(Z)-Methyl 4-[3-(3-oxoquinuclidin-2-yl­idenemeth­yl)-1H-indol-1-ylmeth­yl]benzoate

Thirupathi Reddy Yerram Reddy; Narsimha Reddy Penthala; Sean Parkin; Peter A Crooks

doi:10.1107/S1600536808030018

. 2008 Oct 4;64(Pt 11):o2050. doi: 10.1107/S1600536808030018

(Z)-Methyl 4-[3-(3-oxoquinuclidin-2-ylidenemethyl)-1H-indol-1-ylmethyl]benzoate

Thirupathi Reddy Yerram Reddy ^a, Narsimha Reddy Penthala ^a, Sean Parkin ^b, Peter A Crooks ^a,^*

PMCID: PMC2959505 PMID: 21580918

Abstract

The title compound, C₂₅H₂₄N₂O₃ was prepared by the reaction of (Z)-2-(1H-indol-3-ylmethylene)-1-azabicyclo[2.2.2]octan-3-one with methyl p-(bromomethyl)benzoate, under phase-transfer catalytic (PTC) conditions using triethylbenzylammonium chloride and 50% w/v aqueous NaOH solution in dichloromethane. The crystal structure indicates the presence of a double bond with Z geometry connecting the azabicyclic and indole groups.

Related literature

For related structures, see: Mason et al. (2003 ▶); Zarza et al. (1988 ▶). For related bond angles, see: Wilson (1992 ▶).

Experimental

Crystal data

C₂₅H₂₄N₂O₃
M _r = 400.46
Triclinic,
a = 9.8597 (3) Å
b = 10.3037 (3) Å
c = 11.3515 (4) Å
α = 106.6470 (14)°
β = 111.4372 (13)°
γ = 92.7863 (15)°
V = 1013.13 (6) Å³
Z = 2
Mo Kα radiation
μ = 0.09 mm⁻¹
T = 90.0 (2) K
0.55 × 0.50 × 0.25 mm

Data collection

Nonius KappaCCD diffractometer
Absorption correction: multi-scan (SCALEPACK; Otwinowski & Minor, 1997 ▶) T _min = 0.954, T _max = 0.979
11866 measured reflections
3974 independent reflections
2132 reflections with I > 2σ(I)
R _int = 0.068

Refinement

R[F ² > 2σ(F ²)] = 0.054
wR(F ²) = 0.152
S = 0.97
3974 reflections
272 parameters
H-atom parameters constrained
Δρ_max = 0.27 e Å⁻³
Δρ_min = −0.25 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: SHELX97 and local procedures.

Supplementary Material

Crystal structure: contains datablocks global, I. DOI: 10.1107/S1600536808030018/om2262sup1.cif

e-64-o2050-sup1.cif^{(22.5KB, cif)}

Structure factors: contains datablocks I. DOI: 10.1107/S1600536808030018/om2262Isup2.hkl

e-64-o2050-Isup2.hkl^{(194.8KB, hkl)}

Additional supplementary materials: crystallographic information; 3D view; checkCIF report

Acknowledgments

This investigation was supported by NIH/National Cancer Institute grant PO1 CA104457.

supplementary crystallographic information

Comment

X-ray crystallography confirmed the molecular structure and the atom connectivity for the title compound, as illustrated in Fig. 1. The indole ring is planar with bond distances and angles comparable with those previously reported for other indole derivatives (Mason et al., 2003; Zarza, et al., 1988). The compound is the Z isomer, having the C11—C17 bond in a trans position with respect to the C3—C10 bond. The double bond (C10=C11) has a nearly planar atomic arrangement, since the r.m.s. deviation from the best plane passing through atoms N2, C11, C17, C10 and C3 is 0.0150 (14) Å. Deviations from ideal geometry are observed in the bond angles around atoms C3, C10 and C11. The C10=C11—C17 bond angle is close to the standard planar triangular value of 120°, whereas the C2=C3—C10, C3—C10=C11 and C10=C11—C17 bond angles are more distorted due to the strain induced by the C10=C11—C18=O1 conjugated double bond linkage. These bond angle deformations, which require little energy, are needed to release the intramolecular interactions between non-bonded atoms. In this molecule, the azabicyclic system presents very small distortions around atoms N2, C13, C14, C15, C16 and C17. The value of the C2—C3—C10—C11 torsion angle [-6.3 (4)°] indicates the deviation of the indole ring from the plane of the double bond connected to the azabicyclic ring. The C3—C10 bond length, when compared with the standard value for a single bond connecting a C_ar atom to a Csp² atom (1.470 (15) Å; Wilson, 1992), suggests extensive conjugation, beginning at atom O1 and extending through to the indole ring. The bond angles in the azabicyclic system at C13, C14 and C15 are, on average, smaller than the standard tetrahedral value of 109.5°, while the bond angles at C12 and C16 are, on average, slightly larger than the ideal tetrahedral bond angle.

There are no significant intermolecular hydrogen-bonding interactions in the crystal structure. The packing is essentially stabilized via van der Waals forces.

Experimental

To a stirred solution of diisopropylamine (1.923 g, 19 mmol) in THF (20 ml) at 273 K under nitrogen was added a solution of 2.0 M n-butyllithium (9 ml, 18.8 mmol) and the mixture stirred at 273 K for 30 min. To this solution at 273 K, was added 1-aza-bicyclo[2.2.2]octan-3-one hydrochloride (1.5 g, 9.28 mmol) in one portion and stirring continued until the mixture completely dissolved (20 min). The temperature was lowered to 195 K and a solution of 1-acetyl-1H-indole-3-carboxaldehyde (1.722 g, 9.2 mmol) in THF (25 ml) was added dropwise. Stirring was continued for 30 min at this temperature and then for 90 min at 273 K. The reaction mixture was poured into saturated NaHCO₃ at 273 K and the resulting solution was extracted with CHCl₃ (3 x 15 ml). The combined organic extracts were dried over anhydrous Na₂SO₄ and evaporated to afford (Z)-2-(1-acetyl- 1H-indol-3-ylmethylene)-1-azabicyclo[2.2.2]octan-3-one, which was subsequently refluxed with sodium hydroxide solution (25 ml, 1 N) for 30 min. The reaction mixture was cooled to room temperature, and the yellow solid that separated was collected by filtration, washed with cold water and dried to afford the (Z)-2-(1H-indol-3-ylmethylene) -1-azabicyclo[2.2.2]octan-3-one.

To a stirred mixture of (Z)-2-(1H-indol-3-ylmethylene) -1-azabicyclo[2.2.2]octan-3-one (1.0 g, 3.96 mmol), 50% w/v aqueous NaOH solution (1.52 g, 19 mmol) and benzyltriethylammonium chloride (0.172 g, 0.75 mmol) in dichloromethane (DCM, 25 ml) at room temperature was added methyl-p-(bromomethyl)benzoate (1.0 g, 4.0 mmol) in one portion, then the reaction mixture was stirred vigorously for 1 hr until no (Z)-2-(1H-indol-3-ylmethylene)-1-azabicyclo[2.2.2] octan-3-one was detected by TLC. The organic layer was separated, washed exhaustively with water, dried with Na₂SO₄ and evaporated to afford the crude product. Crystallization from methanol gave a yellow crystalline product of compound (I) that was suitable for X-ray analysis. ¹H NMR (CDCl₃): δ 1.98–2.00 (m, 4H), 2.61 (p, 1H), 2.93–3.02 (m, 2H), 3.08–3.15 (m, 2H), 3.88 (s, 3H), 5.42 (s, 2H), 7.14–7.22 (m, 5H), 7.47 (s, 1H), 7.87 (d, J = 7.2 Hz, 2H), 7.90 (d, J = 7.2 Hz, 1H), 8.38 (s, 1H); ¹³C NMR (CDCl₃): δ 27.1, 41.1, 48.1, 51.0, 52.7, 110.6, 111.5, 118.2, 119.7, 121.6, 123.3, 126.9, 127.1, 129.3, 130.2, 130.6, 134.6, 136.4, 141.3, 142.2, 166.9, 205.6.