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Acta Crystallogr Sect E Struct Rep Online. 2010 August 1; 66(Pt 8): o1942.
Published online 2010 July 7. doi:  10.1107/S1600536810025870
PMCID: PMC3007573

N-Methyl-2-thio­cytisine

Abstract

The rings of the three-ring cytisine system in the title compound [systematic name: (1R,5S)-1,2,3,4,5,6-hexa­hydro-1,5-methano-8H-pyrido[1,2-a][1,5]diazo­cine-8-thione], C12H16N2S, have planar [maximum deviation 0.0170 (7) Å], half-chair and chair conformations. In the crystal structure, relatively short and directional C—H(...)π inter­actions and weaker secondary C—H(...)S contacts join the mol­ecules into helical chains along the [001] direction.

Related literature

For general literature on cytisine, see: Okuda et al. (1961 [triangle]). For synthetic methods, see: Marriere et al. (2000 [triangle]); Imming et al. (2001 [triangle]). For similar structures, see: Freer et al. (1987 [triangle]); Imming et al. (2001 [triangle]). For asymmetry parameters, see: Duax & Norton (1975 [triangle]). For C—H(...)π interactions, see: Desiraju & Steiner (1999 [triangle]); Braga et al. (1998 [triangle]). For a description of the Cambridge Structural Database, see: Allen (2002 [triangle]).

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Object name is e-66-o1942-scheme1.jpg

Experimental

Crystal data

  • C12H16N2S
  • M r = 220.33
  • Orthorhombic, An external file that holds a picture, illustration, etc.
Object name is e-66-o1942-efi4.jpg
  • a = 9.8530 (6) Å
  • b = 10.6964 (7) Å
  • c = 10.8226 (7) Å
  • V = 1140.61 (13) Å3
  • Z = 4
  • Mo Kα radiation
  • μ = 0.25 mm−1
  • T = 100 K
  • 0.5 × 0.2 × 0.1 mm

Data collection

  • Xcalibur, Eos diffractometer
  • Absorption correction: multi-scan (CrysAlis PRO; Oxford Diffraction, 2009 [triangle]) T min = 0.921, T max = 1.000
  • 13752 measured reflections
  • 2744 independent reflections
  • 2604 reflections with I > 2σ(I)
  • R int = 0.019

Refinement

  • R[F 2 > 2σ(F 2)] = 0.021
  • wR(F 2) = 0.056
  • S = 1.07
  • 2744 reflections
  • 200 parameters
  • All H-atom parameters refined
  • Δρmax = 0.25 e Å−3
  • Δρmin = −0.16 e Å−3
  • Absolute structure: Flack (1983 [triangle]), 1015 Friedel pairs
  • Flack parameter: 0.02 (4)

Data collection: CrysAlis PRO (Oxford Diffraction, 2009 [triangle]); cell refinement: CrysAlis PRO; data reduction: CrysAlis PRO; program(s) used to solve structure: SIR92 (Altomare et al., 1993 [triangle]); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008 [triangle]); molecular graphics: Stereochemical Workstation Operation Manual (Siemens, 1989 [triangle]); software used to prepare material for publication: SHELXL97.

Table 1
Hydrogen-bond geometry (Å, °)

Supplementary Material

Crystal structure: contains datablocks I, global. DOI: 10.1107/S1600536810025870/nk2044sup1.cif

Structure factors: contains datablocks I. DOI: 10.1107/S1600536810025870/nk2044Isup2.hkl

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

Acknowledgments

This project has been supported by the Scientific Research Committee of Poland (grant No. N N312 187835).

supplementary crystallographic information

Comment

(-)-Cytisine and its N-methyl derivative are toxic quinolizidine alkaloids, which are found in different plants from the Fabaceae (Leguminosae) family. They can cause nausea, convulsions and ultimately death by respiratory failure. Chemically, these compounds have a tricyclic skeleton, which can be characterized as a bispidine framework fused to 2-pyridone. The absolute configuration of two chiral centers was established as 7R,9S (Okuda et al., 1961), and the crystal structures of both cytisine and N-methylcytisine have been reported (Freer et al., 1987). Also the structure of 2-thiocytisine was determined (Imming et al., 2001), but this is the only structure of thioanalogue of cytisine in the CSD (Allen, 2002; Version 5.31 of Nov. 2009, updated Feb. 2010). During our studies on cytisine derivatives we have synthesized N-methyl-2-thiocytisine (1, Scheme 1), and here we present the results of its structural characterization.

