Ethyl 9-fluoro-5,12-dioxo-5,12-dihydro­indolizino[2,3-g]quinoline-6-carboxyl­ate

Abstract

In the title mol­ecule, C₁₈H₁₁FN₂O₄, the fused four- ring system is essentially planar, with an r.m.s. deviation of 0.032 Å. In the crystal, mol­ecules are connected by π–π stacking inter­actions [centroid–centroid distances = 3.5684 (9) and 3.8247 (9) Å] into chains along [100].

Related literature  

The title compound was obtained in an attempt to synthesize a Top1 (DNA topoisomerase IB) inhibitor. For general background to Top1, see: Pommier (2006 ▶). For the synthesis, see: Shen et al. (2008 ▶); Cheng et al. (2008 ▶). For a related structure, see: Wu et al. (2011 ▶). For the Top1 inhibitory activity of a related indolizinoquinoline-5,12-dione derivative, see: Wu et al. (2010 ▶).

Experimental  

Crystal data  

• C₁₈H₁₁FN₂O₄

• M _r = 338.29

• Monoclinic,

• a = 6.85562 (10) Å

• b = 12.12898 (16) Å

• c = 17.0304 (2) Å

• β = 94.2306 (13)°

• V = 1412.25 (3) ų

• Z = 4

• Cu Kα radiation

• μ = 1.04 mm⁻¹

• T = 136 K

• 0.30 × 0.20 × 0.20 mm

Data collection  

• Agilent Xcalibur Onyx Nova diffractometer

• Absorption correction: multi-scan (CrysAlis PRO; Agilent, 2011 ▶) T _min = 0.550, T _max = 1.000

• 5740 measured reflections

• 2723 independent reflections

• 2278 reflections with I > 2σ(I)

• R _int = 0.025

Refinement  

• R[F ² > 2σ(F ²)] = 0.037

• wR(F ²) = 0.101

• S = 1.08

• 2723 reflections

• 270 parameters

• All H-atom parameters refined

• Δρ_max = 0.30 e Å⁻³

• Δρ_min = −0.24 e Å⁻³

Data collection: CrysAlis PRO (Agilent, 2011 ▶); cell refinement: CrysAlis PRO; data reduction: CrysAlis RED (Agilent, 2011 ▶); program(s) used to solve structure: SHELXS97 (Sheldrick, 2008 ▶); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008 ▶); molecular graphics: OLEX2 (Dolomanov et al., 2009 ▶); software used to prepare material for publication: publCIF (Westrip, 2010 ▶).

Supplementary Material

Supplementary material file. DOI: 10.1107/S160053681202692X/lh5489Isup3.cml

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

supplementary crystallographic information

Comment

Top1 is an essential nuclear enzyme, and can be used as a target to discover anticancer agents (Pommier, 2006). In our previous research, we found ethyl 7-fluoro-5,12-dioxo-5,12-dihydroindolizino[2,3-g] quinoline-6-carboxylate is a strong Top1 inhibitor with a different inhibitory mechanism from camptothecin, a well known Top1 inhibitor (Wu et al. 2010). In order to investigate the Top1 inhibitory activity of the 9-fluoro substituted isomer, the title compound was synthesized according to a modified literature method (Shen et al. 2008; Cheng et al. 2008; Wu et al. 2011) and its crystal structure was determined.

The asymmetric unit of the title compound is shown in figure 1. In the molecule the four fused aromatic rings system is approximately planar with an r.m.s. deviation = 0.032 Å. In the crystal, molecules are connected by π–π stacking interactions to form chains along [100]. Cg1···Cg1ⁱ = 3.5684 (9)Å and Cg1···Cg4ⁱⁱ = 3.8247 (9) Å, where Cg1 and Cg2 are the centroids of the N2/C8/C7/C6/C13 and C4/C5/C6/C13/C14/C15 rings [symmetry codes: (i) -x, 1-y, 1-z, (ii) 1-x, 1-y, 1-z].

Experimental

According to a modified literature method (Shen et al., 2008; Cheng et al., 2008; Wu et al., 2011), 12 equivalents of 3-fluoropyridine reacted with 6,7-dichloroquinoline-5,8-dione and ethyl acetoacetate to give the title compound as orange solid. Needle-shaped crystals suitable for X-ray analysis were obtained by slow evaporation of a solution of the title compound in chloroform-ethyl acetate (20/1, v/v).

