Skip to main content
Acta Crystallographica Section E: Structure Reports Online logoLink to Acta Crystallographica Section E: Structure Reports Online
. 2011 Nov 30;67(Pt 12):o3520–o3521. doi: 10.1107/S1600536811051099

(4R,6S,7S,8S,8aS)-6-Ethyl-7,8-dihy­droxy-4-methyl-1,2,3,5,6,7,8,8a-octa­hydro­indolizin-4-ium iodide

Viktor Vrábel a,*, Július Sivý b, Ľubomír Švorc a, Peter Šafář c, Jozefína Žužiová c
PMCID: PMC3239140  PMID: 22199988

Abstract

The title compound, C11H22NO2 +·I, is a chiral mol­ecule with five stereogenic centres. The absolute configuration was assigned from the synthesis and confirmed by the structure determination. The central six-membered ring of the indolizine system adopts a chair conformation, with two atoms displaced by −0.690 (2) and 0.550 (2) Å from the plane of the other four atoms. The conformation of the pyrrolidine ring is close to that of an envelope, with the flap atom displaced by 0.563 (2) Å from the plane of the remaining four atoms. In the crystal, there are two O—H⋯I hydrogen bonds.

Related literature

For the biological activity of indolizine derivatives, see: Gubin et al. (1992); Gupta et al. (2003); Malonne et al. (1998); Medda et al. (2003); Nardelli (1983); Pearson & Guo (2001); Ruprecht et al. (1989). For puckering analysis, see: Cremer & Pople (1975). For the preparation, see: Šafář et al. (2010). For related structures, see: Clark & Reid (1995); Pedersen (1967).graphic file with name e-67-o3520-scheme1.jpg

Experimental

Crystal data

  • C11H22NO2 +·I

  • M r = 327.20

  • Monoclinic, Inline graphic

  • a = 8.18603 (14) Å

  • b = 10.82977 (14) Å

  • c = 8.19874 (13) Å

  • β = 110.3688 (19)°

  • V = 681.39 (2) Å3

  • Z = 2

  • Mo Kα radiation

  • μ = 2.34 mm−1

  • T = 298 K

  • 0.30 × 0.25 × 0.20 mm

Data collection

  • Oxford Diffraction Gemini R CCD diffractometer

  • Absorption correction: multi-scan (CrysAlis PRO; Oxford Diffraction, 2009) T min = 0.520, T max = 0.638

  • 18648 measured reflections

  • 3330 independent reflections

  • 3176 reflections with I > 2σ(I)

  • R int = 0.020

Refinement

  • R[F 2 > 2σ(F 2)] = 0.019

  • wR(F 2) = 0.049

  • S = 0.91

  • 3330 reflections

  • 141 parameters

  • 1 restraint

  • H-atom parameters constrained

  • Δρmax = 0.64 e Å−3

  • Δρmin = −0.69 e Å−3

  • Absolute structure: Flack (1983), 1359 Friedel pairs

  • Flack parameter: −0.026 (17)

Data collection: CrysAlis PRO (Oxford Diffraction, 2009); cell refinement: CrysAlis PRO; data reduction: CrysAlis PRO; program(s) used to solve structure: SHELXS97 (Sheldrick, 2008); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008); molecular graphics: DIAMOND (Brandenburg, 2001); software used to prepare material for publication: SHELXL97, PLATON (Spek, 2009) and WinGX (Farrugia, 1999).

Supplementary Material

Crystal structure: contains datablock(s) I, global. DOI: 10.1107/S1600536811051099/bq2323sup1.cif

e-67-o3520-sup1.cif (18.7KB, cif)

Structure factors: contains datablock(s) I. DOI: 10.1107/S1600536811051099/bq2323Isup2.hkl

e-67-o3520-Isup2.hkl (163.3KB, hkl)

Supplementary material file. DOI: 10.1107/S1600536811051099/bq2323Isup3.cml

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

Table 1. Hydrogen-bond geometry (Å, °).