The configuration 7R,9S is confirmed by the value of the Flack parameter. The overall conformation of 1 is similar to other cytisine derivatives (Fig. 1). The ring A is almost planar, maximum deviation from the least-squares plane is 0.0170 (7) Å, ring B has the half-chair conformation, with five atoms almost coplanar (maximum deviation of 0.0497 (7) Å) and the bridgehead C8 atom significantly out of this plane, by -0.7560 (15) Å, and ring C is close to ideal chair conformation. This might be also described using the description of the asymmetry parameters (Duax & Norton, 1975), which measure the deviation from the ideal symmetry of the certain conformation. The ideal half-chair should possess Cs symmetry, and the appropriate asymmetry parameter for B, ΔCsN1 is relatively high, equal to 8.4°. Ring C is much closer to the ideal chair symmetry of D3d, maximum values of the asymmetry parameters are ΔCs9=2.61°, and ΔC28–9=2.50°.

In the crystal structure - in absence of the possibility of stronger interactions - relatively short and directional, (Table 1) C—H···π interactions play quite an important role. Their geometrical characteristics fit quite well to the category of weak hydrogen bonds (cf. for instance Desiraju & Steiner, 1999, Braga et al., 1998). Together with longer, probably of secondary nature, but still directional C—H···S contacts (Table 1) they connect the molecules, related by 21 screw, into infinite chains along the [001] direction (Fig. 2).

Experimental

(-)-Cytisine was isolated from the seeds of Laburnum anagyroides (Marriere et al., 2000), white crystals, mp. 153 oC. N-methylcytisine was prepared adequately to the procedure: cytisine (1, 0.38 g, 2 mmol) was dissolved in 4 ml of 10% KOH and dimethyl sulfate (1.3 ml, 14 mmol) was added. The mixture was refluxed for 3 h. To cold mixture 12 ml of CH2Cl2 was added and the mixture was stirred for 20 min. Then organic layer was separated and washed with water, dried above MgSO4. The solvent was evaporated to give crude oil of N-methylcytisine that was purified on Al2O3. Yield 81%, (0.33 g) white crystals, m.p. 135–136 oC.

N-methyl-thiocytisine (1) was prepared according to the literature procedure of thiocytisine synthesis (Imming et al., 2001). A mixture of N-methylcytisine (0.204 g, 1 mmol) and Lawesson's reagent (0.5 mmol, 0.202 g) was taken in a glass tube that was placed in an alumina bath inside the microwave oven and irradiated twice for 2 min. The crude material was dissolved in CH2Cl2 (40 ml) and filtered, the solvent was evaporated. The residue was purified by column chromatography (Al2O3, CH2Cl2). The yield 25% of yellow crystals (55 mg), m.p. 147 oC.

Refinement

The positions of hydrogen atoms were found in the difference Fourier maps and both positional and isotropic displacement prameters were freely refined.

Figures

Fig. 1.
Anisotropic ellipsoid representation of molecule 1 together with atom labelling scheme. The ellipsoids are drawn at 50% probability level, hydrogen atoms are depicted as spheres with arbitrary radii.
Fig. 2.
The chain of the molecules 1; weak hydrogen bonds are drawn as dashed lines. Symmetry codes: (i) x,y,z; (ii) 3/2 - x, 2 - y,-1/2 + z; (iii) 3/2 - x,2 - y,1/2 + z; (iv) x,y,-1 + z.

Crystal data

C12H16N2SF(000) = 472
Mr = 220.33Dx = 1.283 Mg m3
Orthorhombic, P212121Mo Kα radiation, λ = 0.71073 Å
Hall symbol: P 2ac 2abCell parameters from 11220 reflections
a = 9.8530 (6) Åθ = 3.4–29.0°
b = 10.6964 (7) ŵ = 0.25 mm1
c = 10.8226 (7) ÅT = 100 K
V = 1140.61 (13) Å3Prism, colourless
Z = 40.5 × 0.2 × 0.1 mm

Data collection

Xcalibur, Eos diffractometer2744 independent reflections
Radiation source: Enhance (Mo) X-ray Source2604 reflections with I > 2σ(I)
graphiteRint = 0.019
Detector resolution: 16.1544 pixels mm-1θmax = 29.0°, θmin = 3.4°
ω–scanh = −12→12
Absorption correction: multi-scan (CrysAlis PRO; Oxford Diffraction, 2009)k = −13→13
Tmin = 0.921, Tmax = 1.000l = −14→14
13752 measured reflections

