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

Shi, C.; Ji, M.

doi:10.1107/S1600536808041457

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

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.

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Supporting information

	Crystallographic Information File (CIF) https://doi.org/10.1107/S1600536808041457/ci2738sup1.cif Contains datablocks global, I
	Structure factor file (CIF format) https://doi.org/10.1107/S1600536808041457/ci2738Isup2.hkl Contains datablock I

CCDC reference: 717307

checkCIF report

Key indicators

Single-crystal X-ray study
T = 223 K
Mean (C-C) = 0.003 Å
R factor = 0.059
wR factor = 0.135
Data-to-parameter ratio = 13.2

checkCIF/PLATON results

No syntax errors found



Alert level C
ABSTM02_ALERT_3_C  The ratio of expected to reported Tmax/Tmin(RR') is < 0.90
            Tmin and Tmax reported:      0.756     0.962
            Tmin(prime) and Tmax expected:      0.949     0.962
            RR(prime) =      0.797
            Please check that your absorption correction is appropriate.
            Value of measurement temperature given =   223.000
            Value of melting point given =     0.000
PLAT411_ALERT_2_C Short Inter H...H Contact  H18    ..  H18     ..       2.14 Ang.
PLAT432_ALERT_2_C Short Inter X...Y Contact  O2     ..  C12     ..       2.98 Ang.
PLAT061_ALERT_4_C Tmax/Tmin Range Test RR' too Large .............       0.80

Alert level G
PLAT793_ALERT_4_G The Model has Chirality at C3      (Verify) ....          R

   0 ALERT level A = In general: serious problem
   0 ALERT level B = Potentially serious problem
   4 ALERT level C = Check and explain
   1 ALERT level G = General alerts; check

   0 ALERT type 1 CIF construction/syntax error, inconsistent or missing data
   2 ALERT type 2 Indicator that the structure model may be wrong or deficient
   1 ALERT type 3 Indicator that the structure quality may be low
   2 ALERT type 4 Improvement, methodology, query or suggestion
   0 ALERT type 5 Informative message, check

Comment top

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.

Related literature top

For the biological activities of podophyllotoxin and its derivatives, see: Bosmans et al. (1989); Eycken et al. (1989); Hitosuyanagi et al. (1997, 1999); Lienard et al. (1991); Magedov et al. (2007); Poli & Giambastiani (2002); Tomioka et al. (1989, 1993); Tratrat et al. (2002). Cg1 is centroid of the C13–C18 ring.

Experimental top

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).

Computing details top

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

Figures top

	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.

(I) top

Crystal data top

C₁₉H₁₇NO₂	F(000) = 616
M_r = 291.34	D_x = 1.317 Mg m⁻³
Monoclinic, P2₁/c	Mo Kα radiation, λ = 0.71070 Å
Hall symbol: -P 2ybc	Cell parameters from 4940 reflections
a = 9.178 (2) Å	θ = 3.3–25.3°
b = 11.457 (2) Å	µ = 0.09 mm⁻¹
c = 14.350 (4) Å	T = 223 K
β = 103.124 (5)°	Block, colourless
V = 1469.5 (6) Å³	0.60 × 0.48 × 0.45 mm
Z = 4

Data collection top

Rigaku Mercury diffractometer	2675 independent reflections
Radiation source: fine-focus sealed tube	2364 reflections with I > 2σ(I)
Graphite monochromator	R_int = 0.034
Detector resolution: 7.31 pixels mm^-1	θ_max = 25.3°, θ_min = 3.3°
ω scans	h = −11→11
Absorption correction: multi-scan (Jacobson, 1998)	k = −13→12
T_min = 0.756, T_max = 0.962	l = −17→17
13947 measured reflections

