2,2-Bis(hy­droxy­meth­yl)-2,3-dihydro-1H-pyrrolizin-1-one

Yousuf Ali; Yu Peng; Erbing Hua; Nighat Afza; Rashid Ali Khan

doi:10.1107/S1600536810018970

. 2010 Jun 5;66(Pt 7):o1579–o1580. doi: 10.1107/S1600536810018970

2,2-Bis(hydroxymethyl)-2,3-dihydro-1H-pyrrolizin-1-one

Yousuf Ali ^a, Yu Peng ^a,^*, Erbing Hua ^a, Nighat Afza ^b, Rashid Ali Khan ^b

PMCID: PMC3006763 PMID: 21587820

Abstract

The title compound, C₉H₁₁NO₃, was prepared by an Aldol reaction of 2,3-dihydro-1H-pyrrolizin-1-one with formaldehyde. The asymmetric unit contains six molecules. The pyrrolizine ring system in each molecule is planar, the maximum atomic deviation being 0.066 (2) Å. In the crystal structure, molecules are liked together by an extensive O—H⋯O hydrogen-bonding network.

Related literature

For general background to 2,3-dihydropyrrolizine derivatives and for the biological activity of related compounds, see: Meinwald & Meinwald (1965 ▶); Skvortsov & Astakhova (1992 ▶); Albrecht et al. (2008 ▶); Mishra et al. (2008 ▶); Morúaa et al. (2009 ▶). For the preparation of the starting material, see: Clemo & Ramage (1931 ▶); Braunholtz et al. (1962 ▶). For a related structure, see: Ali et al. (2010 ▶).

Experimental

Crystal data

C₉H₁₁NO₃
M _r = 181.19
Monoclinic,
a = 10.2601 (8) Å
b = 39.863 (3) Å
c = 12.412 (1) Å
β = 90.273 (6)°
V = 5076.4 (7) Å³
Z = 24
Cu Kα radiation
μ = 0.90 mm⁻¹
T = 113 K
0.22 × 0.18 × 0.16 mm

Data collection

Rigaku Saturn70 CCD diffractometer
Absorption correction: multi-scan (CrystalClear; Rigaku, 2009 ▶) T _min = 0.827, T _max = 0.870
51559 measured reflections
9889 independent reflections
8550 reflections with I > 2σ(I)
R _int = 0.059

Refinement

R[F ² > 2σ(F ²)] = 0.045
wR(F ²) = 0.122
S = 1.09
9889 reflections
751 parameters
H atoms treated by a mixture of independent and constrained refinement
Δρ_max = 0.26 e Å⁻³
Δρ_min = −0.27 e Å⁻³

Data collection: CrystalClear (Rigaku, 2009 ▶); cell refinement: CrystalClear; data reduction: CrystalClear; 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: publCIF (Westrip, 2010 ▶).

Supplementary Material

Crystal structure: contains datablocks I, global. DOI: 10.1107/S1600536810018970/xu2763sup1.cif

e-66-o1579-sup1.cif^{(44.1KB, cif)}

Structure factors: contains datablocks I. DOI: 10.1107/S1600536810018970/xu2763Isup2.hkl

e-66-o1579-Isup2.hkl^{(473.9KB, 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
O2—H2⋯O3ⁱ	0.91 (3)	1.85 (3)	2.7513 (19)	172 (2)
O3—H3⋯O4	0.87 (3)	1.95 (3)	2.7612 (17)	154 (3)
O5—H5⋯O6ⁱⁱ	0.82 (3)	1.98 (3)	2.7776 (17)	166 (2)
O6—H6⋯O1ⁱⁱⁱ	0.90 (3)	1.80 (3)	2.6801 (16)	168 (2)
O8—H8⋯O16	0.88 (3)	1.85 (3)	2.7219 (16)	168 (2)
O9—H9⋯O11^iv	0.84 (3)	1.96 (3)	2.7841 (18)	168 (2)
O11—H11⋯O13^v	0.85 (2)	1.92 (2)	2.7239 (16)	157 (2)
O12—H12⋯O8	0.84 (3)	2.00 (3)	2.8186 (18)	167 (2)
O14—H14⋯O18	0.87 (3)	1.95 (3)	2.8063 (18)	168 (2)
O15—H15⋯O10^vi	0.93 (3)	1.86 (3)	2.7290 (16)	155 (3)
O17—H17⋯O15^v	0.88 (3)	1.96 (3)	2.8144 (18)	166 (3)
O18—H18⋯O7^vii	0.86 (2)	1.92 (2)	2.7579 (17)	168 (2)

