0046 (3)0.0016 (3)
C120.0183 (3)0.0130 (4)0.0151 (3)−0.0003 (3)0.0024 (3)0.0021 (3)
C130.0125 (3)0.0117 (3)0.0114 (3)0.0011 (3)0.0027 (2)0.0014 (2)
C140.0157 (3)0.0109 (3)0.0134 (3)0.0010 (3)0.0042 (2)0.0012 (3)
C150.0148 (3)0.0150 (4)0.0128 (3)0.0007 (3)0.0038 (2)−0.0007 (3)
C160.0150 (3)0.0163 (4)0.0131 (3)0.0002 (3)0.0038 (2)0.0022 (3)
C170.0152 (3)0.0132 (4)0.0154 (3)0.0002 (3)0.0032 (2)0.0039 (3)
C180.0141 (3)0.0115 (3)0.0135 (3)0.0012 (3)0.0027 (2)0.0009 (3)
C190.0139 (3)0.0126 (3)0.0123 (3)−0.0011 (3)0.0023 (2)0.0003 (3)
Geometric parameters (Å, °) top
N1—C11.4636 (10)C7—C121.3940 (11)
N1—C51.4644 (10)C7—C81.3964 (12)
N1—C61.4688 (11)C8—C91.3915 (11)
N2—C131.3924 (10)C8—H80.9500
N2—C31.4491 (11)C9—C101.3977 (12)
N2—H2N0.847 (14)C9—H90.9500
N3—C191.1492 (11)C10—C111.3867 (13)
C1—C21.5203 (12)C10—H100.9500
C1—H1A0.9900C11—C121.4004 (12)
C1—H1B0.9900C11—H110.9500
C2—C31.5414 (11)C12—H120.9500
C2—H2A0.9900C13—C141.4042 (11)
C2—H2B0.9900C13—C181.4047 (12)
C3—C191.4946 (11)C14—C151.3986 (11)
C3—C41.5443 (11)C14—H140.9500
C4—C51.5242 (12)C15—C161.3887 (12)
C4—H4A0.9900C15—H150.9500
C4—H4B0.9900C16—C171.3955 (12)
C5—H5A0.9900C16—H160.9500
C5—H5B0.9900C17—C181.3888 (11)
C6—C71.5119 (11)C17—H170.9500
C6—H6A0.9900C18—H180.9500
C6—H6B0.9900
C1—N1—C5110.18 (6)C7—C6—H6B109.4
C1—N1—C6110.34 (6)H6A—C6—H6B108.0
C5—N1—C6110.76 (7)C12—C7—C8118.96 (7)
C13—N2—C3126.55 (7)C12—C7—C6121.47 (7)
C13—N2—H2N118.2 (9)C8—C7—C6119.57 (7)
C3—N2—H2N113.6 (9)C9—C8—C7120.60 (7)
N1—C1—C2111.03 (6)C9—C8—H8119.7
N1—C1—H1A109.4C7—C8—H8119.7
C2—C1—H1A109.4C8—C9—C10120.23 (8)
N1—C1—H1B109.4C8—C9—H9119.9
C2—C1—H1B109.4C10—C9—H9119.9
H1A—C1—H1B108.0C11—C10—C9119.43 (8)
C1—C2—C3111.66 (7)C11—C10—H10120.3
C1—C2—H2A109.3C9—C10—H10120.3
C3—C2—H2A109.3C10—C11—C12120.29 (8)
C1—C2—H2B109.3C10—C11—H11119.9
C3—C2—H2B109.3C12—C11—H11119.9
H2A—C2—H2B108.0C7—C12—C11120.44 (8)
N2—C3—C19109.02 (7)C7—C12—H12119.8
N2—C3—C2108.01 (7)C11—C12—H12119.8
C19—C3—C2106.94 (6)N2—C13—C14123.69 (7)
N2—C3—C4114.82 (6)N2—C13—C18117.84 (7)
C19—C3—C4110.37 (7)C14—C13—C18118.43 (7)
C2—C3—C4107.35 (6)C15—C14—C13120.06 (8)
C5—C4—C3112.06 (6)C15—C14—H14120.0
C5—C4—H4A109.2C13—C14—H14120.0
C3—C4—H4A109.2C16—C15—C14121.12 (8)
C5—C4—H4B109.2C16—C15—H15119.4
C3—C4—H4B109.2C14—C15—H15119.4
H4A—C4—H4B107.9C15—C16—C17118.91 (7)
N1—C5—C4110.80 (7)C15—C16—H16120.5
N1—C5—H5A109.5C17—C16—H16120.5
C4—C5—H5A109.5C18—C17—C16120.59 (8)
N1—C5—H5B109.5C18—C17—H17119.7
C4—C5—H5B109.5C16—C17—H17119.7
H5A—C5—H5B108.1C17—C18—C13120.88 (8)
N1—C6—C7111.21 (7)C17—C18—H18119.6
N1—C6—H6A109.4C13—C18—H18119.6
C7—C6—H6A109.4N3—C19—C3177.73 (8)
N1—C6—H6B109.4
C5—N1—C1—C260.63 (9)C12—C7—C8—C9−1.83 (13)
C6—N1—C1—C2−176.75 (6)C6—C7—C8—C9179.10 (8)
N1—C1—C2—C3−58.68 (9)C7—C8—C9—C100.10 (13)
C13—N2—C3—C1963.33 (10)C8—C9—C10—C111.61 (14)
C13—N2—C3—C2179.19 (8)C9—C10—C11—C12−1.57 (14)
C13—N2—C3—C4−61.08 (11)C8—C7—C12—C111.86 (13)
C1—C2—C3—N2177.84 (6)C6—C7—C12—C11−179.09 (8)
C1—C2—C3—C19−64.94 (8)C10—C11—C12—C7−0.17 (14)
C1—C2—C3—C453.51 (8)C3—N2—C13—C14−9.65 (13)
N2—C3—C4—C5−173.35 (7)C3—N2—C13—C18172.56 (8)
C19—C3—C4—C562.96 (8)N2—C13—C14—C15−177.68 (8)
C2—C3—C4—C5−53.26 (8)C18—C13—C14—C150.09 (12)
C1—N1—C5—C4−59.98 (8)C13—C14—C15—C160.65 (12)
C6—N1—C5—C4177.65 (6)C14—C15—C16—C17−0.77 (12)
C3—C4—C5—N157.77 (8)C15—C16—C17—C180.15 (12)
C1—N1—C6—C769.20 (8)C16—C17—C18—C130.59 (12)
C5—N1—C6—C7−168.52 (6)N2—C13—C18—C17177.20 (7)
N1—C6—C7—C12−116.76 (9)C14—C13—C18—C17−0.70 (12)
N1—C6—C7—C862.28 (10)
Hydrogen-bond geometry (Å, °) top
D—H···AD—HH···AD···AD—H···A
N2—H2N···N3i0.847 (14)2.756 (13)3.5044 (12)148.2 (11)
Symmetry codes: (i) −x+3/2, y+1/2, −z+3/2.
Table 1
Hydrogen-bond geometry (Å, °) top
D—H···AD—HH···AD···AD—H···A
N2—H2N···N3i0.847 (14)2.756 (13)3.5044 (12)148.2 (11)
Symmetry codes: (i) −x+3/2, y+1/2, −z+3/2.
Acknowledgements top

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

references
References top

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