D—H⋯A D—H H⋯A DA D—H⋯A
O1—H1⋯I1i 0.82 2.80 3.6187 (18) 173
O2—H2⋯I1ii 0.82 2.67 3.4798 (16) 172

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

Acknowledgments

The authors thank the Grant Agency of Slovak Republic (grant Nos. 1/0429/11, 1/0679/11) and the Slovak Research and Development Agency (under contract No. APVV-0204–10) for financial support of this research program.

supplementary crystallographic information

Comment

Indolizine derivatives have been found to possess a variety of biological activities such as antiinflammatory (Malonne et al., 1998), antiviral (Medda et al., 2003), and antitumor (Pearson & Guo, 2001) activities. They have also shown to be calcium entry blockers (Gupta et al., 2003). As such, indolizines are important synthetic targets in view of developing new pharmaceuticals for the treatment of cardiovascular diseases (Gubin et al., 1992) and HIV infections (Ruprecht et al., 1989). Based on these facts and in continuation of our interest in developing simple and efficient route for the synthesis of novel indolizine derivatives, we report here the synthesis, molecular and crystal structure of the title compound. The molecular structure of the compound and the atom labeling scheme are shown in Fig. 1. The absolute configuration was established by synthesis and confirmed by the structure determination. The expected stereochemistry of atoms N1, C5, C6, C7 and C8 was confirmed as R,S,S,S and S, respectively (Fig.1). The central six-membered N-heterocyclic ring is not planar and adopts a chair conformation (Cremer & Pople, 1975). A calculation of least-squares planes shows that this ring is puckered in such a manner that the four atoms C6, C7, N1 and C9 are coplanar within 0.022 (2) Å, while atoms C8 and C5 are displaced from this plane on opposite sides, with out-of-plane displacements of -0.690 (2) and 0.550 (2) Å, respectively. The pyrrolidine ring attached to the indolizine ring system has envelope conformation, with atom N1 on the flap. The maximum deviation from planarity for N1 is -0.563 (2) Å. The two aromatic rings are almost perpendicular to each other. The dihedral angle between the plane of the four atoms C2, C3, C4 and C5 of pyrrolidine ring and the plane of the four atoms C6, C7, N1 and C9 forming the base of the chair conformation is 89.6 (1)°. Intermolecular O1–H1···I1 and O2–H2···I1 hydrogen bonds link the molecules into extended chains running along the b axis (Table 1. and Figure 2.).

Experimental

The title compound was prepared according to a standard protocol described in literature (Šafář et al., 2010).

Refinement

All H atoms were positioned with idealized geometry using a riding model with C—H distances in the range 0.93 - 0.98 Å and O—H distance 0.82 Å. The Uiso(H) values were set at 1.5Ueq(C-methyl,O) and 1.2Ueq(other C atoms)

Figures

Fig. 1.

Fig. 1.

Molecular structure of the title compound showing the atom labeling scheme. Displacement ellipsoids are drawn at the 50% probability level (Brandenburg, 2001).

Fig. 2.

Fig. 2.

Packing view of the title compound. Molecular chains along b are generated by O–H···I hydrogen bonds which are shown as dashed lines. H atoms not involved in hydrogen bonding have been omitted.

Crystal data

C11H22NO2+·I F(000) = 328
Mr = 327.20 Dx = 1.595 Mg m3
Monoclinic, P21 Mo Kα radiation, λ = 0.71073 Å
Hall symbol: P 2yb Cell parameters from 3330 reflections
a = 8.18603 (14) Å θ = 3.6–29.4°
b = 10.82977 (14) Å µ = 2.34 mm1
c = 8.19874 (13) Å T = 298 K
β = 110.3688 (19)° Prism, colourless
V = 681.39 (2) Å3 0.30 × 0.25 × 0.20 mm
Z = 2

