(1S*,5R*)-9-Phenyl-9-aza­bicyclo­[3.3.1]nonan-3-one

Jiang, Z.; He, Q.; Li, Z.; Wang, Z.

doi:10.1107/S1600536812020065

organic compounds

CRYSTALLOGRAPHIC
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ISSN: 2056-9890

Volume 68| Part 6| June 2012| Page o1691

doi:10.1107/S1600536812020065

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(1S,5R)-9-Phenyl-9-azabicyclo[3.3.1]nonan-3-one

Zhen-ju Jiang,^a Qi He,^a Zhen Li ^b and Zhou-yu Wang ^a ^*

^aDepartment of Pharmaceutics Engineering, Xihua University, Chengdu 610039, People's Republic of China, and ^bResearch Institute of Natural Gas Economy, Petrochina Oil and Gas Field Company, Chengdu 610051, People's Republic of China
^*Correspondence e-mail: zhouyuwang77@gmail.com

(Received 1 March 2012; accepted 4 May 2012; online 12 May 2012)

In the title compound, C₁₄H₁₇NO, the piperidinone and piperidine rings both adopt a chair conformation. The chiral crystals were obtained from a racemic reaction product via spontaneous resolution.

Related literature

For the synthesis, see: Zhang (2003 ). For applications of the compound, see: Vernekar et al. (2010 ); Lazny et al. (2011 ). For puckering analysis, see: Cremer & Pople (1975 ).

Experimental

Crystal data

C₁₄H₁₇NO
M_r = 215.29
Orthorhombic, P 2₁ 2₁ 2₁
a = 9.4028 (3) Å
b = 10.2524 (5) Å
c = 12.0473 (6) Å
V = 1161.38 (9) Å³
Z = 4
Mo Kα radiation
μ = 0.08 mm⁻¹
T = 293 K
0.40 × 0.40 × 0.35 mm

Data collection

Agilent Xcalibur Eos diffractometer
Absorption correction: multi-scan (ABSPACK in CrysAlis PRO; Agilent, 2011 ) T_min = 0.918, T_max = 1.000
3285 measured reflections
2218 independent reflections
1722 reflections with I > 2σ(I)
R_int = 0.015

Refinement

R[F² > 2σ(F²)] = 0.043
wR(F²) = 0.092
S = 1.02
2218 reflections
145 parameters
H-atom parameters constrained
Δρ_max = 0.12 e Å⁻³
Δρ_min = −0.13 e Å⁻³

Data collection: CrysAlis PRO (Agilent, 2011); cell refinement: CrysAlis PRO; data reduction: CrysAlis PRO; program(s) used to solve structure: SHELXS97 (Sheldrick, 2008 ); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008); molecular graphics: OLEX2 (Dolomanov et al., 2009 ); software used to prepare material for publication: OLEX2.

Supporting information

Crystal structure: contains datablocks global, I. DOI: 10.1107/S1600536812020065/fy2049sup1.cif

Structure factors: contains datablock I. DOI: 10.1107/S1600536812020065/fy2049Isup3.hkl

Supporting information file. DOI: 10.1107/S1600536812020065/fy2049Isup4.cdx

Supporting information file. DOI: 10.1107/S1600536812020065/fy2049Isup4.cml

checkCIF report

Comment top

The compound 1S*,5R*-9-phenyl-9-aza-bicyclo[3.3.1]nonan-3-one is an important intermediate for synthesizing granisetron derivatives. The bicyclic skeleton of 9-azabicyclo[3.3.1]nonane is a key substructure of a variety of bioactive compounds (Vernekar et al., 2010; Lazny et al., 2011). The racemic title compound was synthesized by the Mannich reaction and spontaneous resolution occurred on recrystallization from a mixture of ethyl acetate and petroleum ether.

In the title structure the N1/C1—C5 piperidinone ring adopts a chair conformation with puckering parameters (Cremer & Pople, 1975): Q = 0.5159 (3) Å, θ = 158.26 (3)° and ϕ = 173.0692 (12)°. The N1/C1/C8—C5 piperidine ring has a chair conformation, too [Q = 0.5727 (3) Å, θ = 7.74 (12)° and ϕ = 23.8669 (13)°]. The relative configuration of C1 and C5 is S*, R* respectively.