Refinement

Refinement on F2Secondary atom site location: difference Fourier map
Least-squares matrix: fullHydrogen site location: inferred from neighbouring sites
R[F2 > 2σ(F2)] = 0.021H atoms treated by a mixture of independent and constrained refinement
wR(F2) = 0.056w = 1/[σ2(Fo2) + (0.040P)2] where P = (Fo2 + 2Fc2)/3
S = 1.07(Δ/σ)max = 0.001
2744 reflectionsΔρmax = 0.25 e Å3
200 parametersΔρmin = −0.16 e Å3
0 restraintsAbsolute structure: Flack (1983), 1015 Friedel pairs
Primary atom site location: structure-invariant direct methodsFlack parameter: 0.02 (4)

Special details

Experimental. For cytisine: EI—MS m/z: 190 (96%), m/z: 146 (100%), 147 (99%), 148 (42%), 134 (32%), 160 (29%), 109 (20%).For N-methylcytisine:EI—MS m/z: 204 (54%), m/z: 58 (100%), 146 (15%), 160 (9%). 13C-NMR: 163.5; 151.30; 138.5; 116.5; 104.6; 62.5; 62.1; 49.9; 46.2; 35.4; 35.4; 27.9; 25.4.For 1:EI—MS m/z 220 (92%), 162 (100%), 58 (47%), 189 (27), 176 (27%), 130 (23%)82 (17%), 117 (16%). 13C-NMR: 179.6; 133.5; 132.9; 154.4; 113.7; 62.6; 62.0; 58.4; 46.4; 36.3; 29.0. GC—MS analyses were performed on gas chromatograph CP3800 associated with mass spectrometer (4000MS, ion trap). The column was: VF-5 ms 30 m x 0.25 mm x 0.39 mm (Varian Part No. CP8944); carried gas was helium with flow 1 ml/min. Injector type 1177, std. on column, temp. 250 oC. Temperature program during GC—MS analysis: 80¯C/1¯C/1 min; 180¯C/20¯C/1 min/ 280¯C/10¯C/1 min, hold 20 minutes. NMR spectra were measured on a Bruker AVANCE 600 (600.31 MHz for 1H and 150.052 MHz for 13C) spectrometer.
Geometry. All s.u.'s (except the s.u. in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell s.u.'s are taken into account individually in the estimation of s.u.'s in distances, angles and torsion angles; correlations between s.u.'s in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell s.u.'s is used for estimating s.u.'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 > 2σ(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)

xyzUiso*/Ueq
N10.90884 (9)0.93342 (8)0.93639 (8)0.01107 (18)
C20.93960 (11)0.84480 (9)0.84655 (9)0.0124 (2)
S21.05611 (3)0.87330 (3)0.73429 (2)0.01503 (7)
C30.86834 (12)0.73023 (11)0.85333 (10)0.0161 (2)
H30.8883 (14)0.6684 (13)0.7933 (13)0.021 (3)*
C40.77017 (12)0.70978 (11)0.94042 (11)0.0195 (2)
H40.7145 (14)0.6306 (15)0.9409 (13)0.027 (4)*
C50.74016 (12)0.80336 (11)1.02604 (10)0.0174 (2)
H50.6694 (15)0.7997 (14)1.0879 (12)0.024 (4)*
C60.80976 (11)0.91409 (10)1.02375 (9)0.0129 (2)
C70.77873 (12)1.01441 (11)1.11690 (10)0.0150 (2)
H70.6821 (15)1.0028 (12)1.1408 (12)0.016 (3)*
C80.80632 (12)1.14397 (11)1.06434 (10)0.0174 (2)
H8A0.7864 (15)1.2061 (15)1.1303 (13)0.026 (4)*
H8B0.7486 (14)1.1589 (14)0.9908 (12)0.023 (4)*
C90.95672 (12)1.14670 (9)1.03299 (10)0.0150 (2)
H90.9853 (14)1.2232 (14)0.9994 (12)0.019 (3)*
C100.98425 (12)1.05431 (10)0.92880 (10)0.0137 (2)
H10A0.9562 (15)1.0889 (13)0.8476 (12)0.020 (3)*
H10B1.0795 (16)1.0292 (14)0.9265 (13)0.022 (4)*
C111.04178 (12)1.12303 (11)1.14906 (9)0.0160 (2)
H11A1.1421 (14)1.1253 (14)1.1292 (11)0.018 (3)*
H11B1.0252 (14)1.1959 (13)1.2076 (12)0.022 (4)*
N121.00916 (10)1.00157 (9)1.20468 (8)0.0139 (2)
C130.86495 (12)0.99465 (10)1.23364 (10)0.0154 (2)
H13A0.8353 (13)1.0555 (12)1.2962 (12)0.015 (3)*
H13B0.8429 (13)0.9123 (13)1.2648 (12)0.020 (3)*
C141.08925 (14)0.98412 (12)1.31729 (11)0.0202 (3)
H14A1.0719 (14)0.9084 (15)1.3549 (13)0.025 (4)*
H14B1.1830 (16)0.9908 (12)1.2980 (12)0.022 (4)*
H14C1.0686 (18)1.0426 (17)1.3806 (15)0.039 (5)*