Data collection

Oxford Diffraction Gemini R CCD diffractometer 3330 independent reflections
Radiation source: fine-focus sealed tube 3176 reflections with I > 2σ(I)
graphite Rint = 0.020
Detector resolution: 10.434 pixels mm-1 θmax = 29.4°, θmin = 3.6°
ω and φ scans h = −11→11
Absorption correction: multi-scan (CrysAlis PRO; Oxford Diffraction, 2009) k = −14→14
Tmin = 0.520, Tmax = 0.638 l = −11→10
18648 measured reflections

Refinement

Refinement on F2 Hydrogen site location: inferred from neighbouring sites
Least-squares matrix: full H-atom parameters constrained
R[F2 > 2σ(F2)] = 0.019 w = 1/[σ2(Fo2) + (0.0335P)2 + 0.2787P] where P = (Fo2 + 2Fc2)/3
wR(F2) = 0.049 (Δ/σ)max < 0.001
S = 0.91 Δρmax = 0.64 e Å3
3330 reflections Δρmin = −0.69 e Å3
141 parameters Extinction correction: SHELXL97 (Sheldrick, 2008), Fc*=kFc[1+0.001xFc2λ3/sin(2θ)]-1/4
1 restraint Extinction coefficient: 0.044 (2)
Primary atom site location: structure-invariant direct methods Absolute structure: Flack (1983), 1359 Friedel pairs
Secondary atom site location: difference Fourier map Flack parameter: −0.026 (17)

Special details

Geometry. All e.s.d.'s (except the e.s.d. in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell e.s.d.'s are taken into account individually in the estimation of e.s.d.'s in distances, angles and torsion angles; correlations between e.s.d.'s in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell e.s.d.'s is used for estimating e.s.d.'s involving l.s. planes.
Refinement. Refinement of F2 against ALL reflections. The weighted R-factor wR and goodness of fit S are based on F2, conventional R-factors R are based on F, with F set to zero for negative F2. The threshold expression of F2 > σ(F2) is used only for calculating R-factors(gt) etc. and is not relevant to the choice of reflections for refinement. R-factors based on F2 are statistically about twice as large as those based on F, and R- factors based on ALL data will be even larger.

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å2)

x y z Uiso*/Ueq
C2 0.5506 (4) 0.1519 (3) 0.1098 (4) 0.0581 (7)
H2A 0.4507 0.2056 0.0599 0.070*
H2B 0.6055 0.1385 0.0237 0.070*
C3 0.4953 (5) 0.0317 (3) 0.1635 (5) 0.0735 (9)
H3A 0.5487 −0.0365 0.1238 0.088*
H3B 0.3697 0.0229 0.1134 0.088*
C4 0.5545 (4) 0.0321 (3) 0.3627 (4) 0.0538 (6)
H4A 0.4590 0.0099 0.4012 0.065*
H4B 0.6495 −0.0256 0.4122 0.065*
C5 0.6143 (3) 0.1645 (2) 0.4157 (3) 0.0376 (4)
H5 0.5115 0.2133 0.4092 0.045*
C6 0.7478 (3) 0.1787 (2) 0.5989 (3) 0.0358 (4)
H6 0.7088 0.1294 0.6787 0.043*
C7 0.9331 (3) 0.13766 (19) 0.6181 (3) 0.0336 (4)
H7 1.0133 0.1641 0.7321 0.040*
C8 0.9902 (3) 0.19544 (19) 0.4777 (3) 0.0340 (4)
H8 0.9914 0.2854 0.4913 0.041*
C9 0.8601 (3) 0.1627 (2) 0.2992 (3) 0.0395 (5)
H9A 0.8994 0.1978 0.2103 0.047*
H9B 0.8562 0.0737 0.2853 0.047*
C10 0.6736 (4) 0.3470 (2) 0.2554 (4) 0.0565 (7)
H10A 0.7083 0.3703 0.1592 0.085*
H10B 0.7517 0.3834 0.3603 0.085*
H10C 0.5572 0.3757 0.2352 0.085*
C11 1.1720 (3) 0.1536 (3) 0.4865 (3) 0.0477 (6)
H11A 1.1688 0.0662 0.4598 0.057*
H11B 1.2044 0.1977 0.3994 0.057*
C12 1.3095 (3) 0.1765 (3) 0.6658 (4) 0.0586 (7)
H12A 1.4233 0.1615 0.6611 0.088*
H12B 1.2894 0.1220 0.7492 0.088*
H12C 1.3020 0.2606 0.6998 0.088*
N1 0.6791 (2) 0.20968 (18) 0.2730 (2) 0.0373 (4)
O1 0.7466 (2) 0.30534 (17) 0.6448 (3) 0.0537 (5)
H1 0.8265 0.3185 0.7367 0.080*
O2 0.9442 (2) 0.00727 (14) 0.6053 (2) 0.0444 (4)
H2 0.9405 −0.0249 0.6945 0.067*
I1 0.11548 (2) 0.38255 (2) 0.028309 (17) 0.05615 (7)

Atomic displacement parameters (Å2)

U11 U22 U33 U12 U13 U23
C2 0.0441 (13) 0.079 (2) 0.0373 (12) −0.0013 (13) −0.0032 (10) −0.0131 (12)
C3 0.0651 (18) 0.070 (2) 0.072 (2) −0.0226 (16) 0.0065 (16) −0.0302 (17)
C4 0.0494 (13) 0.0441 (13) 0.0663 (17) −0.0150 (11) 0.0180 (12) −0.0109 (12)
C5 0.0291 (9) 0.0385 (10) 0.0444 (12) −0.0017 (8) 0.0118 (8) −0.0050 (9)
C6 0.0329 (9) 0.0395 (11) 0.0371 (10) 0.0043 (8) 0.0150 (8) −0.0039 (9)
C7 0.0351 (10) 0.0352 (10) 0.0304 (10) 0.0048 (8) 0.0112 (8) 0.0018 (8)
C8 0.0288 (9) 0.0361 (10) 0.0351 (10) 0.0007 (8) 0.0088 (8) 0.0050 (8)
C9 0.0354 (10) 0.0501 (12) 0.0321 (10) 0.0021 (9) 0.0107 (8) 0.0033 (9)
C10 0.0488 (13) 0.0441 (14) 0.0606 (15) 0.0033 (9) −0.0011 (11) 0.0162 (10)
C11 0.0309 (10) 0.0685 (17) 0.0435 (13) 0.0013 (10) 0.0127 (10) 0.0097 (11)
C12 0.0313 (11) 0.082 (2) 0.0570 (16) −0.0028 (12) 0.0086 (11) 0.0059 (15)
N1 0.0317 (8) 0.0411 (9) 0.0318 (9) −0.0007 (7) 0.0017 (7) 0.0010 (7)
O1 0.0487 (10) 0.0491 (10) 0.0534 (10) 0.0136 (8) 0.0054 (8) −0.0195 (8)
O2 0.0575 (10) 0.0344 (8) 0.0492 (10) 0.0114 (7) 0.0286 (8) 0.0114 (7)
I1 0.06754 (11) 0.06164 (10) 0.04070 (9) −0.00802 (11) 0.02063 (6) −0.01043 (10)

Geometric parameters (Å, °)

