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Acta Crystallogr Sect E Struct Rep Online. 2009 January 1; 65(Pt 1): o100.
Published online 2008 December 13. doi:  10.1107/S1600536808041457
PMCID: PMC2968025

7-Methyl-9-p-tolyl-4,9-dihydro­furo[3,4-b]quinolin-1(3H)-one

Abstract

In the title compound, C19H17NO2, the dihydro­pyridine ring adopts a flattened boat conformation while the furan­one ring is almost planar (r.m.s. deviation 0.018 Å). The mol­ecules are linked into chains along the b axis by N—H(...)O inter­molecular hydrogen bonds. In addition, C—H(...)π inter­actions involving the phenyl ring of the tolyl group as π acceptor are observed.

Related literature

For the biological activities of podophyllotoxin and its derivatives, see: Bosmans et al. (1989 [triangle]); Eycken et al. (1989 [triangle]); Hitosuyanagi et al. (1997 [triangle], 1999 [triangle]); Lienard et al. (1991 [triangle]); Magedov et al. (2007 [triangle]); Poli & Giambastiani (2002 [triangle]); Tomioka et al. (1989 [triangle], 1993 [triangle]); Tratrat et al. (2002 [triangle]).

An external file that holds a picture, illustration, etc.
Object name is e-65-0o100-scheme1.jpg

Experimental

Crystal data

  • C19H17NO2
  • M r = 291.34
  • Monoclinic, An external file that holds a picture, illustration, etc.
Object name is e-65-0o100-efi1.jpg
  • a = 9.178 (2) Å
  • b = 11.457 (2) Å
  • c = 14.350 (4) Å
  • β = 103.124 (5)°
  • V = 1469.5 (6) Å3
  • Z = 4
  • Mo Kα radiation
  • μ = 0.09 mm−1
  • T = 223 (2) K
  • 0.60 × 0.48 × 0.45 mm

Data collection

  • Rigaku Mercury diffractometer
  • Absorption correction: multi-scan (Jacobson, 1998 [triangle]) T min = 0.756, T max = 0.962
  • 13947 measured reflections
  • 2675 independent reflections
  • 2364 reflections with I > 2σ(I)
  • R int = 0.034

Refinement

  • R[F 2 > 2σ(F 2)] = 0.059
  • wR(F 2) = 0.135
  • S = 1.16
  • 2675 reflections
  • 202 parameters
  • H-atom parameters constrained
  • Δρmax = 0.23 e Å−3
  • Δρmin = −0.21 e Å−3

Data collection: CrystalClear (Rigaku, 2000 [triangle]); cell refinement: CrystalClear; data reduction: CrystalStructure (Rigaku/MSC, 2003 [triangle]); program(s) used to solve structure: SHELXS97 (Sheldrick, 2008 [triangle]); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008 [triangle]); molecular graphics: SHELXTL (Sheldrick, 2008 [triangle]); software used to prepare material for publication: SHELXTL.

Table 1
Hydrogen-bond geometry (Å, °)

Supplementary Material

Crystal structure: contains datablocks global, I. DOI: 10.1107/S1600536808041457/ci2738sup1.cif

Structure factors: contains datablocks I. DOI: 10.1107/S1600536808041457/ci2738Isup2.hkl

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

Acknowledgments

The authors are grateful to the Foundation of the Key Laboratory of Biotechnology of Medical Plants of Jiangsu Province for financial support.

supplementary crystallographic information

Comment

Podophyllotoxin is an antitumor lignan that inhibits microtubule assembly (Eycken et al., 1989; Tomioka et al., 1989; Bosmans et al., 1989). Because of mostly unsuccessfull attempts to use it for the treatment of human neoplasia and complicated side effects, extensive structural modifications have been performed in order to obtain more potent and less toxic anticancer agents (Tomioka et al., 1993; Lienard et al., 1991; Poli et al., 2002). Among them, 4-aza-podophyllotoxin (9-aryl-4,9-dihydrofuro [3,4-b]quinolin-1(3H)-one) derivatives reported as powerful DNA topoisomerase II inhibitors, have recently attached considerable interest (Hitosuyanagi et al., 1997; Hitosuyanagi et al., 1999; Tratrat et al., 2002; Magedov et al., 2007). We report here the crystal structure of the title compound, which was synthesized by the three-component reaction of 4-methylaniline with 4-methylbenzaldehyde and tetronic acid catalyzed by L-proline using ethanol as solvent at 353 K.

In the title compound, the dihydropyridine ring (C1-C5/N1) adopts a flattened boat conformation, with atoms C3 and N1 deviating from the C1/C2/C4/C5 plane (r.m.s. deviation 0.009 Å) by 0.102 (3) and 0.050 (3) Å, respectively (Fig. 1). The five-membered ring is almost planar (r.m.s. deviation 0.018 Å). The dihedral angle between C1/C2/C6/C7-C9 and C1/C2/C4/C5 planes is 2.9 (1)° and that between C1/C2/C4/C5 and C13-C18 plane is 79.77 (7)°.

The molecules are linked into chains (Fig.2) along the b axis by N—H···O intermolecular hydrogen bonds (Table 1). In addition, C—H···π interactions involving the phenyl ring of the tolyl group are observed.

Experimental

The title compound was prepared by the reaction of 4-methylaniline (1 mmol) and 4-methylbenzaldehyde (1 mmol) with tetronic acid (1 mmol) in the presence of L-proline (0.1 mmol) in ethanol (2 ml) at 353 K. Crystals of the title compound suitable for X-ray diffraction were obtained by slow evaporation of a N,N-dimethylformamide and ethanol solution. 1H NMR (DMSO-d6, δ): 2.12 (3H, s, CH3), 2.22 (3H, s, CH3), 4.85 (1H, d, J = 16.0 Hz, CH), 4.91 (1H, s, CH), 4.94 (1H, d, J = 16.0 Hz, CH), 6.80–6.84 (2H, m, ArH), 6.93 (1H, d, J = 8.0 Hz, ArH), 7.04–7.08 (4H, m, ArH), 9.94 (1H, s, NH).

Refinement

H atoms were placed in calculated positions (N-H = 0.87 Å and C-H = 0.94–0.99 Å), and included in the final cycles of refinement using a riding model, with Uiso(H) = 1.2–1.5 Ueq(C). A rotating group model was used for the methyl groups.

Figures

Fig. 1.
The molecular structure of the title compound, showing 30% probability displacement ellipsoids and the atom-numbering scheme.
Fig. 2.
The crystal packing of the title compound. Hydrogen bonds are shown as dashed lines.

Crystal data

C19H17NO2F(000) = 616
Mr = 291.34Dx = 1.317 Mg m3
Monoclinic, P21/cMo Kα radiation, λ = 0.71070 Å
Hall symbol: -P 2ybcCell parameters from 4940 reflections
a = 9.178 (2) Åθ = 3.3–25.3°
b = 11.457 (2) ŵ = 0.09 mm1
c = 14.350 (4) ÅT = 223 K
β = 103.124 (5)°Block, colourless
V = 1469.5 (6) Å30.60 × 0.48 × 0.45 mm
Z = 4

Data collection

Rigaku Mercury diffractometer2675 independent reflections
Radiation source: fine-focus sealed tube2364 reflections with I > 2σ(I)
graphiteRint = 0.034
Detector resolution: 7.31 pixels mm-1θmax = 25.3°, θmin = 3.3°
ω scansh = −11→11
Absorption correction: multi-scan (Jacobson, 1998)k = −13→12
Tmin = 0.756, Tmax = 0.962l = −17→17
13947 measured reflections

Refinement

Refinement on F2Primary atom site location: structure-invariant direct methods
Least-squares matrix: fullSecondary atom site location: difference Fourier map
R[F2 > 2σ(F2)] = 0.059Hydrogen site location: inferred from neighbouring sites
wR(F2) = 0.135H-atom parameters constrained
S = 1.16w = 1/[σ2(Fo2) + (0.0497P)2 + 0.6176P] where P = (Fo2 + 2Fc2)/3
2675 reflections(Δ/σ)max = 0.001
202 parametersΔρmax = 0.23 e Å3
0 restraintsΔρmin = −0.21 e Å3

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)

xyzUiso*/Ueq
O1−0.06775 (18)0.28146 (14)0.77022 (11)0.0528 (4)
O2−0.09551 (18)0.13853 (14)0.66103 (12)0.0549 (5)
N10.14394 (19)0.50270 (15)0.68136 (12)0.0396 (4)
H10.15880.56170.72050.048*
C10.1948 (2)0.50585 (16)0.59568 (14)0.0343 (5)
C20.1821 (2)0.40751 (17)0.53741 (13)0.0329 (5)
C30.1160 (2)0.29193 (17)0.56127 (14)0.0342 (5)
H30.03270.27090.50690.041*
C40.0523 (2)0.31008 (18)0.64815 (14)0.0366 (5)
C50.0727 (2)0.40748 (18)0.70132 (14)0.0374 (5)
C60.2347 (2)0.41594 (18)0.45381 (14)0.0382 (5)
H60.22590.35050.41340.046*
C70.2994 (2)0.51643 (18)0.42757 (15)0.0400 (5)
C80.3088 (2)0.61316 (18)0.48745 (16)0.0424 (5)
H80.35110.68270.47100.051*
C90.2572 (2)0.60876 (18)0.57031 (16)0.0401 (5)
H90.26410.67500.60970.048*
C100.3607 (3)0.5198 (2)0.33889 (16)0.0513 (6)
H10A0.46860.51130.35650.077*
H10B0.33520.59380.30640.077*
H10C0.31780.45650.29660.077*
C11−0.0401 (2)0.2330 (2)0.68790 (16)0.0440 (5)
C120.0028 (3)0.3941 (2)0.78519 (16)0.0479 (6)
H12A0.07880.39610.84550.058*
H12B−0.07090.45570.78600.058*
C130.2291 (2)0.19179 (16)0.57700 (13)0.0319 (4)
C140.3781 (2)0.20786 (18)0.62247 (15)0.0409 (5)
H140.41240.28290.64290.049*
C150.4770 (2)0.11455 (19)0.63815 (16)0.0437 (5)
H150.57760.12790.66870.052*
C160.4311 (2)0.00218 (17)0.60993 (14)0.0383 (5)
C170.2828 (2)−0.01293 (18)0.56396 (15)0.0425 (5)
H170.2484−0.08790.54330.051*
C180.1838 (2)0.07991 (17)0.54770 (15)0.0394 (5)
H180.08370.06670.51610.047*
C190.5382 (3)−0.0990 (2)0.62813 (17)0.0511 (6)
H19A0.5792−0.11180.57230.077*
H19B0.4856−0.16860.64080.077*
H19C0.6187−0.08200.68300.077*

Atomic displacement parameters (Å2)