Refinement

All H atoms were refined indpendently with isotropic displacement parameters.

Figures

Fig. 1.

The molecular structure of the title compound. The displacement ellipsoids are at the 30% probability level and H atoms are shown as small spheres of arbitrary radii.

Crystal data

C18H11FN2O4	F(000) = 696
Mr = 338.29	Dx = 1.591 Mg m−3
Monoclinic, P21/c	Cu Kα radiation, λ = 1.5418 Å
Hall symbol: -P 2ybc	Cell parameters from 3543 reflections
a = 6.85562 (10) Å	θ = 2.6–72.7°
b = 12.12898 (16) Å	µ = 1.04 mm−1
c = 17.0304 (2) Å	T = 136 K
β = 94.2306 (13)°	Needle, orange
V = 1412.25 (3) Å3	0.30 × 0.20 × 0.20 mm
Z = 4

Data collection

Agilent Xcalibur Onyx Nova diffractometer	2723 independent reflections
Radiation source: Nova (Cu) X-ray Source	2278 reflections with I > 2σ(I)
Mirror monochromator	Rint = 0.025
Detector resolution: 8.2417 pixels mm-1	θmax = 72.9°, θmin = 5.2°
ω scans	h = −8→8
Absorption correction: multi-scan (CrysAlis PRO; Agilent, 2011)	k = −14→10
Tmin = 0.550, Tmax = 1.000	l = −20→20
5740 measured reflections

Refinement

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)] = 0.037	Hydrogen site location: inferred from neighbouring sites
wR(F2) = 0.101	All H-atom parameters refined
S = 1.08	w = 1/[σ2(Fo2) + (0.0396P)2 + 0.8533P] where P = (Fo2 + 2Fc2)/3
2723 reflections	(Δ/σ)max = 0.001
270 parameters	Δρmax = 0.30 e Å−3
0 restraints	Δρmin = −0.24 e Å−3

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 (Ų)

	x	y	z	Uiso*/Ueq
F1	0.02823 (18)	0.90196 (9)	0.34624 (7)	0.0382 (3)
O2	0.28727 (18)	0.79052 (10)	0.60332 (7)	0.0266 (3)
O3	0.1029 (2)	0.36760 (11)	0.33751 (7)	0.0301 (3)
O1	0.3911 (2)	0.34756 (10)	0.58977 (7)	0.0307 (3)
N1	0.4460 (2)	0.68373 (12)	0.73454 (9)	0.0241 (3)
O4	0.2439 (2)	0.28907 (10)	0.44611 (8)	0.0291 (3)
C4	0.4124 (2)	0.51043 (14)	0.66509 (10)	0.0199 (4)
N2	0.1785 (2)	0.66666 (11)	0.45980 (8)	0.0195 (3)
C13	0.2564 (2)	0.62440 (14)	0.53105 (10)	0.0192 (4)
C6	0.2735 (2)	0.51065 (14)	0.52314 (10)	0.0193 (4)
C16	0.1782 (2)	0.37539 (14)	0.40402 (10)	0.0204 (4)
C14	0.3084 (2)	0.68974 (14)	0.60029 (10)	0.0199 (4)
C7	0.2028 (2)	0.48181 (14)	0.44537 (10)	0.0199 (4)
C5	0.3582 (2)	0.44629 (14)	0.59152 (10)	0.0202 (4)
C15	0.3912 (2)	0.62469 (14)	0.66995 (10)	0.0206 (4)
C12	0.1396 (3)	0.77509 (15)	0.44053 (11)	0.0238 (4)
C1	0.5239 (3)	0.62799 (15)	0.79713 (11)	0.0270 (4)
C10	0.0304 (3)	0.71363 (16)	0.30895 (11)	0.0286 (4)
C3	0.4925 (2)	0.45453 (15)	0.73164 (10)	0.0223 (4)
C18	0.2975 (3)	0.09848 (17)	0.46821 (13)	0.0328 (5)
C8	0.1448 (2)	0.58082 (14)	0.40663 (10)	0.0204 (4)
C2	0.5502 (3)	0.51463 (15)	0.79815 (11)	0.0253 (4)
C9	0.0689 (2)	0.60677 (15)	0.32938 (11)	0.0231 (4)
C17	0.2236 (3)	0.18208 (15)	0.40799 (12)	0.0265 (4)
C11	0.0667 (3)	0.79580 (15)	0.36591 (11)	0.0266 (4)
H1	0.568 (3)	0.6713 (18)	0.8436 (12)	0.028 (5)*
H17A	0.302 (3)	0.1835 (16)	0.3619 (12)	0.023 (5)*
H2	0.607 (3)	0.4777 (17)	0.8449 (12)	0.026 (5)*
H9	0.043 (3)	0.5454 (19)	0.2945 (13)	0.033 (6)*
H3	0.513 (3)	0.3732 (18)	0.7311 (12)	0.031 (5)*
H12	0.167 (3)	0.8305 (18)	0.4819 (13)	0.032 (6)*
H10	−0.018 (3)	0.7362 (18)	0.2575 (13)	0.034 (6)*
H17B	0.079 (3)	0.1699 (18)	0.3898 (12)	0.033 (6)*
H18A	0.439 (4)	0.117 (2)	0.4875 (15)	0.052 (7)*
H18B	0.217 (4)	0.099 (2)	0.5139 (15)	0.045 (7)*
H18C	0.291 (3)	0.022 (2)	0.4457 (13)	0.039 (6)*