C2—C3 1.494 (5) C8—C9 1.522 (3)
C2—N1 1.520 (3) C8—C11 1.533 (3)
C2—H2A 0.9700 C8—H8 0.9800
C2—H2B 0.9700 C9—N1 1.510 (3)
C3—C4 1.533 (5) C9—H9A 0.9700
C3—H3A 0.9700 C9—H9B 0.9700
C3—H3B 0.9700 C10—N1 1.493 (3)
C4—C5 1.528 (3) C10—H10A 0.9600
C4—H4A 0.9700 C10—H10B 0.9600
C4—H4B 0.9700 C10—H10C 0.9600
C5—N1 1.523 (3) C11—C12 1.529 (4)
C5—C6 1.527 (3) C11—H11A 0.9700
C5—H5 0.9800 C11—H11B 0.9700
C6—O1 1.423 (3) C12—H12A 0.9600
C6—C7 1.535 (3) C12—H12B 0.9600
C6—H6 0.9800 C12—H12C 0.9600
C7—O2 1.421 (3) O1—H1 0.8200
C7—C8 1.519 (3) O2—H2 0.8200
C7—H7 0.9800
C3—C2—N1 106.7 (2) C7—C8—C11 113.04 (18)
C3—C2—H2A 110.4 C9—C8—C11 108.61 (19)
N1—C2—H2A 110.4 C7—C8—H8 108.5
C3—C2—H2B 110.4 C9—C8—H8 108.5
N1—C2—H2B 110.4 C11—C8—H8 108.5
H2A—C2—H2B 108.6 N1—C9—C8 112.42 (18)
C2—C3—C4 107.2 (2) N1—C9—H9A 109.1
C2—C3—H3A 110.3 C8—C9—H9A 109.1
C4—C3—H3A 110.3 N1—C9—H9B 109.1
C2—C3—H3B 110.3 C8—C9—H9B 109.1
C4—C3—H3B 110.3 H9A—C9—H9B 107.9
H3A—C3—H3B 108.5 N1—C10—H10A 109.5
C5—C4—C3 104.9 (2) N1—C10—H10B 109.5
C5—C4—H4A 110.8 H10A—C10—H10B 109.5
C3—C4—H4A 110.8 N1—C10—H10C 109.5
C5—C4—H4B 110.8 H10A—C10—H10C 109.5
C3—C4—H4B 110.8 H10B—C10—H10C 109.5
H4A—C4—H4B 108.8 C12—C11—C8 112.0 (2)
N1—C5—C6 113.69 (17) C12—C11—H11A 109.2
N1—C5—C4 104.21 (19) C8—C11—H11A 109.2
C6—C5—C4 115.0 (2) C12—C11—H11B 109.2
N1—C5—H5 107.9 C8—C11—H11B 109.2
C6—C5—H5 107.9 H11A—C11—H11B 107.9
C4—C5—H5 107.9 C11—C12—H12A 109.5
O1—C6—C5 106.78 (18) C11—C12—H12B 109.5
O1—C6—C7 110.46 (18) H12A—C12—H12B 109.5
C5—C6—C7 114.51 (17) C11—C12—H12C 109.5
O1—C6—H6 108.3 H12A—C12—H12C 109.5
C5—C6—H6 108.3 H12B—C12—H12C 109.5
C7—C6—H6 108.3 C10—N1—C9 110.1 (2)
O2—C7—C8 108.01 (17) C10—N1—C2 109.6 (2)
O2—C7—C6 111.47 (18) C9—N1—C2 109.31 (19)
C8—C7—C6 110.88 (17) C10—N1—C5 112.8 (2)
O2—C7—H7 108.8 C9—N1—C5 111.69 (16)
C8—C7—H7 108.8 C2—N1—C5 103.01 (19)
C6—C7—H7 108.8 C6—O1—H1 109.5
C7—C8—C9 109.65 (17) C7—O2—H2 109.5
N1—C2—C3—C4 13.6 (3) C7—C8—C9—N1 60.6 (2)
C2—C3—C4—C5 10.0 (3) C11—C8—C9—N1 −175.43 (19)
C3—C4—C5—N1 −29.6 (3) C7—C8—C11—C12 −54.9 (3)
C3—C4—C5—C6 −154.8 (2) C9—C8—C11—C12 −176.8 (2)
N1—C5—C6—O1 77.7 (2) C8—C9—N1—C10 71.0 (2)
C4—C5—C6—O1 −162.2 (2) C8—C9—N1—C2 −168.5 (2)
N1—C5—C6—C7 −44.9 (3) C8—C9—N1—C5 −55.1 (2)
C4—C5—C6—C7 75.2 (3) C3—C2—N1—C10 −152.2 (3)
O1—C6—C7—O2 168.90 (18) C3—C2—N1—C9 87.0 (3)
C5—C6—C7—O2 −70.5 (2) C3—C2—N1—C5 −31.8 (3)
O1—C6—C7—C8 −70.7 (2) C6—C5—N1—C10 −78.1 (2)
C5—C6—C7—C8 49.9 (2) C4—C5—N1—C10 155.86 (19)
O2—C7—C8—C9 66.0 (2) C6—C5—N1—C9 46.5 (2)
C6—C7—C8—C9 −56.5 (2) C4—C5—N1—C9 −79.5 (2)
O2—C7—C8—C11 −55.4 (2) C6—C5—N1—C2 163.7 (2)
C6—C7—C8—C11 −177.79 (19) C4—C5—N1—C2 37.7 (2)