U11U22U33U12U13U23
O10.0578 (10)0.0565 (10)0.0538 (10)−0.0026 (8)0.0326 (8)0.0054 (8)
O20.0594 (10)0.0468 (10)0.0643 (11)−0.0111 (8)0.0259 (9)0.0068 (8)
N10.0428 (10)0.0394 (10)0.0397 (10)−0.0028 (8)0.0160 (8)−0.0071 (8)
C10.0297 (10)0.0376 (11)0.0370 (11)0.0023 (8)0.0104 (9)0.0015 (9)
C20.0303 (10)0.0354 (11)0.0337 (10)0.0012 (8)0.0085 (8)0.0035 (8)
C30.0328 (10)0.0368 (11)0.0343 (10)−0.0020 (8)0.0104 (8)−0.0007 (8)
C40.0340 (10)0.0408 (11)0.0366 (11)0.0017 (9)0.0116 (9)0.0047 (9)
C50.0313 (10)0.0456 (12)0.0370 (11)0.0033 (9)0.0111 (9)0.0021 (9)
C60.0396 (11)0.0398 (11)0.0369 (11)0.0026 (9)0.0123 (9)0.0015 (9)
C70.0359 (11)0.0454 (12)0.0400 (11)0.0018 (9)0.0114 (9)0.0112 (9)
C80.0407 (12)0.0365 (11)0.0512 (13)−0.0021 (9)0.0129 (10)0.0089 (10)
C90.0385 (11)0.0340 (11)0.0481 (12)0.0002 (8)0.0103 (10)−0.0023 (9)
C100.0523 (14)0.0589 (15)0.0469 (13)0.0007 (11)0.0198 (11)0.0130 (11)
C110.0407 (12)0.0475 (13)0.0478 (13)0.0029 (10)0.0184 (10)0.0087 (10)
C120.0490 (13)0.0545 (14)0.0462 (13)−0.0018 (10)0.0232 (11)−0.0011 (11)
C130.0363 (10)0.0334 (10)0.0283 (9)−0.0030 (8)0.0122 (8)0.0000 (8)
C140.0415 (12)0.0364 (11)0.0433 (12)−0.0054 (9)0.0067 (9)−0.0045 (9)
C150.0369 (11)0.0479 (13)0.0449 (12)−0.0005 (9)0.0065 (10)−0.0002 (10)
C160.0470 (12)0.0396 (12)0.0316 (10)0.0030 (9)0.0158 (9)0.0032 (8)
C170.0502 (13)0.0344 (11)0.0438 (12)−0.0068 (9)0.0123 (10)−0.0035 (9)
C180.0368 (11)0.0394 (11)0.0416 (11)−0.0067 (9)0.0082 (9)−0.0005 (9)
C190.0589 (14)0.0472 (13)0.0496 (13)0.0105 (11)0.0172 (11)0.0042 (11)

Geometric parameters (Å, °)