Refinement top

Refinement on F²	Primary atom site location: structure-invariant direct methods
Least-squares matrix: full	Secondary atom site location: difference Fourier map
R[F² > 2σ(F²)] = 0.059	Hydrogen site location: inferred from neighbouring sites
wR(F²) = 0.135	H-atom parameters constrained
S = 1.16	w = 1/[σ²(F_o²) + (0.0497P)² + 0.6176P] where P = (F_o² + 2F_c²)/3
2675 reflections	(Δ/σ)_max = 0.001
202 parameters	Δρ_max = 0.23 e Å⁻³
0 restraints	Δρ_min = −0.21 e Å⁻³

Crystal data top

C₁₉H₁₇NO₂	V = 1469.5 (6) Å³
M_r = 291.34	Z = 4
Monoclinic, P2₁/c	Mo Kα radiation
a = 9.178 (2) Å	µ = 0.09 mm⁻¹
b = 11.457 (2) Å	T = 223 K
c = 14.350 (4) Å	0.60 × 0.48 × 0.45 mm
β = 103.124 (5)°

Data collection top

Rigaku Mercury diffractometer	2675 independent reflections
Absorption correction: multi-scan (Jacobson, 1998)	2364 reflections with I > 2σ(I)
T_min = 0.756, T_max = 0.962	R_int = 0.034
13947 measured reflections

Refinement top

R[F² > 2σ(F²)] = 0.059	0 restraints
wR(F²) = 0.135	H-atom parameters constrained
S = 1.16	Δρ_max = 0.23 e Å⁻³
2675 reflections	Δρ_min = −0.21 e Å⁻³
202 parameters

Special details top

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) top

	x	y	z	U_iso*/U_eq
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)
N1	0.14394 (19)	0.50270 (15)	0.68136 (12)	0.0396 (4)
H1	0.1588	0.5617	0.7205	0.048*
C1	0.1948 (2)	0.50585 (16)	0.59568 (14)	0.0343 (5)
C2	0.1821 (2)	0.40751 (17)	0.53741 (13)	0.0329 (5)
C3	0.1160 (2)	0.29193 (17)	0.56127 (14)	0.0342 (5)
H3	0.0327	0.2709	0.5069	0.041*
C4	0.0523 (2)	0.31008 (18)	0.64815 (14)	0.0366 (5)
C5	0.0727 (2)	0.40748 (18)	0.70132 (14)	0.0374 (5)
C6	0.2347 (2)	0.41594 (18)	0.45381 (14)	0.0382 (5)
H6	0.2259	0.3505	0.4134	0.046*
C7	0.2994 (2)	0.51643 (18)	0.42757 (15)	0.0400 (5)
C8	0.3088 (2)	0.61316 (18)	0.48745 (16)	0.0424 (5)
H8	0.3511	0.6827	0.4710	0.051*
C9	0.2572 (2)	0.60876 (18)	0.57031 (16)	0.0401 (5)
H9	0.2641	0.6750	0.6097	0.048*
C10	0.3607 (3)	0.5198 (2)	0.33889 (16)	0.0513 (6)
H10A	0.4686	0.5113	0.3565	0.077*
H10B	0.3352	0.5938	0.3064	0.077*
H10C	0.3178	0.4565	0.2966	0.077*
C11	−0.0401 (2)	0.2330 (2)	0.68790 (16)	0.0440 (5)
C12	0.0028 (3)	0.3941 (2)	0.78519 (16)	0.0479 (6)
H12A	0.0788	0.3961	0.8455	0.058*
H12B	−0.0709	0.4557	0.7860	0.058*
C13	0.2291 (2)	0.19179 (16)	0.57700 (13)	0.0319 (4)
C14	0.3781 (2)	0.20786 (18)	0.62247 (15)	0.0409 (5)
H14	0.4124	0.2829	0.6429	0.049*
C15	0.4770 (2)	0.11455 (19)	0.63815 (16)	0.0437 (5)
H15	0.5776	0.1279	0.6687	0.052*
C16	0.4311 (2)	0.00218 (17)	0.60993 (14)	0.0383 (5)
C17	0.2828 (2)	−0.01293 (18)	0.56396 (15)	0.0425 (5)
H17	0.2484	−0.0879	0.5433	0.051*
C18	0.1838 (2)	0.07991 (17)	0.54770 (15)	0.0394 (5)
H18	0.0837	0.0667	0.5161	0.047*
C19	0.5382 (3)	−0.0990 (2)	0.62813 (17)	0.0511 (6)
H19A	0.5792	−0.1118	0.5723	0.077*
H19B	0.4856	−0.1686	0.6408	0.077*
H19C	0.6187	−0.0820	0.6830	0.077*