Atomic displacement parameters (Ų)

	U11	U22	U33	U12	U13	U23
F1	0.0529 (7)	0.0221 (6)	0.0372 (7)	0.0044 (5)	−0.0126 (5)	0.0072 (5)
O2	0.0321 (7)	0.0185 (6)	0.0281 (7)	0.0017 (5)	−0.0049 (5)	−0.0011 (5)
O3	0.0403 (7)	0.0246 (7)	0.0237 (7)	−0.0013 (6)	−0.0091 (6)	−0.0024 (5)
O1	0.0468 (8)	0.0173 (7)	0.0265 (7)	0.0026 (6)	−0.0071 (6)	0.0008 (5)
N1	0.0267 (8)	0.0217 (8)	0.0235 (8)	0.0003 (6)	−0.0008 (6)	−0.0025 (6)
O4	0.0408 (8)	0.0168 (6)	0.0278 (7)	0.0042 (6)	−0.0096 (6)	−0.0034 (5)
C4	0.0181 (8)	0.0186 (8)	0.0229 (9)	−0.0005 (6)	0.0003 (6)	−0.0009 (7)
N2	0.0178 (7)	0.0175 (7)	0.0229 (7)	0.0000 (5)	−0.0005 (5)	0.0003 (6)
C13	0.0175 (8)	0.0178 (8)	0.0218 (9)	0.0005 (6)	−0.0015 (6)	0.0025 (6)
C6	0.0169 (8)	0.0202 (8)	0.0208 (8)	0.0004 (6)	0.0009 (6)	−0.0008 (7)
C16	0.0165 (8)	0.0220 (9)	0.0227 (9)	−0.0015 (6)	0.0012 (6)	−0.0008 (7)
C14	0.0183 (8)	0.0160 (8)	0.0252 (9)	−0.0001 (6)	0.0010 (7)	−0.0008 (7)
C7	0.0173 (8)	0.0196 (8)	0.0223 (8)	−0.0005 (6)	−0.0016 (6)	−0.0004 (7)
C5	0.0201 (8)	0.0179 (9)	0.0225 (9)	−0.0007 (7)	0.0012 (7)	0.0019 (7)
C15	0.0212 (8)	0.0181 (8)	0.0219 (9)	−0.0023 (7)	−0.0010 (7)	−0.0002 (7)
C12	0.0235 (9)	0.0192 (9)	0.0284 (9)	0.0015 (7)	−0.0011 (7)	0.0025 (7)
C1	0.0330 (10)	0.0241 (9)	0.0231 (9)	−0.0005 (8)	−0.0046 (8)	−0.0025 (7)
C10	0.0277 (9)	0.0320 (10)	0.0251 (9)	0.0004 (8)	−0.0049 (7)	0.0037 (8)
C3	0.0230 (8)	0.0194 (9)	0.0243 (9)	−0.0006 (7)	0.0003 (7)	0.0020 (7)
C18	0.0386 (11)	0.0218 (10)	0.0375 (12)	0.0030 (8)	−0.0018 (9)	0.0016 (8)
C8	0.0174 (8)	0.0199 (9)	0.0237 (9)	−0.0011 (6)	−0.0001 (7)	−0.0002 (7)
C2	0.0297 (9)	0.0226 (9)	0.0229 (9)	0.0005 (7)	−0.0027 (7)	0.0028 (7)
C9	0.0219 (8)	0.0235 (9)	0.0234 (9)	−0.0002 (7)	−0.0023 (7)	0.0005 (7)
C17	0.0309 (10)	0.0186 (9)	0.0293 (10)	0.0002 (7)	−0.0023 (8)	−0.0053 (7)
C11	0.0286 (9)	0.0183 (9)	0.0320 (10)	0.0021 (7)	−0.0029 (8)	0.0069 (7)