Related literature top

For the synthesis, see: Zhang (2003). For applications of the compound, see: Vernekar et al. (2010); Lazny et al. (2011). For puckering analysis, see: Cremer & Pople (1975).

Experimental top

To a stirred solution of glutaraldehyde (1.32 ml, 5 mmol) and aniline (0.55 ml,6 mmol) in water (10 ml), 3-oxopentanedioic acid (0.88 g,6 mmol) was added. The mixture was stirred overnight at room temperature. Then the pH was adjusted to 5 with aq. HCl and the mixture was refluxed for another one hour. Then sodium hydroxide was added to increase the pH to 9. The mixture was extracted with ethyl-acetate. The combined extract was dried over anhydrous MgSO₄ and evaporated in vacuo. The residue was purified through column chromatography on silica gel (eluent: hexane/EtOAc = 4/1) to give 9-phenyl-9-aza-bicyclo[3.3.1]nonan-3-one. Then the racemic mixture was crystallized from a solution in a 1:10 (v/v) mixture of ethyl acetate and petroleum ether to produce the title compound.

Computing details top

Data collection: CrysAlis PRO (Agilent, 2011); cell refinement: CrysAlis PRO (Agilent, 2011); data reduction: CrysAlis PRO (Agilent, 2011); program(s) used to solve structure: SHELXS97 (Sheldrick, 2008); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008); molecular graphics: OLEX2 (Dolomanov et al., 2009); software used to prepare material for publication: OLEX2 (Dolomanov et al., 2009).

Figures top

	Fig. 1. The molecular structure of the title compound.
	Fig. 2. A packing diagram for the title compound.

(1S*,5R*)-9-Phenyl-9-azabicyclo[3.3.1]nonan-3-one top

Crystal data top

C₁₄H₁₇NO	D_x = 1.231 Mg m⁻³
M_r = 215.29	Mo Kα radiation, λ = 0.7107 Å
Orthorhombic, P2₁2₁2₁	Cell parameters from 1237 reflections
a = 9.4028 (3) Å	θ = 2.9–29.0°
b = 10.2524 (5) Å	µ = 0.08 mm⁻¹
c = 12.0473 (6) Å	T = 293 K
V = 1161.38 (9) Å³	Block, colourless
Z = 4	0.40 × 0.40 × 0.35 mm
F(000) = 464

Data collection top

Agilent Xcalibur Eos diffractometer	2218 independent reflections
Radiation source: Enhance (Mo) X-ray Source	1722 reflections with I > 2σ(I)
Graphite monochromator	R_int = 0.015
Detector resolution: 16.0874 pixels mm^-1	θ_max = 26.4°, θ_min = 2.9°
ω scans	h = −11→7
Absorption correction: multi-scan (ABSPACK in CrysAlis PRO; Agilent, 2011)	k = −9→12
T_min = 0.918, T_max = 1.000	l = −8→15
3285 measured reflections

Refinement top

Refinement on F²	Primary atom site location: structure-invariant direct methods
Least-squares matrix: full	Secondary atom site location: difference Fourier map
R[F² > 2σ(F²)] = 0.043	Hydrogen site location: inferred from neighbouring sites
wR(F²) = 0.092	H-atom parameters constrained
S = 1.02	w = 1/[σ²(F_o²) + (0.0394P)²] where P = (F_o² + 2F_c²)/3
2218 reflections	(Δ/σ)_max < 0.001
145 parameters	Δρ_max = 0.12 e Å⁻³
0 restraints	Δρ_min = −0.13 e Å⁻³

Crystal data top

C₁₄H₁₇NO	V = 1161.38 (9) Å³
M_r = 215.29	Z = 4
Orthorhombic, P2₁2₁2₁	Mo Kα radiation
a = 9.4028 (3) Å	µ = 0.08 mm⁻¹
b = 10.2524 (5) Å	T = 293 K
c = 12.0473 (6) Å	0.40 × 0.40 × 0.35 mm

Data collection top

Agilent Xcalibur Eos diffractometer	2218 independent reflections
Absorption correction: multi-scan (ABSPACK in CrysAlis PRO; Agilent, 2011)	1722 reflections with I > 2σ(I)
T_min = 0.918, T_max = 1.000	R_int = 0.015
3285 measured reflections