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Symmetry codes: (i) Inline graphic ; (ii) ; (iii) ; (iv) ; (v) ; (vi) ; (vii) .

Acknowledgments

YA is grateful to the Pakistan Council of Scientific & Industrial Research, Ministry of Science & Technology, Government of Pakistan, for financial support. PY is grateful to Tianjin University of Science & Technology for research funding (research grant No. 2009 0431). The authors are grateful to Dr Song Haibin (Nankai University) for the data collection.

supplementary crystallographic information

Comment

Title compound was prepared in order to synthesize new derivatives of this series. Derivatives of 2,3-dihydropyrrolizine became known through studies of their synthesis (Clemo & Ramage, 1931; Braunholtz et al., 1962), and isolation from natural source (Meinwald & Meinwald, 1965). Depending on their structure derivatives of 2,3-dihydropyrrolizine have shown merit as analgesics, anti-inflammatory agents, myorelaxants, inhibitors of thrombocyte aggregation, fibrinolytics, temperature-lowering substances and drugs for the treatment of glaucoma and conjunctivitis (Skvortsov et al., 1992). The most important of these, Ketorolac, is reported in literature as one of the most effective nonsteroidal anti-inflammatory drugs to alleviate renoureteral colic (Morúaa et al., 2009). But it suffers from the general side effects of NSAIDs, owing to presence of free carboxylic acid group (Mishra et al., 2008). Licofelone(2-[6-(4-Chlorophenyl)-2,2- dimethyl-7-phenyl-2,3-dihydro-1Hpyrrolizin-5-yl] acetic acid) is a dual inhibitor of both cyclooxygenase isoforms and 5-lipoxygenase (Albrecht et al., 2008). Crystal structures of related molecules are reported (Ali et al., 2010).

Numbering scheme for the title compound is shown in an ORTEP (Farrugia, 1997) plot of the molecule at 70% ellipsoid probability limit (Fig. 1). In the crystal structure of the title compound, molecules are connected via intermolecular O—H···O hydrogen bonds (Table 1) to form discrete zigzag chains (Fig. 3). Assymetric unit contains, nearly identical, six molecules. The pyrrolizin ring system is almost planner [maximum deviation = 0.066 (2) Å] with two methylene groups, bearing hydroxyl groups, above and below the plane of the ring. Thus forming a flying bird like shape (Fig. 2).

Experimental

A 100 ml round bottom one neck flask, equipped with a magnetic stirrer, is charged with 20 ml of Ethanol 95%, 4.03 g (33.3 mmol) of 2,3-dihydro-1H-pyrrolizin-1-one and 8 ml formalin (formaldehyde 37% aquous). The reaction vessel is immersed in a bath of cold water and l.6 ml of 5% sodium hydroxide aqueous solution is added slowly (during about 10 minutes) from a dropping funnel. The rate of addition was adjusted so that the temperature remains between 293 and 298 K. The mixture was stirred overnight at room temperature. Dilute hydrochloric acid was added to render the mixture just acidic to litmus paper (pH = 5 to 6). Solvents were removed under diminished pressure. The residue was subjected directly to Flash Column chromatography (Petroleum Ether : Ethyl Acetate = 1:1) to give 3.77 g (62.5%) of crystalline mass, m.p. 121-122 °C. Single crystals for X-Ray analysis were prepared by evaporation from a methanol solution.