O1—C111.380 (3)C8—H80.94
O1—C121.438 (3)C9—H90.94
O2—C111.220 (3)C10—H10A0.97
N1—C51.336 (3)C10—H10B0.97
N1—C11.411 (3)C10—H10C0.97
N1—H10.87C12—H12A0.98
C1—C21.392 (3)C12—H12B0.98
C1—C91.395 (3)C13—C181.383 (3)
C2—C61.395 (3)C13—C141.387 (3)
C2—C31.528 (3)C14—C151.387 (3)
C3—C41.506 (3)C14—H140.94
C3—C131.529 (3)C15—C161.386 (3)
C3—H30.99C15—H150.94
C4—C51.341 (3)C16—C171.382 (3)
C4—C111.430 (3)C16—C191.504 (3)
C5—C121.494 (3)C17—C181.384 (3)
C6—C71.386 (3)C17—H170.94
C6—H60.94C18—H180.94
C7—C81.393 (3)C19—H19A0.97
C7—C101.504 (3)C19—H19B0.97
C8—C91.377 (3)C19—H19C0.97
C11—O1—C12108.95 (16)C7—C10—H10C109.5
C5—N1—C1118.85 (17)H10A—C10—H10C109.5
C5—N1—H1120.6H10B—C10—H10C109.5
C1—N1—H1120.6O2—C11—O1118.87 (19)
C2—C1—C9120.68 (18)O2—C11—C4131.6 (2)
C2—C1—N1120.25 (17)O1—C11—C4109.52 (19)
C9—C1—N1119.06 (18)O1—C12—C5103.48 (17)
C1—C2—C6117.57 (18)O1—C12—H12A111.1
C1—C2—C3123.37 (17)C5—C12—H12A111.1
C6—C2—C3119.06 (17)O1—C12—H12B111.1
C4—C3—C2108.32 (16)C5—C12—H12B111.1
C4—C3—C13111.04 (16)H12A—C12—H12B109.0
C2—C3—C13113.10 (15)C18—C13—C14117.52 (18)
C4—C3—H3108.1C18—C13—C3120.23 (17)
C2—C3—H3108.1C14—C13—C3122.24 (17)
C13—C3—H3108.1C13—C14—C15120.86 (19)
C5—C4—C11107.79 (19)C13—C14—H14119.6
C5—C4—C3123.77 (18)C15—C14—H14119.6
C11—C4—C3128.43 (19)C16—C15—C14121.6 (2)
N1—C5—C4124.70 (19)C16—C15—H15119.2
N1—C5—C12125.25 (19)C14—C15—H15119.2
C4—C5—C12110.05 (19)C17—C16—C15117.18 (19)
C7—C6—C2122.99 (19)C17—C16—C19121.35 (19)
C7—C6—H6118.5C15—C16—C19121.5 (2)
C2—C6—H6118.5C16—C17—C18121.46 (19)
C6—C7—C8117.62 (19)C16—C17—H17119.3
C6—C7—C10121.1 (2)C18—C17—H17119.3
C8—C7—C10121.2 (2)C13—C18—C17121.37 (19)
C9—C8—C7121.21 (19)C13—C18—H18119.3
C9—C8—H8119.4C17—C18—H18119.3
C7—C8—H8119.4C16—C19—H19A109.5
C8—C9—C1119.9 (2)C16—C19—H19B109.5
C8—C9—H9120.0H19A—C19—H19B109.5
C1—C9—H9120.0C16—C19—H19C109.5
C7—C10—H10A109.5H19A—C19—H19C109.5
C7—C10—H10B109.5H19B—C19—H19C109.5
H10A—C10—H10B109.5
C5—N1—C1—C2−5.5 (3)C7—C8—C9—C10.3 (3)
C5—N1—C1—C9174.32 (18)C2—C1—C9—C8−0.8 (3)
C9—C1—C2—C60.3 (3)N1—C1—C9—C8179.35 (18)
N1—C1—C2—C6−179.82 (17)C12—O1—C11—O2−177.5 (2)
C9—C1—C2—C3179.55 (17)C12—O1—C11—C41.7 (2)
N1—C1—C2—C3−0.6 (3)C5—C4—C11—O2174.9 (2)
C1—C2—C3—C47.1 (2)C3—C4—C11—O2−3.7 (4)
C6—C2—C3—C4−173.67 (17)C5—C4—C11—O1−4.1 (2)
C1—C2—C3—C13−116.4 (2)C3—C4—C11—O1177.31 (18)
C6—C2—C3—C1362.8 (2)C11—O1—C12—C51.1 (2)
C2—C3—C4—C5−8.9 (3)N1—C5—C12—O1175.80 (19)
C13—C3—C4—C5115.9 (2)C4—C5—C12—O1−3.7 (2)
C2—C3—C4—C11169.54 (19)C4—C3—C13—C1893.7 (2)
C13—C3—C4—C11−65.7 (3)C2—C3—C13—C18−144.25 (18)
C1—N1—C5—C44.0 (3)C4—C3—C13—C14−84.7 (2)
C1—N1—C5—C12−175.41 (19)C2—C3—C13—C1437.3 (2)
C11—C4—C5—N1−174.73 (19)C18—C13—C14—C15−0.4 (3)
C3—C4—C5—N14.0 (3)C3—C13—C14—C15178.10 (19)
C11—C4—C5—C124.8 (2)C13—C14—C15—C16−0.5 (3)
C3—C4—C5—C12−176.55 (18)C14—C15—C16—C171.0 (3)
C1—C2—C6—C70.7 (3)C14—C15—C16—C19−179.2 (2)
C3—C2—C6—C7−178.55 (18)C15—C16—C17—C18−0.7 (3)
C2—C6—C7—C8−1.2 (3)C19—C16—C17—C18179.6 (2)
C2—C6—C7—C10177.29 (19)C14—C13—C18—C170.7 (3)
C6—C7—C8—C90.7 (3)C3—C13—C18—C17−177.80 (18)
C10—C7—C8—C9−177.79 (19)C16—C17—C18—C13−0.2 (3)

Hydrogen-bond geometry (Å, °)

D—H···AD—HH···AD···AD—H···A
N1—H1···O2i0.872.112.862 (2)144
C19—H19A···Cg1ii0.972.693.645 (3)167

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

Footnotes

Supplementary data and figures for this paper are available from the IUCr electronic archives (Reference: CI2738).

References

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