Atomic displacement parameters (Å²) top

	U¹¹	U²²	U³³	U¹²	U¹³	U²³
O1	0.0578 (10)	0.0565 (10)	0.0538 (10)	−0.0026 (8)	0.0326 (8)	0.0054 (8)
O2	0.0594 (10)	0.0468 (10)	0.0643 (11)	−0.0111 (8)	0.0259 (9)	0.0068 (8)
N1	0.0428 (10)	0.0394 (10)	0.0397 (10)	−0.0028 (8)	0.0160 (8)	−0.0071 (8)
C1	0.0297 (10)	0.0376 (11)	0.0370 (11)	0.0023 (8)	0.0104 (9)	0.0015 (9)
C2	0.0303 (10)	0.0354 (11)	0.0337 (10)	0.0012 (8)	0.0085 (8)	0.0035 (8)
C3	0.0328 (10)	0.0368 (11)	0.0343 (10)	−0.0020 (8)	0.0104 (8)	−0.0007 (8)
C4	0.0340 (10)	0.0408 (11)	0.0366 (11)	0.0017 (9)	0.0116 (9)	0.0047 (9)
C5	0.0313 (10)	0.0456 (12)	0.0370 (11)	0.0033 (9)	0.0111 (9)	0.0021 (9)
C6	0.0396 (11)	0.0398 (11)	0.0369 (11)	0.0026 (9)	0.0123 (9)	0.0015 (9)
C7	0.0359 (11)	0.0454 (12)	0.0400 (11)	0.0018 (9)	0.0114 (9)	0.0112 (9)
C8	0.0407 (12)	0.0365 (11)	0.0512 (13)	−0.0021 (9)	0.0129 (10)	0.0089 (10)
C9	0.0385 (11)	0.0340 (11)	0.0481 (12)	0.0002 (8)	0.0103 (10)	−0.0023 (9)
C10	0.0523 (14)	0.0589 (15)	0.0469 (13)	0.0007 (11)	0.0198 (11)	0.0130 (11)
C11	0.0407 (12)	0.0475 (13)	0.0478 (13)	0.0029 (10)	0.0184 (10)	0.0087 (10)
C12	0.0490 (13)	0.0545 (14)	0.0462 (13)	−0.0018 (10)	0.0232 (11)	−0.0011 (11)
C13	0.0363 (10)	0.0334 (10)	0.0283 (9)	−0.0030 (8)	0.0122 (8)	0.0000 (8)
C14	0.0415 (12)	0.0364 (11)	0.0433 (12)	−0.0054 (9)	0.0067 (9)	−0.0045 (9)
C15	0.0369 (11)	0.0479 (13)	0.0449 (12)	−0.0005 (9)	0.0065 (10)	−0.0002 (10)
C16	0.0470 (12)	0.0396 (12)	0.0316 (10)	0.0030 (9)	0.0158 (9)	0.0032 (8)
C17	0.0502 (13)	0.0344 (11)	0.0438 (12)	−0.0068 (9)	0.0123 (10)	−0.0035 (9)
C18	0.0368 (11)	0.0394 (11)	0.0416 (11)	−0.0067 (9)	0.0082 (9)	−0.0005 (9)
C19	0.0589 (14)	0.0472 (13)	0.0496 (13)	0.0105 (11)	0.0172 (11)	0.0042 (11)