Atomic displacement parameters (Å2)

U11U22U33U12U13U23
N10.0113 (4)0.0105 (4)0.0114 (4)−0.0004 (3)0.0001 (3)0.0008 (3)
C20.0118 (5)0.0134 (5)0.0120 (4)0.0027 (4)−0.0021 (4)0.0009 (3)
S20.01402 (13)0.01866 (13)0.01242 (12)0.00195 (11)0.00257 (9)−0.00147 (10)
C30.0192 (6)0.0131 (5)0.0161 (5)0.0004 (4)−0.0022 (4)−0.0024 (4)
C40.0222 (6)0.0154 (5)0.0208 (6)−0.0067 (5)−0.0026 (5)0.0016 (4)
C50.0170 (6)0.0195 (6)0.0157 (5)−0.0047 (4)0.0021 (4)0.0011 (4)
C60.0112 (5)0.0164 (5)0.0112 (5)0.0003 (4)−0.0007 (4)0.0015 (4)
C70.0126 (6)0.0187 (5)0.0138 (5)0.0018 (4)0.0029 (4)−0.0026 (4)
C80.0202 (6)0.0158 (6)0.0162 (5)0.0059 (5)−0.0004 (4)−0.0017 (4)
C90.0213 (6)0.0092 (5)0.0144 (5)−0.0012 (4)0.0009 (4)0.0000 (4)
C100.0151 (6)0.0120 (5)0.0141 (5)−0.0028 (4)0.0025 (4)0.0009 (4)
C110.0197 (5)0.0131 (5)0.0153 (5)−0.0033 (5)−0.0002 (4)−0.0005 (4)
N120.0165 (5)0.0126 (4)0.0126 (4)−0.0005 (3)−0.0012 (3)0.0012 (3)
C130.0182 (6)0.0167 (5)0.0112 (5)−0.0007 (4)0.0027 (4)−0.0005 (4)
C140.0253 (7)0.0179 (6)0.0176 (6)−0.0012 (5)−0.0061 (5)0.0016 (4)

Geometric parameters (Å, °)

