2,4-Bis(3-methoxy­phen­yl)-3-aza­bicyclo­[3.3.1]nonan-9-one

P Parthiban; V Ramkumar; Yeon Tae Jeong

doi:10.1107/S1600536809050697

. 2009 Dec 4;66(Pt 1):o48–o49. doi: 10.1107/S1600536809050697

2,4-Bis(3-methoxyphenyl)-3-azabicyclo[3.3.1]nonan-9-one

P Parthiban ^a, V Ramkumar ^b, Yeon Tae Jeong ^a,^*

PMCID: PMC2980113 PMID: 21580151

Abstract

In the crystal structure, the title compound, C₂₂H₂₅NO₃, exists in a twin-chair conformation with equatorial orientations of the meta-methoxyphenyl groups on both sides of the secondary amino group. The title compound is a positional isomer of 2,4-bis(2-methoxyphenyl)-3-azabicyclo[3.3.1]nonan-9-one and 2,4-bis(4-methoxyphenyl)-3-azabicyclo[3.3.1]nonan-9-one, which both also exhibit twin-chair conformations with equatorial dispositions of the anisyl rings on both sides of the secondary amino group. In the title compound, the meta-methoxyphenyl rings are orientated at an angle of 25.02 (3)° with respect to each other, whereas in the ortho and para isomers, the anisyl rings are orientated at dihedral angles of 33.86 (3) and 37.43 (4)°, respectively. The crystal packing is dominated by van der Waals interactions and by an intermolecular N—H⋯O hydrogen bond, whereas in the ortho isomer, an intermolecular N—H⋯π interaction (H⋯Cg = 2.75 Å) is found.

Related literature

For the synthesis and biological activity of 3-azabicyclo[3.3.1]nonan-9-ones, see: Jeyaraman & Avila (1981 ▶). For the nicotinic acetylcholine receptor antogonistic activity of diterpenoid/norditerpenoid alkaloids, see: Hardick et al. (1996 ▶); Barker et al. (2005 ▶). For the structures of the ortho and para OMe-substitued isomers, see: Parthiban et al. (2009a ▶); Cox et al. (1985 ▶). For related structures, see: Parthiban et al. (2008a ▶,b ▶,c ▶, 2009b ▶,c ▶), Smith-Verdier et al. (1983 ▶); Padegimas & Kovacic (1972 ▶). For ring puckering analysis, see: Cremer & Pople (1975 ▶); Nardelli (1983 ▶).

Experimental

Crystal data

C₂₂H₂₅NO₃
M _r = 351.43
Monoclinic,
a = 22.3843 (9) Å
b = 6.5666 (3) Å
c = 13.0745 (4) Å
β = 106.382 (2)°
V = 1843.78 (13) Å³
Z = 4
Mo Kα radiation
μ = 0.08 mm⁻¹
T = 298 K
0.40 × 0.28 × 0.15 mm

Data collection

Bruker APEXII CCD area-detector diffractometer
Absorption correction: multi-scan (SADABS; Bruker, 1999 ▶) T _min = 0.967, T _max = 0.988
12835 measured reflections
3971 independent reflections
2326 reflections with I > 2σ(I)
R _int = 0.037

Refinement

R[F ² > 2σ(F ²)] = 0.049
wR(F ²) = 0.136
S = 1.06
3971 reflections
241 parameters
H atoms treated by a mixture of independent and constrained refinement
Δρ_max = 0.30 e Å⁻³
Δρ_min = −0.23 e Å⁻³

Data collection: APEX2 (Bruker, 2004 ▶); cell refinement: APEX2 and SAINT-Plus (Bruker, 2004 ▶); data reduction: SAINT-Plus and XPREP (Bruker, 2004 ▶); program(s) used to solve structure: SHELXS97 (Sheldrick, 2008 ▶); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008 ▶); molecular graphics: ORTEP-3 (Farrugia, 1997 ▶); software used to prepare material for publication: SHELXL97.

Supplementary Material

Crystal structure: contains datablocks global, I. DOI: 10.1107/S1600536809050697/zl2238sup1.cif

e-66-00o48-sup1.cif^{(21.5KB, cif)}

Structure factors: contains datablocks I. DOI: 10.1107/S1600536809050697/zl2238Isup2.hkl

e-66-00o48-Isup2.hkl^{(194.7KB, 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
N1—H1N⋯O1ⁱ	0.890 (18)	2.352 (18)	3.1901 (19)	157.0 (16)

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Symmetry code: (i) Inline graphic .