Geometric parameters (Å, º) top

O1—C11	1.380 (3)	C8—H8	0.94
O1—C12	1.438 (3)	C9—H9	0.94
O2—C11	1.220 (3)	C10—H10A	0.97
N1—C5	1.336 (3)	C10—H10B	0.97
N1—C1	1.411 (3)	C10—H10C	0.97
N1—H1	0.87	C12—H12A	0.98
C1—C2	1.392 (3)	C12—H12B	0.98
C1—C9	1.395 (3)	C13—C18	1.383 (3)
C2—C6	1.395 (3)	C13—C14	1.387 (3)
C2—C3	1.528 (3)	C14—C15	1.387 (3)
C3—C4	1.506 (3)	C14—H14	0.94
C3—C13	1.529 (3)	C15—C16	1.386 (3)
C3—H3	0.99	C15—H15	0.94
C4—C5	1.341 (3)	C16—C17	1.382 (3)
C4—C11	1.430 (3)	C16—C19	1.504 (3)
C5—C12	1.494 (3)	C17—C18	1.384 (3)
C6—C7	1.386 (3)	C17—H17	0.94
C6—H6	0.94	C18—H18	0.94
C7—C8	1.393 (3)	C19—H19A	0.97
C7—C10	1.504 (3)	C19—H19B	0.97
C8—C9	1.377 (3)	C19—H19C	0.97

C11—O1—C12	108.95 (16)	C7—C10—H10C	109.5
C5—N1—C1	118.85 (17)	H10A—C10—H10C	109.5
C5—N1—H1	120.6	H10B—C10—H10C	109.5
C1—N1—H1	120.6	O2—C11—O1	118.87 (19)
C2—C1—C9	120.68 (18)	O2—C11—C4	131.6 (2)
C2—C1—N1	120.25 (17)	O1—C11—C4	109.52 (19)
C9—C1—N1	119.06 (18)	O1—C12—C5	103.48 (17)
C1—C2—C6	117.57 (18)	O1—C12—H12A	111.1
C1—C2—C3	123.37 (17)	C5—C12—H12A	111.1
C6—C2—C3	119.06 (17)	O1—C12—H12B	111.1
C4—C3—C2	108.32 (16)	C5—C12—H12B	111.1
C4—C3—C13	111.04 (16)	H12A—C12—H12B	109.0
C2—C3—C13	113.10 (15)	C18—C13—C14	117.52 (18)
C4—C3—H3	108.1	C18—C13—C3	120.23 (17)
C2—C3—H3	108.1	C14—C13—C3	122.24 (17)
C13—C3—H3	108.1	C13—C14—C15	120.86 (19)
C5—C4—C11	107.79 (19)	C13—C14—H14	119.6
C5—C4—C3	123.77 (18)	C15—C14—H14	119.6
C11—C4—C3	128.43 (19)	C16—C15—C14	121.6 (2)
N1—C5—C4	124.70 (19)	C16—C15—H15	119.2
N1—C5—C12	125.25 (19)	C14—C15—H15	119.2
C4—C5—C12	110.05 (19)	C17—C16—C15	117.18 (19)
C7—C6—C2	122.99 (19)	C17—C16—C19	121.35 (19)
C7—C6—H6	118.5	C15—C16—C19	121.5 (2)
C2—C6—H6	118.5	C16—C17—C18	121.46 (19)
C6—C7—C8	117.62 (19)	C16—C17—H17	119.3
C6—C7—C10	121.1 (2)	C18—C17—H17	119.3
C8—C7—C10	121.2 (2)	C13—C18—C17	121.37 (19)
C9—C8—C7	121.21 (19)	C13—C18—H18	119.3
C9—C8—H8	119.4	C17—C18—H18	119.3
C7—C8—H8	119.4	C16—C19—H19A	109.5
C8—C9—C1	119.9 (2)	C16—C19—H19B	109.5
C8—C9—H9	120.0	H19A—C19—H19B	109.5
C1—C9—H9	120.0	C16—C19—H19C	109.5
C7—C10—H10A	109.5	H19A—C19—H19C	109.5
C7—C10—H10B	109.5	H19B—C19—H19C	109.5
H10A—C10—H10B	109.5