N1—C61.3747 (13)C8—H8B0.991 (14)
N1—C21.3913 (13)C9—C101.5237 (15)
N1—C101.4936 (14)C9—C111.5312 (14)
C2—C31.4143 (15)C9—H90.939 (14)
C2—S21.6990 (11)C10—H10A0.993 (14)
C3—C41.3682 (16)C10—H10B0.976 (16)
C3—H30.948 (14)C11—N121.4674 (14)
C4—C51.3957 (16)C11—H11A1.012 (13)
C4—H41.009 (16)C11—H11B1.018 (14)
C5—C61.3688 (16)N12—C131.4570 (15)
C5—H50.968 (15)N12—C141.4638 (15)
C6—C71.5037 (15)C13—H13A0.983 (13)
C7—C81.5225 (16)C13—H13B0.968 (14)
C7—C131.5371 (16)C14—H14A0.922 (16)
C7—H70.994 (14)C14—H14B0.950 (16)
C8—C91.5205 (16)C14—H14C0.950 (17)
C8—H8A0.995 (15)
C6—N1—C2122.20 (9)C10—C9—C11113.73 (9)
C6—N1—C10121.42 (9)C8—C9—H9113.3 (9)
C2—N1—C10116.29 (9)C10—C9—H9103.0 (8)
N1—C2—C3116.48 (9)C11—C9—H9107.3 (8)
N1—C2—S2121.65 (8)N1—C10—C9115.61 (9)
C3—C2—S2121.87 (8)N1—C10—H10A103.5 (8)
C4—C3—C2121.69 (10)C9—C10—H10A111.3 (8)
C4—C3—H3120.5 (8)N1—C10—H10B104.0 (9)
C2—C3—H3117.8 (8)C9—C10—H10B111.6 (8)
C3—C4—C5119.50 (11)H10A—C10—H10B110.3 (12)
C3—C4—H4121.5 (8)N12—C11—C9111.29 (9)
C5—C4—H4118.9 (8)N12—C11—H11A108.8 (8)
C6—C5—C4120.16 (11)C9—C11—H11A110.8 (7)
C6—C5—H5114.1 (9)N12—C11—H11B112.8 (8)
C4—C5—H5125.7 (9)C9—C11—H11B107.2 (8)
C5—C6—N1119.89 (10)H11A—C11—H11B105.7 (11)
C5—C6—C7120.23 (10)C13—N12—C14109.89 (9)
N1—C6—C7119.88 (9)C13—N12—C11110.29 (9)
C6—C7—C8111.27 (9)C14—N12—C11109.66 (9)
C6—C7—C13109.91 (9)N12—C13—C7110.81 (9)
C8—C7—C13109.48 (9)N12—C13—H13A113.8 (8)
C6—C7—H7106.3 (8)C7—C13—H13A108.1 (8)
C8—C7—H7112.4 (8)N12—C13—H13B109.9 (8)
C13—C7—H7107.3 (8)C7—C13—H13B106.7 (8)
C9—C8—C7105.96 (9)H13A—C13—H13B107.2 (10)
C9—C8—H8A109.9 (9)N12—C14—H14A112.3 (9)
C7—C8—H8A107.7 (8)N12—C14—H14B109.4 (8)
C9—C8—H8B112.1 (8)H14A—C14—H14B110.0 (12)
C7—C8—H8B110.1 (9)N12—C14—H14C113.7 (10)
H8A—C8—H8B110.8 (12)H14A—C14—H14C102.7 (13)
C8—C9—C10109.04 (9)H14B—C14—H14C108.5 (13)
C8—C9—C11110.31 (9)
C6—N1—C2—C3−3.20 (14)N1—C6—C7—C13−91.68 (11)
C10—N1—C2—C3−179.95 (9)C6—C7—C8—C9−61.04 (12)
C6—N1—C2—S2176.50 (8)C13—C7—C8—C960.65 (11)
C10—N1—C2—S2−0.25 (13)C7—C8—C9—C1065.86 (11)
N1—C2—C3—C42.75 (15)C7—C8—C9—C11−59.71 (11)
S2—C2—C3—C4−176.95 (9)C6—N1—C10—C97.35 (14)
C2—C3—C4—C5−0.81 (17)C2—N1—C10—C9−175.87 (9)
C3—C4—C5—C6−0.84 (18)C8—C9—C10—N1−39.82 (12)
C4—C5—C6—N10.42 (17)C11—C9—C10—N183.75 (12)
C4—C5—C6—C7−179.26 (11)C8—C9—C11—N1259.15 (12)
C2—N1—C6—C51.69 (15)C10—C9—C11—N12−63.71 (12)
C10—N1—C6—C5178.28 (10)C9—C11—N12—C13−57.09 (12)
C2—N1—C6—C7−178.62 (9)C9—C11—N12—C14−178.23 (9)
C10—N1—C6—C7−2.04 (15)C14—N12—C13—C7179.28 (9)
C5—C6—C7—C8−150.56 (10)C11—N12—C13—C758.27 (12)
N1—C6—C7—C829.76 (14)C6—C7—C13—N1260.91 (12)
C5—C6—C7—C1388.00 (13)C8—C7—C13—N12−61.59 (12)

Hydrogen-bond geometry (Å, °)

D—H···AD—HH···AD···AD—H···A
C5—H5···S2i0.968 (15)2.893 (14)3.6861 (12)139.9 (11)
C7—H7···S2ii0.994 (14)2.879 (14)3.7338 (12)144.6 (10)
C13—H13A···Cg1ii0.983 (13)2.648 (13)3.5717 (14)156.5 (10)

Symmetry codes: (i) x−1/2, −y+3/2, −z+2; (ii) −x+3/2, −y+2, z+1/2.

Footnotes

Supplementary data and figures for this paper are available from the IUCr electronic archives (Reference: NK2044).

References

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  • Duax, W. L. & Norton, D. A. (1975). In Atlas of Steroid Structures New York: Plenum.
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  • Sheldrick, G. M. (2008). Acta Cryst. A64, 112–122. [PubMed]
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