rac-(Z)-Methyl 1-benzyl-3-[(3-hy­droxy­quinuclidin-2-yl­idene)meth­yl]-1H-indole-6-carboxyl­ate

Narsimha Reddy Penthala; Purushotham Rao Ponugoti; Sean Parkin; Peter A Crooks

doi:10.1107/S1600536812040731

. 2012 Oct 13;68(Pt 11):o3111. doi: 10.1107/S1600536812040731

rac-(Z)-Methyl 1-benzyl-3-[(3-hydroxyquinuclidin-2-ylidene)methyl]-1H-indole-6-carboxylate

Narsimha Reddy Penthala ^a, Purushotham Rao Ponugoti ^a, Sean Parkin ^b, Peter A Crooks ^a,^*

PMCID: PMC3515217 PMID: 23284437

Abstract

In the title compound, C₂₅H₂₆N₂O₃, the double bond connecting the aza-bicyclic and indole units has Z geometry. The compound was obtained as a racemate, and since the crystal is centrosymmetric it contains equal amounts of the S and R enantiomers. However, the structure is disordered such that the asymmetric unit contains both enantiomers in unequal amounts [refined occupancies 0.904 (2) and 0.096 (2)]. The dihedral angle between the benzene ring of the benzyl group and the mean plane of the indole ring is 76.07 (3) °. In the crystal, molecules are linked by O—H⋯O_carbonyl hydrogen bonds into chains propagating in [110].

Related literature

For background literature, see: Sekhar et al., (2003 ▶), Amudhan et al., (2010 ▶). For the biological activity of N-benzyl indole quinuclidinone, see: Sonar et al. (2007 ▶). For a similar crystal structure, see: Sonar et al., (2004 ▶).

Experimental

Crystal data

C₂₅H₂₆N₂O₃
M _r = 402.48
Triclinic,
a = 6.1619 (1) Å
b = 10.3119 (2) Å
c = 16.5959 (3) Å
α = 75.6705 (7)°
β = 80.0939 (7)°
γ = 85.9410 (7)°
V = 1006.04 (3) Å³
Z = 2
Mo Kα radiation
μ = 0.09 mm⁻¹
T = 90 K
0.28 × 0.22 × 0.12 mm

Data collection

Nonius KappaCCD diffractometer
9126 measured reflections
4597 independent reflections
3831 reflections with I > 2σ(I)
R _int = 0.024

Refinement

R[F ² > 2σ(F ²)] = 0.039
wR(F ²) = 0.102
S = 1.04
4597 reflections
312 parameters
64 restraints
H-atom parameters constrained
Δρ_max = 0.27 e Å⁻³
Δρ_min = −0.20 e Å⁻³

Data collection: COLLECT (Nonius, 1998 ▶); cell refinement: SCALEPACK (Otwinowski & Minor, 1997 ▶); data reduction: DENZO-SMN (Otwinowski & Minor, 1997 ▶); program(s) used to solve structure: SHELXS97 (Sheldrick, 2008 ▶); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008 ▶); molecular graphics: XP in SHELXTL (Sheldrick, 2008 ▶); software used to prepare material for publication: SHELXL97 and local procedures.

Supplementary Material

Click here for additional data file.^{(28KB, cif)}

Crystal structure: contains datablock(s) global, I. DOI: 10.1107/S1600536812040731/hg5242sup1.cif

e-68-o3111-sup1.cif^{(28KB, cif)}

Click here for additional data file.^{(225.2KB, hkl)}

Structure factors: contains datablock(s) I. DOI: 10.1107/S1600536812040731/hg5242Isup2.hkl

e-68-o3111-Isup2.hkl^{(225.2KB, 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
O1—H1A⋯O2ⁱ	0.84	1.97	2.7989 (13)	169

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Symmetry code: (i) Inline graphic .

Acknowledgments

This investigation was supported by NIH/National Cancer Institute grant PO1 CA140409.

supplementary crystallographic information

Comment

The N-benzyl indole quinuclidin-3-one moiety has been found to possess interesting biological properties which range from NADPH oxidase activity (Sekhar et al., 2003), thermal sensitizing activity to radiation treatment (Sonar et al., 2007), and also exhibit antiangiogenic properties (Amudhan et al., 2010). Previously, we reported the crystal structure of Z-(S)-2-(1- phenylsulfonyl-1H-indol-3-ylmethylene)-1-azabicyclo[2.2.2]octan-3-ol (Sonar et al., 2004) and in continuation of our research work on the N-benzyl indole quinuclidin-3-one scaffold (Sonar et al., 2007) we designed and synthesized a novel series of carboxymethyl N-benzyl indole quinuclidin-3-ones as potent anticancer agents. The title compound was prepared by the reduction of Z-methyl 1-benzyl-3-[(3-oxoquinuclidin-2-ylidene)methyl]-1H-indole-6-carboxylate with NaBH₄ in methanol at room temperature (Sonar et al., 2004). Recrystallization of the title compound from methanol afforded colorless needles that were suitable for X-ray analysis.

The X-ray studies revealed that the title compound is the Z isomer having the C2—C18 bond in a trans position with respect to the C19—C20 bond. The double bond (C18═C19) has a nearly planar atomic arrangement, since the r.m.s. deviation from the best plane passing through atoms N2, C19, C20, C18 and C2 is 0.265 (1) Å. In this molecule, the azabicyclic system presents very small distortions around atoms N2, C24, C21, C22, C23 and C20. The value of the C1—C2—C18—C19 torsion angle [-5.1 (2)°] indicates the deviation of the indole ring from the plane of the double bond connected to the azabicyclic ring. The dihedral angle between the benzene ring of the benzyl group and with the mean plane of the indole ring is 76.07 (3) Å. The crystal of the title compound is a racemic equimolar mixture of R and S configurations. However, the structure is disordered such that the asymmetric unit contains both enantiomers, but in unequal amounts [refined occupancies 0.904 (2) and 0.096 (2)]. The hydrogen atom of the disordered OH group is involved in an intermolecular hydrogen bond with the carbonyl oxygen O2 on an adjacent molecule, thus forming an infinite chain-like structure along the (110) direction.

Experimental

The compound Z-methyl 1-benzyl-3-[(3-oxoquinuclidin-2-ylidene)methyl] -1H-indole-6-carboxylate was prepared by the available literature procedure (Sonar et al., 2004). To a stirred solution of Z-methyl 1-benzyl-3-((3-oxoquinuclidin-2-ylidene)methyl)-1H-indole-6-carboxylate (0.40 g, 1 mmol) in methanol (15 ml) at 273 K was added NaBH₄ (0.38 g, 10 mmol) over a period of 15 min and stirring was continued for 2 h at room temperature. Water (50 ml) was added and the mixture was extracted with CHCl₃ (3 times 10 ml). The combined organic layers were dried over Na₂SO₄ and evaporated to give the title compound as a white solid. Recrystallization from methanol afforded colorless needles suitable for X-ray analysis.