Geometric parameters (Å, º)

F1—C11	1.352 (2)	C7—C8	1.413 (2)
O2—C14	1.232 (2)	C12—C11	1.354 (3)
O3—C16	1.213 (2)	C12—H12	0.98 (2)
O1—C5	1.219 (2)	C1—C2	1.387 (3)
N1—C15	1.343 (2)	C1—H1	0.98 (2)
N1—C1	1.339 (2)	C10—C9	1.363 (3)
O4—C16	1.329 (2)	C10—C11	1.400 (3)
O4—C17	1.453 (2)	C10—H10	0.95 (2)
C4—C5	1.498 (2)	C3—C2	1.380 (3)
C4—C15	1.397 (2)	C3—H3	1.00 (2)
C4—C3	1.398 (2)	C18—C17	1.503 (3)
N2—C13	1.387 (2)	C18—H18A	1.02 (3)
N2—C12	1.377 (2)	C18—H18B	0.99 (3)
N2—C8	1.388 (2)	C18—H18C	1.00 (2)
C13—C6	1.392 (2)	C8—C9	1.414 (2)
C13—C14	1.443 (2)	C2—H2	0.97 (2)
C6—C7	1.420 (2)	C9—H9	0.96 (2)
C6—C5	1.484 (2)	C17—H17A	0.98 (2)
C16—C7	1.474 (2)	C17—H17B	1.02 (2)
C14—C15	1.501 (2)
C1—N1—C15	116.99 (15)	N1—C1—H1	117.0 (12)
C16—O4—C17	116.44 (13)	C2—C1—H1	119.3 (12)
C15—C4—C5	122.98 (15)	C9—C10—C11	118.60 (17)
C15—C4—C3	118.01 (16)	C9—C10—H10	123.7 (14)
C3—C4—C5	118.99 (15)	C11—C10—H10	117.7 (13)
C13—N2—C8	109.17 (14)	C4—C3—H3	121.3 (12)
C12—N2—C13	128.08 (15)	C2—C3—C4	118.75 (16)
C12—N2—C8	122.75 (15)	C2—C3—H3	119.9 (12)
N2—C13—C6	108.13 (14)	C17—C18—H18A	109.7 (15)
N2—C13—C14	124.58 (15)	C17—C18—H18B	110.7 (14)
C6—C13—C14	127.29 (15)	C17—C18—H18C	111.0 (13)
C13—C6—C7	108.00 (15)	H18A—C18—H18B	109 (2)
C13—C6—C5	118.44 (15)	H18A—C18—H18C	109.6 (19)
C7—C6—C5	133.55 (16)	H18B—C18—H18C	107.2 (19)
O3—C16—O4	123.11 (16)	N2—C8—C7	107.77 (14)
O3—C16—C7	122.68 (16)	N2—C8—C9	118.18 (15)
O4—C16—C7	114.21 (14)	C7—C8—C9	134.04 (16)
O2—C14—C13	123.79 (16)	C1—C2—H2	120.8 (12)
O2—C14—C15	121.81 (15)	C3—C2—C1	118.96 (17)
C13—C14—C15	114.40 (14)	C3—C2—H2	120.2 (12)
C6—C7—C16	132.87 (15)	C10—C9—C8	120.02 (17)
C8—C7—C6	106.93 (14)	C10—C9—H9	123.8 (13)
C8—C7—C16	120.18 (15)	C8—C9—H9	116.1 (13)
O1—C5—C4	119.70 (15)	O4—C17—C18	106.34 (15)
O1—C5—C6	124.04 (16)	O4—C17—H17A	107.5 (12)
C6—C5—C4	116.21 (14)	O4—C17—H17B	108.8 (12)