C5—N1—C1—C2	−5.5 (3)	C7—C8—C9—C1	0.3 (3)
C5—N1—C1—C9	174.32 (18)	C2—C1—C9—C8	−0.8 (3)
C9—C1—C2—C6	0.3 (3)	N1—C1—C9—C8	179.35 (18)
N1—C1—C2—C6	−179.82 (17)	C12—O1—C11—O2	−177.5 (2)
C9—C1—C2—C3	179.55 (17)	C12—O1—C11—C4	1.7 (2)
N1—C1—C2—C3	−0.6 (3)	C5—C4—C11—O2	174.9 (2)
C1—C2—C3—C4	7.1 (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—O1	177.31 (18)
C6—C2—C3—C13	62.8 (2)	C11—O1—C12—C5	1.1 (2)
C2—C3—C4—C5	−8.9 (3)	N1—C5—C12—O1	175.80 (19)
C13—C3—C4—C5	115.9 (2)	C4—C5—C12—O1	−3.7 (2)
C2—C3—C4—C11	169.54 (19)	C4—C3—C13—C18	93.7 (2)
C13—C3—C4—C11	−65.7 (3)	C2—C3—C13—C18	−144.25 (18)
C1—N1—C5—C4	4.0 (3)	C4—C3—C13—C14	−84.7 (2)
C1—N1—C5—C12	−175.41 (19)	C2—C3—C13—C14	37.3 (2)
C11—C4—C5—N1	−174.73 (19)	C18—C13—C14—C15	−0.4 (3)
C3—C4—C5—N1	4.0 (3)	C3—C13—C14—C15	178.10 (19)
C11—C4—C5—C12	4.8 (2)	C13—C14—C15—C16	−0.5 (3)
C3—C4—C5—C12	−176.55 (18)	C14—C15—C16—C17	1.0 (3)
C1—C2—C6—C7	0.7 (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—C18	179.6 (2)
C2—C6—C7—C10	177.29 (19)	C14—C13—C18—C17	0.7 (3)
C6—C7—C8—C9	0.7 (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, º) top

D—H···A	D—H	H···A	D···A	D—H···A
N1—H1···O2ⁱ	0.87	2.11	2.862 (2)	144
C19—H19A···Cg1ⁱⁱ	0.97	2.69	3.645 (3)	167

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

Experimental details

Crystal data
Chemical formula	C₁₉H₁₇NO₂
M_r	291.34
Crystal system, space group	Monoclinic, P2₁/c
Temperature (K)	223
a, b, c (Å)	9.178 (2), 11.457 (2), 14.350 (4)
β (°)	103.124 (5)
V (Å³)	1469.5 (6)
Z	4
Radiation type	Mo Kα
µ (mm⁻¹)	0.09
Crystal size (mm)	0.60 × 0.48 × 0.45

Data collection
Diffractometer	Rigaku Mercury diffractometer
Absorption correction	Multi-scan (Jacobson, 1998)
T_min, T_max	0.756, 0.962
No. of measured, independent and observed [I > 2σ(I)] reflections	13947, 2675, 2364
R_int	0.034
(sin θ/λ)_max (Å⁻¹)	0.602

Refinement
R[F² > 2σ(F²)], wR(F²), S	0.059, 0.135, 1.16
No. of reflections	2675
No. of parameters	202
H-atom treatment	H-atom parameters constrained
Δρ_max, Δρ_min (e Å⁻³)	0.23, −0.21

Computer programs: CrystalClear (Rigaku, 2000), CrystalStructure (Rigaku/MSC, 2003), SHELXS97 (Sheldrick, 2008), SHELXL97 (Sheldrick, 2008), SHELXTL (Sheldrick, 2008).