Acknowledgments

The authors acknowledge the Department of Chemistry, IIT Madras, for the X-ray data collection.

supplementary crystallographic information

Comment

3-Azabicyclo[3.3.1]nonanes are an important class of heterocyclic compounds due to their broad-spectrum of biological activities such as analgesic, antogonistic, anti-inflammatory, local anesthetic and hypotensive activity (Jeyaraman & Avila, 1981). The 3-azabicyclo[3.3.1]nonane pharmacophore is present in numerous naturally occuring diterpenoid/norditerpenoid alkaloids such as methyllycaconitine, elatine, nudicauline, delsoline, delcorine and so on, they act as potential nicotinic acetylcholine receptor antagonists (Hardick et al. 1996; Barker et al. 2005). However, the biological activity mainly depends on the stereochemistry of the molecule; hence, it is of immense help to establish the structures of the synthesized molecules. For the synthesized title compound, several stereoisomers are possible with conformations such as chair-chair (Parthiban et al., 2008a, 2008b, 2008c, 2009a, 2009b, 2009c), chair-boat (Smith-Verdier et al., 1983) and boat-boat (Padegimas & Kovacic, 1972). Hence, the present crystal study was undertaken to explore the configuration and conformation of the synthesized title compound.

The crystallographic analysis of the title compound shows that the piperidine ring adopts a near ideal chair conformation. The total puckering amplitude, Q_T, is 0.600 (2) Å and the phase angle, θ, is 174.96 (19)° (Cremer & Pople, 1975). The smallest displacement asymmetry parameters being q2 and q3 are 0.053 (2) and -0.598 (2) Å (Nardelli, 1983). The deviation of ring atoms C8 and N1 from the C1/C2/C6/C7 plane are 0.712 (3) and -0.629 (3) Å, respectively.

According to the crystallographic analysis, the cyclohexane ring slightly deviates from the ideal chair conformation. The total puckering amplitude, Q_T = 0.559 (2) Å and phase angle θ = 166.6 (2)° (Cremer & Pople, 1975). The smallest displacement asymmetry parameters being q2 = 0.130 (2) and q3 = -0.544 (2)Å (Nardelli, 1983). The deviation of ring atoms C4 and C8 from the C2/C3/C5/C6 plane are -0.537 (4) and 0.718 (3) Å, respectively.

Hence the title compound, C₂₂H₂₅NO₃, exists in a chair-chair conformation with equatorial orientation of the meta-methoxyphenyl groups on both sides of the secondary amino group on the heterocycle. The title compound is a positional isomer of 2,4-bis(2-methoxyphenyl)-3- azabicyclo[3.3.1]nonan-9-one (Parthiban et al., 2009a) and 2,4-bis (4-methoxyphenyl)-3-azabicyclo[3.3.1]nonan-9-one (Cox et al., 1985). Similar to the title compound the ortho as well as the para isomers also exhibit twin-chair conformations with equatorial disposition of the anisyl rings on both sides of the secondary amino group. In the title compound, the meta-methoxyphenyl rings are orientated at an angle of 25.02 (3)° with respect to one another whereas in the ortho and para isomer, the phenyl rings are orientated at an angle of 33.86 (3)° and 37.43 (4)° respectively.

The torsion angles of C8-C2-C1-C9 and C8-C6-C7-C15 are 179.64 (4) and 178.66 (3)°, respectively, for the title compound, which is very similar to those of its ortho isomer (-179.66 (3) and -179.76 (4)°, respectively) and those for the para isomer (178.2 (2) and 177.9 (4)°, respectively).

The crystal packing is dominated by shape recognition, by van der Waals interactions and is stabilized by an intermolecular N-H···O hydrogen bond (Table 1). In the ortho isomer, on the other hand, the crystal structure exhibits an intermolecular N-H···π interaction (N1-H1A···Cg1 = 2.75 Å).

Experimental

The title compound was synthesized by a modified Mannich reaction using 0.1 mol (13.61 g/12.18 ml) meta-methoxybenzaldehyde, 0.05 mol (4.90 g/5.18 ml) cyclohexanone and 0.075 mol (5.78 g) ammonium acetate in 50 ml of absolute ethanol. The mixture was gently warmed on a hot plate with medium stirring and stirring was continued for about 15 h at a temperature of 303–308 K (30–35° C). After 12 h, the product formed was a spongy solid which was stirred for an additional 3 h until the reaction was complete as confirmed by the absence of aldehyde and cyclohexanone in the reaction mixture by TLC. After this, the crude compound was separated by filtration and washed with a 1:5 ethanol-ether mixture. X-ray diffraction quality crystals of 2,4-bis(3-methoxyphenyl)-3-azabicyclo[3.3.1]nonan-9-one were obtained by slow evaporation from ethanol.