N1—C15—C4	123.62 (16)	C18—C17—H17A	112.4 (11)
N1—C15—C14	115.71 (15)	C18—C17—H17B	112.2 (12)
C4—C15—C14	120.65 (15)	H17A—C17—H17B	109.3 (16)
N2—C12—H12	117.3 (13)	F1—C11—C12	117.46 (17)
C11—C12—N2	116.90 (17)	F1—C11—C10	118.99 (16)
C11—C12—H12	125.8 (13)	C12—C11—C10	123.55 (17)
N1—C1—C2	123.66 (17)
O2—C14—C15—N1	−2.0 (2)	C14—C13—C6—C5	−1.6 (3)
O2—C14—C15—C4	179.59 (17)	C7—C6—C5—O1	3.6 (3)
O3—C16—C7—C6	175.43 (17)	C7—C6—C5—C4	−179.07 (17)
O3—C16—C7—C8	−2.5 (3)	C7—C8—C9—C10	−178.48 (19)
N1—C1—C2—C3	−0.5 (3)	C5—C4—C15—N1	−177.38 (16)
O4—C16—C7—C6	−4.0 (3)	C5—C4—C15—C14	0.9 (3)
O4—C16—C7—C8	178.07 (15)	C5—C4—C3—C2	177.18 (16)
C4—C3—C2—C1	1.0 (3)	C5—C6—C7—C16	3.4 (3)
N2—C13—C6—C7	−0.53 (19)	C5—C6—C7—C8	−178.46 (17)
N2—C13—C6—C5	178.65 (14)	C15—N1—C1—C2	0.2 (3)
N2—C13—C14—O2	0.6 (3)	C15—C4—C5—O1	175.68 (17)
N2—C13—C14—C15	−179.64 (15)	C15—C4—C5—C6	−1.8 (2)
N2—C12—C11—F1	−179.88 (16)	C15—C4—C3—C2	−1.3 (2)
N2—C12—C11—C10	0.0 (3)	C12—N2—C13—C6	−178.91 (16)
N2—C8—C9—C10	−0.2 (3)	C12—N2—C13—C14	1.3 (3)
C13—N2—C12—C11	178.63 (17)	C12—N2—C8—C7	179.30 (15)
C13—N2—C8—C7	0.03 (18)	C12—N2—C8—C9	0.6 (2)
C13—N2—C8—C9	−178.66 (15)	C1—N1—C15—C4	−0.4 (3)
C13—C6—C7—C16	−177.61 (17)	C1—N1—C15—C14	−178.78 (16)
C13—C6—C7—C8	0.54 (19)	C3—C4—C5—O1	−2.7 (2)
C13—C6—C5—O1	−175.32 (17)	C3—C4—C5—C6	179.87 (15)
C13—C6—C5—C4	2.0 (2)	C3—C4—C15—N1	1.0 (3)
C13—C14—C15—N1	178.18 (15)	C3—C4—C15—C14	179.27 (15)
C13—C14—C15—C4	−0.2 (2)	C8—N2—C13—C6	0.31 (19)
C6—C13—C14—O2	−179.20 (17)	C8—N2—C13—C14	−179.48 (16)
C6—C13—C14—C15	0.6 (3)	C8—N2—C12—C11	−0.5 (3)
C6—C7—C8—N2	−0.35 (18)	C9—C10—C11—F1	−179.75 (17)
C6—C7—C8—C9	178.04 (18)	C9—C10—C11—C12	0.4 (3)
C16—O4—C17—C18	−177.06 (16)	C17—O4—C16—O3	0.8 (3)
C16—C7—C8—N2	178.08 (15)	C17—O4—C16—C7	−179.83 (15)
C16—C7—C8—C9	−3.5 (3)	C11—C10—C9—C8	−0.2 (3)
C14—C13—C6—C7	179.26 (16)