(8aRS)-8,8a-Dihydro­furo[3,2-f]indolizine-6,9(4H,7H)-dione

Abstract

The title compound, C₁₀H₉NO₃, is a chiral mol­ecule with one stereogenic carbon atom, but which crystallizes as a racemate in the centrosymmetric space group P2₁/n. The central six-membered ring of the indolizine moiety adopts a definite envelope conformation, while the conformation of the oxopyrrolidine ring is close to that of a flat-envelope with a maximum deviation of 0.352 (1) Å for the flap atom.

Related literature

For properties of indolizine derivatives, see: Malonne et al. (1998 ▶); Medda et al. (2003 ▶); Sonnet et al. (2000 ▶); Campagna et al. (1990 ▶); Pearson & Guo (2001 ▶); Gupta et al. (2003 ▶); Teklu et al. (2005 ▶). For their role as synthetic targets for pharmaceuticals, see: Gubin et al. (1992 ▶); Ruprecht et al. (1989 ▶). For the synthesis of the title compound, see: Szemes et al. (1998 ▶). For metric comparison with related compounds, see: Pedersen (1967 ▶).

Experimental

Crystal data

• C₁₀H₉NO₃

• M _r = 191.18

• Monoclinic,

• a = 7.63534 (19) Å

• b = 11.7583 (2) Å

• c = 9.9234 (3) Å

• β = 105.775 (3)°

• V = 857.35 (4) ų

• Z = 4

• Mo Kα radiation

• μ = 0.11 mm⁻¹

• T = 298 K

• 0.49 × 0.23 × 0.13 mm

Data collection

• Oxford Diffraction Gemini R CCD diffractometer

• Absorption correction: analytical (Clark & Reid, 1995 ▶) T _min = 0.952, T _max = 0.992

• 14552 measured reflections

• 2213 independent reflections

• 1646 reflections with I > 2σ(I)

• R _int = 0.018

Refinement

• R[F ² > 2σ(F ²)] = 0.040

• wR(F ²) = 0.120

• S = 1.03

• 2213 reflections

• 127 parameters

• H-atom parameters constrained

• Δρ_max = 0.20 e Å⁻³

• Δρ_min = −0.16 e Å⁻³

Data collection: CrysAlis CCD (Oxford Diffraction, 2006 ▶); cell refinement: CrysAlis RED (Oxford Diffraction, 2006 ▶); data reduction: CrysAlis RED; 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: enCIFer (Allen et al., 2004 ▶).

Supplementary Material

Supplementary material file. DOI: 10.1107/S1600536811027383/bg2407Isup3.cml

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

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), aromatase inhibitory (Sonnet et al., 2000), analgestic (Campagna et al., 1990) and antitumor (Pearson & Guo, 2001) activities. They have also shown to be calcium entry blockers (Gupta et al., 2003) and potent antioxidants inhibiting lipid peroxidation in vitro (Teklu et al., 2005). 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, (I). The molecular structure and the atom labeling scheme are shown in Fig. 1.

The molecule crystallizes in the monoclinic space group P21/n. Accordingly, the compound is a racemate and consists of two enantiomeric pairs in the unit cell with relative configuration R and S on the C5 carbon atom. The central N-heterocyclic ring is not planar and adopts an envelope conformation for both enantiomers. A calculation of least-squares planes shows that this ring is puckered in such a manner that the five atoms C5, C6, C7, C10 and C11 are coplanar, while atom N1 is displaced from this plane with an out-of-plane displacement of 0.479 (2) Å.

The oxopyrrolidine ring attached to the indolizine ring system has a flat-envelope conformation, with atom C4 on the flap. The maximum deviation from planarity for C4 is 0.352 (1) Å. Obviously, the change of stereochemical centre on C5 from R to S causes changes in orientation of N1, C2, O1, C3 and C4.

The N1—C5 and N1—C11 bonds are approximately equivalent and both are much longer than the N1—C2 bond. Moreover, the N1 atom is sp² hybridized, as evidenced by the sum of the valence angles around it [358.8 (3)° ]. These data are consistent with conjugation of the lone-pair electrons on N1 with the adjacent carbonyl and agree with literature values for simple amides (Pedersen, 1967).

Experimental

The title compound rac-(8a)-8,8a-dihydrofuro[3,2-f]indolizine-6,9 (4H,7H)-dione was prepared according to a standard protocol described in literature (Szemes et al., 1998).

Refinement

All H atoms were placed in geometrically idealized positions and constrained to ride on their parent atoms, with C—H distances in the range 0.93 - 0.98Å and O—H distance 0.85Å and U_iso set at 1.2U_eq of the parent atom.

Figures

Fig. 1.

Molecular structure of (I) with the atomic numbering scheme; the chiral centre is C5. Displacement ellipsoids are drawn at the 50% probability level (Brandenburg, 2001).

Fig. 2.

Packing diagram.

Crystal data

C10H9NO3	F(000) = 400
Mr = 191.18	Dx = 1.481 Mg m−3
Monoclinic, P21/n	Mo Kα radiation, λ = 0.71073 Å
Hall symbol: -P 2yn	Cell parameters from 7934 reflections
a = 7.63534 (19) Å	θ = 3.5–29.3°
b = 11.7583 (2) Å	µ = 0.11 mm−1
c = 9.9234 (3) Å	T = 298 K
β = 105.775 (3)°	Block, yellow
V = 857.35 (4) Å3	0.49 × 0.23 × 0.13 mm
Z = 4

Data collection

Oxford Diffraction Gemini R CCD diffractometer	2213 independent reflections
Radiation source: fine-focus sealed tube	1646 reflections with I > 2σ(I)
graphite	Rint = 0.018
Detector resolution: 10.4340 pixels mm-1	θmax = 29.4°, θmin = 3.5°
Rotation method data acquisition using ω and φ scans	h = −10→10
Absorption correction: analytical (Clark & Reid, 1995)	k = −15→14
Tmin = 0.952, