cis-2,5-Bis(2-fluoro-5-meth­oxy­pheneth­yl)pyrrolidinium formate

Purushothama Rao Ponugoti; Narsimha Reddy Penthala; Linda P Dwoskin; Sean Parkin; Peter A Crooks

doi:10.1107/S1600536811006143

. 2011 Feb 26;67(Pt 3):o737. doi: 10.1107/S1600536811006143

cis-2,5-Bis(2-fluoro-5-methoxyphenethyl)pyrrolidinium formate

Purushothama Rao Ponugoti ^a, Narsimha Reddy Penthala ^a, Linda P Dwoskin ^a, Sean Parkin ^b, Peter A Crooks ^a,^*

PMCID: PMC3052016 PMID: 21522476

Abstract

In the title compound, C₂₂H₂₈F₂NO₂ ⁺·CHO₂ ⁻, there are three independent pyrrolidinium formate salt molecules. In each cation, the central pyrrolidinium ring is not planar and the 2,5-disubstituted phenylethyl groups are in equatorial positions. In the crystal, the ions are linked into a pair of chains parallel to the c axis by N—H⋯O hydrogen bonds between the NH group of the pyrrolidinium ring and the formate O atoms.

Related literature

For background to the use of lobelane analogues, see: Zheng et al. (2005 ▶). For pyrrolidine analogues of lobelane (systematic name 2-[6-(2-hydroxy-2-phenyl-ethyl)-1-methyl-2-piperidyl]-1-phenyl-ethanone), see: Vartak et al. (2009 ▶).

Experimental

Crystal data

C₂₂H₂₈F₂NO₂ ⁺·CHO₂ ⁻
M _r = 421.47
Orthorhombic,
a = 7.8338 (1) Å
b = 27.8759 (3) Å
c = 29.3202 (3) Å
V = 6402.78 (13) Å³
Z = 12
Mo Kα radiation
μ = 0.10 mm⁻¹
T = 90 K
0.28 × 0.18 × 0.06 mm

Data collection

Nonius KappaCCD diffractometer
Absorption correction: multi-scan (SCALEPACK; Otwinowski & Minor, 1997 ▶) T _min = 0.973, T _max = 0.994
80877 measured reflections
8166 independent reflections
5100 reflections with I > 2σ(I)
R _int = 0.051

Refinement

R[F ² > 2σ(F ²)] = 0.056
wR(F ²) = 0.155
S = 1.00
8166 reflections
817 parameters
H-atom parameters constrained
Δρ_max = 0.34 e Å⁻³
Δρ_min = −0.28 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

Crystal structure: contains datablocks global, I. DOI: 10.1107/S1600536811006143/hg2767sup1.cif

e-67-0o737-sup1.cif^{(42.4KB, cif)}

Structure factors: contains datablocks I. DOI: 10.1107/S1600536811006143/hg2767Isup2.hkl

e-67-0o737-Isup2.hkl^{(399.5KB, 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
N1A—H1A1⋯O2S3	0.92	1.84	2.750 (4)	172
N1A—H1A2⋯O2S1ⁱ	0.92	1.83	2.737 (4)	167
N1A—H1A2⋯O1S1ⁱ	0.92	2.60	3.314 (4)	135
N1B—H1B1⋯O1S3	0.92	1.83	2.729 (4)	166
N1B—H1B1⋯O2S3	0.92	2.61	3.329 (4)	136
N1B—H1B2⋯O1S1	0.92	1.84	2.756 (4)	173
N1C—H1C1⋯O2S2ⁱⁱ	0.92	1.85	2.743 (4)	165
N1C—H1C1⋯O1S2ⁱⁱ	0.92	2.61	3.330 (4)	135
N1C—H1C2⋯O1S2	0.92	1.82	2.733 (4)	173

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Symmetry codes: (i) Inline graphic ; (ii) .

Acknowledgments

This research was supported by NIH grant RO1 DA13519. The University of Kentucky holds patents on lobeline and the analogs described in the current work. A potential royalty stream to LPD and PAC may occur consistent with University of Kentucky policy.

supplementary crystallographic information

Comment

In endeavoring to develop lobelane analogs with high affinity for dihydrotetrabenazine binding sites on VMAT2 and as inhibiters of [³H]-DA uptake into cystolic vesicles (Zheng et al. (2005)), we have undertaken the design, synthesis and structural analysis of a series of 2,5-disubstitued phenethylpyrrolidine analogs. The primary goal of the X-ray analysis of the title compound was to confirm the stereochemistry of the substituted phenethyl groups in the molecule, and to obtain detailed information on the structural conformation of the molecule that may be useful in structure-activity relationship (SAR) analysis. The title compound is prepared by utilizing a previously reported procedure (Vartak et al. 2009). The X-ray studies revealed that the crystal lattice has three independent (2R,5S)-2,5-bis(2-fluoro-5-methoxyphenethyl) pyrrolidinium formate molecules. The central pyrrolidinium ring is not planar and the 2,5-disubstituted phenylethyl groups are in equatorial positions. The angle between the exact plane defined by C6, C7, C8 and by the mean plane passing closest to the atoms of the pyrrolidinium ring (N1, C2, C3, C4, C5) for molecule A is: 51.8 (3)° and 48.7 (3)°; molecule B is: 48.4 (3)° and 47.8 (3)° and for molecule C is: 48.5 (3)° and 44.8 (3)°. The dihedral angles between C5,C6, C7 plane to C8, C9, C13 planes and C2, C17, C18 plane to C19, C20, C24 plane for ion A is 86.26 (4)° and 73.06 (4)°; for ion B is: 81.87 (4)° and 74.37 (4)° and for ion C is: 72.58 (4)° and 84.89 (4)°. The molecules are linked into dimeric chains by a series of N—H···O hydrogen bonds. Significant intermolecular hydrogen-bonding interactions are found between pyrrolidinium N(1)—H(1)···O (formate anion) and N(1)—H(2)···O (formate anion).

Experimental

The title compound was prepared by the reaction of (3S,5R, 7aR)-5-(benzotriazol-1-yl)-3-phenyl[2,1-b]oxazolopyrrolidine with 2-fluoro 5-methoxyphenethyl magnesium bromide in tetrahydrofuran to afford a mixture of crude 2R,5S- and 2R,5R-di-2-fluoro-5-methoxyethylpyrrolidine diastereomers, which are separated by silica gel column chromatography. The obtained 2R,5R compound was hydrogenolyzed by catalytic-transfer hydrogenation with palladium hydroxide-over-carbon, employing ammonium formate as the hydrogen source in refluxing methanol. These conditions afforded quantitative conversion to the product, (2R,5S)-2,5-bis-(2-fluoro-5-methoxyphenethyl)pyrrolidine within 30 min. The formate salt is prepared by treatment with formic acid in methylene chloride and recrystallization from diethyl ether. The crystals obtained from the solution of diethyl ether are suitable for X-ray diffraction studies. ¹H NMR (CDCl₃): δ 1.60–1.75 (m, 2H), 1.80–1.95 (m, 2H), 1.95–2.20 (m, 4H), 2.52–2.70 (m, 4H), 3.28 (t, J=6.0 Hz, 2H), 3.68 (s, 6H), 6.55–6.70 (m, 4H), 6.83 (t, J =9.3 Hz, 2H), 8.58 (s, 1H), 9.20 (bs, 2H) p.p.m.; ¹³C NMR (DMSO d₆): δ 26.78, 29.68, 33.74, 55.88, 59.23, 112.69, 115.42, 115.59, 128.28, 128.51, 155.66, 168.47 p.p.m..