Refinement top

R[F² > 2σ(F²)] = 0.043	0 restraints
wR(F²) = 0.092	H-atom parameters constrained
S = 1.02	Δρ_max = 0.12 e Å⁻³
2218 reflections	Δρ_min = −0.13 e Å⁻³
145 parameters

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

	x	y	z	U_iso*/U_eq
O1	−0.58709 (17)	−0.01586 (16)	−0.68342 (15)	0.0838 (6)
N1	−0.19284 (14)	−0.18245 (14)	−0.65084 (12)	0.0368 (4)
C1	−0.31907 (18)	−0.26416 (18)	−0.63463 (16)	0.0409 (5)
H1	−0.2985	−0.3506	−0.6653	0.049*
C2	−0.4480 (2)	−0.20832 (19)	−0.69713 (16)	0.0472 (5)
H2A	−0.4367	−0.2265	−0.7757	0.057*
H2B	−0.5329	−0.2532	−0.6721	0.057*
C3	−0.4692 (2)	−0.0642 (2)	−0.68231 (16)	0.0510 (6)
C4	−0.3376 (2)	0.01633 (18)	−0.67070 (17)	0.0489 (5)
H4A	−0.3618	0.0971	−0.6332	0.059*
H4B	−0.3032	0.0386	−0.7442	0.059*
C5	−0.2173 (2)	−0.05077 (18)	−0.60634 (17)	0.0412 (5)
H5	−0.1302	0.0001	−0.6174	0.049*
C6	−0.2468 (2)	−0.0573 (2)	−0.48223 (17)	0.0494 (5)
H6A	−0.1612	−0.0854	−0.4442	0.059*
H6B	−0.2703	0.0293	−0.4556	0.059*
C7	−0.3672 (2)	−0.1497 (2)	−0.45334 (16)	0.0522 (6)
H7A	−0.3705	−0.1626	−0.3736	0.063*
H7B	−0.4571	−0.1122	−0.4766	0.063*
C8	−0.3452 (2)	−0.2797 (2)	−0.51068 (17)	0.0510 (5)
H8A	−0.4286	−0.3338	−0.4994	0.061*
H8B	−0.2646	−0.3239	−0.4774	0.061*
C9	−0.11420 (18)	−0.19480 (18)	−0.75009 (15)	0.0363 (4)
C10	−0.1472 (2)	−0.28634 (19)	−0.83142 (16)	0.0435 (5)
H10	−0.2261	−0.3400	−0.8221	0.052*
C11	−0.0647 (2)	−0.2989 (2)	−0.92593 (16)	0.0537 (6)
H11	−0.0896	−0.3602	−0.9794	0.064*
C12	0.0534 (2)	−0.2223 (2)	−0.94206 (16)	0.0597 (6)
H12	0.1084	−0.2308	−1.0058	0.072*
C13	0.0880 (2)	−0.1329 (2)	−0.8617 (2)	0.0605 (6)
H13	0.1680	−0.0807	−0.8712	0.073*
C14	0.0069 (2)	−0.1187 (2)	−0.76732 (18)	0.0497 (5)
H14	0.0333	−0.0574	−0.7142	0.060*