Hydrogen-bond geometry (Å, °)

D—H···A D—H H···A D···A D—H···A
O1—H1···I1i 0.82 2.80 3.6187 (18) 173.
O2—H2···I1ii 0.82 2.67 3.4798 (16) 172.

Symmetry codes: (i) x+1, y, z+1; (ii) −x+1, y−1/2, −z+1.

Footnotes

Supplementary data and figures for this paper are available from the IUCr electronic archives (Reference: BQ2323).

References

  1. Brandenburg, K. (2001). DIAMOND Crystal Impact GbR, Bonn, Germany.
  2. Clark, R. C. & Reid, J. S. (1995). Acta Cryst. A51, 887–897.
  3. Cremer, D. & Pople, J. A. (1975). J. Am. Chem. Soc. 97, 1354–1362.
  4. Farrugia, L. J. (1999). J. Appl. Cryst. 32, 837–838.
  5. Flack, H. D. (1983). Acta Cryst. A39, 876–881.
  6. Gubin, J., Lucchetti, J., Mahaux, J., Nisato, D., Rosseels, G., Clinet, M., Polster, P. & Chatelain, P. (1992). J. Med. Chem. 35, 981–988. [DOI] [PubMed]
  7. Gupta, S. P., Mathur, A. N., Nagappa, A. N., Kumar, D. & Kumaran, S. (2003). Eur. J. Med. Chem. 38, 867–873. [DOI] [PubMed]
  8. Malonne, H., Hanuise, J. & Fontaine, J. (1998). Pharm. Pharmacol. Commun. 4, 241–243.
  9. Medda, S., Jaisankar, P., Manna, R. K., Pal, B., Giri, V. S. & Basu, M. K. (2003). J. Drug Target. 11, 123–128. [DOI] [PubMed]
  10. Nardelli, M. (1983). Acta Cryst. C39, 1141–1142.
  11. Oxford Diffraction (2009). CrysAlis PRO Oxford Diffraction Ltd, Yarnton, England.
  12. Pearson, W. H. & Guo, L. (2001). Tetrahedron Lett. 42, 8267–8271.
  13. Pedersen, B. F. (1967). Acta Chem. Scand. 21, 1415–1424.
  14. Ruprecht, R. M., Mullaney, S., Andersen, J. & Bronson, R. (1989). J. Acquir. Immune Defic. Syndr. 2, 149–157. [PubMed]
  15. Šafář, P., Žužiová, J., Tóthová, E., Marchalín, Š., Prónayová, N., Švorc, Ľ., Vrábel, V., Comesse, S. & Daich, A. (2010). Tetrahedron Asymmetry, 21, 623–630.
  16. Sheldrick, G. M. (2008). Acta Cryst. A64, 112–122. [DOI] [PubMed]
  17. Spek, A. L. (2009). Acta Cryst. D65, 148–155. [DOI] [PMC free article] [PubMed]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Crystal structure: contains datablock(s) I, global. DOI: 10.1107/S1600536811051099/bq2323sup1.cif

e-67-o3520-sup1.cif (18.7KB, cif)

Structure factors: contains datablock(s) I. DOI: 10.1107/S1600536811051099/bq2323Isup2.hkl

e-67-o3520-Isup2.hkl (163.3KB, hkl)

Supplementary material file. DOI: 10.1107/S1600536811051099/bq2323Isup3.cml

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


Articles from Acta Crystallographica Section E: Structure Reports Online are provided here courtesy of International Union of Crystallography

RESOURCES