Atomic displacement parameters (Å²) top

	U¹¹	U²²	U³³	U¹²	U¹³	U²³
O1	0.0585 (9)	0.0818 (13)	0.1110 (16)	0.0252 (10)	−0.0147 (10)	0.0074 (12)
N1	0.0385 (8)	0.0357 (8)	0.0362 (9)	−0.0040 (7)	0.0001 (7)	−0.0009 (7)
C1	0.0411 (10)	0.0361 (10)	0.0455 (12)	−0.0027 (9)	0.0024 (9)	0.0022 (9)
C2	0.0401 (10)	0.0537 (12)	0.0478 (13)	−0.0053 (10)	−0.0056 (9)	−0.0027 (11)
C3	0.0514 (12)	0.0589 (13)	0.0428 (13)	0.0091 (12)	−0.0071 (10)	0.0064 (11)
C4	0.0646 (13)	0.0389 (10)	0.0431 (12)	0.0059 (11)	0.0016 (11)	0.0032 (9)
C5	0.0461 (11)	0.0371 (10)	0.0405 (11)	−0.0071 (9)	0.0010 (9)	−0.0024 (9)
C6	0.0536 (11)	0.0577 (13)	0.0370 (12)	0.0021 (11)	−0.0035 (10)	−0.0052 (11)
C7	0.0590 (13)	0.0634 (13)	0.0343 (11)	−0.0013 (11)	0.0053 (10)	0.0057 (10)
C8	0.0501 (12)	0.0536 (12)	0.0494 (12)	−0.0058 (11)	0.0045 (10)	0.0128 (11)
C9	0.0371 (9)	0.0379 (10)	0.0340 (10)	0.0052 (9)	−0.0020 (8)	0.0040 (9)
C10	0.0425 (10)	0.0446 (11)	0.0434 (11)	0.0035 (10)	−0.0026 (9)	−0.0023 (10)
C11	0.0581 (13)	0.0581 (14)	0.0450 (13)	0.0129 (12)	−0.0016 (11)	−0.0081 (11)
C12	0.0618 (14)	0.0737 (16)	0.0436 (13)	0.0145 (13)	0.0173 (12)	0.0027 (12)
C13	0.0533 (13)	0.0651 (15)	0.0630 (16)	−0.0072 (12)	0.0156 (12)	0.0051 (13)
C14	0.0495 (11)	0.0528 (13)	0.0467 (13)	−0.0078 (11)	0.0043 (10)	−0.0023 (10)

Geometric parameters (Å, º) top

O1—C3	1.215 (2)	C6—C7	1.517 (3)
N1—C1	1.466 (2)	C7—H7A	0.9700
N1—C5	1.471 (2)	C7—H7B	0.9700
N1—C9	1.412 (2)	C7—C8	1.516 (3)
C1—H1	0.9800	C8—H8A	0.9700
C1—C2	1.537 (3)	C8—H8B	0.9700
C1—C8	1.522 (3)	C9—C10	1.392 (3)
C2—H2A	0.9700	C9—C14	1.396 (3)
C2—H2B	0.9700	C10—H10	0.9300
C2—C3	1.501 (3)	C10—C11	1.384 (3)
C3—C4	1.494 (3)	C11—H11	0.9300
C4—H4A	0.9700	C11—C12	1.374 (3)
C4—H4B	0.9700	C12—H12	0.9300
C4—C5	1.534 (3)	C12—C13	1.373 (3)
C5—H5	0.9800	C13—H13	0.9300
C5—C6	1.522 (3)	C13—C14	1.376 (3)
C6—H6A	0.9700	C14—H14	0.9300
C6—H6B	0.9700

C1—N1—C5	110.46 (14)	C7—C6—C5	112.88 (17)
C9—N1—C1	119.07 (15)	C7—C6—H6A	109.0
C9—N1—C5	118.22 (14)	C7—C6—H6B	109.0
N1—C1—H1	107.9	C6—C7—H7A	109.6
N1—C1—C2	111.11 (15)	C6—C7—H7B	109.6
N1—C1—C8	108.76 (15)	H7A—C7—H7B	108.2
C2—C1—H1	107.9	C8—C7—C6	110.08 (16)
C8—C1—H1	107.9	C8—C7—H7A	109.6
C8—C1—C2	113.10 (16)	C8—C7—H7B	109.6
C1—C2—H2A	108.7	C1—C8—H8A	109.2
C1—C2—H2B	108.7	C1—C8—H8B	109.2
H2A—C2—H2B	107.6	C7—C8—C1	112.14 (16)
C3—C2—C1	114.39 (17)	C7—C8—H8A	109.2
C3—C2—H2A	108.7	C7—C8—H8B	109.2
C3—C2—H2B	108.7	H8A—C8—H8B	107.9
O1—C3—C2	121.5 (2)	C10—C9—N1	122.68 (16)
O1—C3—C4	122.1 (2)	C10—C9—C14	117.02 (18)
C4—C3—C2	116.42 (18)	C14—C9—N1	120.20 (17)
C3—C4—H4A	108.7	C9—C10—H10	119.4
C3—C4—H4B	108.7	C11—C10—C9	121.13 (19)
C3—C4—C5	114.20 (16)	C11—C10—H10	119.4
H4A—C4—H4B	107.6	C10—C11—H11	119.5
C5—C4—H4A	108.7	C12—C11—C10	121.1 (2)
C5—C4—H4B	108.7	C12—C11—H11	119.5
N1—C5—C4	110.04 (15)	C11—C12—H12	120.9
N1—C5—H5	108.0	C13—C12—C11	118.28 (19)
N1—C5—C6	110.25 (16)	C13—C12—H12	120.9
C4—C5—H5	108.0	C12—C13—H13	119.3
C6—C5—C4	112.44 (16)	C12—C13—C14	121.5 (2)
C6—C5—H5	108.0	C14—C13—H13	119.3
C5—C6—H6A	109.0	C9—C14—H14	119.5
C5—C6—H6B	109.0	C13—C14—C9	121.0 (2)
H6A—C6—H6B	107.8	C13—C14—H14	119.5

O1—C3—C4—C5	146.4 (2)	C5—N1—C1—C2	61.85 (19)
N1—C1—C2—C3	−46.2 (2)	C5—N1—C1—C8	−63.28 (19)
N1—C1—C8—C7	58.9 (2)	C5—N1—C9—C10	−142.12 (17)
N1—C5—C6—C7	−54.0 (2)	C5—N1—C9—C14	41.6 (2)
N1—C9—C10—C11	−177.64 (17)	C5—C6—C7—C8	49.0 (2)
N1—C9—C14—C13	177.52 (18)	C6—C7—C8—C1	−51.6 (2)
C1—N1—C5—C4	−63.47 (19)	C8—C1—C2—C3	76.4 (2)
C1—N1—C5—C6	61.12 (19)	C9—N1—C1—C2	−79.9 (2)
C1—N1—C9—C10	−3.3 (2)	C9—N1—C1—C8	155.02 (16)
C1—N1—C9—C14	−179.62 (16)	C9—N1—C5—C4	78.60 (18)
C1—C2—C3—O1	−148.4 (2)	C9—N1—C5—C6	−156.81 (15)
C1—C2—C3—C4	34.0 (2)	C9—C10—C11—C12	0.7 (3)
C2—C1—C8—C7	−65.0 (2)	C10—C9—C14—C13	1.0 (3)
C2—C3—C4—C5	−35.9 (2)	C10—C11—C12—C13	0.2 (3)
C3—C4—C5—N1	49.8 (2)	C11—C12—C13—C14	−0.4 (3)
C3—C4—C5—C6	−73.5 (2)	C12—C13—C14—C9	−0.2 (3)
C4—C5—C6—C7	69.2 (2)	C14—C9—C10—C11	−1.2 (3)

Experimental details

Crystal data
Chemical formula	C₁₄H₁₇NO
M_r	215.29
Crystal system, space group	Orthorhombic, P2₁2₁2₁
Temperature (K)	293
a, b, c (Å)	9.4028 (3), 10.2524 (5), 12.0473 (6)
V (Å³)	1161.38 (9)
Z	4
Radiation type	Mo Kα
µ (mm⁻¹)	0.08
Crystal size (mm)	0.40 × 0.40 × 0.35

Data collection
Diffractometer	Agilent Xcalibur Eos diffractometer
Absorption correction	Multi-scan (ABSPACK in CrysAlis PRO; Agilent, 2011)
T_min, T_max	0.918, 1.000
No. of measured, independent and observed [I > 2σ(I)] reflections	3285, 2218, 1722
R_int	0.015
(sin θ/λ)_max (Å⁻¹)	0.625

Refinement
R[F² > 2σ(F²)], wR(F²), S	0.043, 0.092, 1.02
No. of reflections	2218
No. of parameters	145
H-atom treatment	H-atom parameters constrained
Δρ_max, Δρ_min (e Å⁻³)	0.12, −0.13

Computer programs: CrysAlis PRO (Agilent, 2011), SHELXS97 (Sheldrick, 2008), SHELXL97 (Sheldrick, 2008), OLEX2 (Dolomanov et al., 2009).

Acknowledgements

This work was supported by the Open Fund of the Key Laboratory of Sichuan Province (grant No. Szjj2011-005) and the Research Fund of the Key Laboratory of TCM Biotechnology (Xihua University).

References

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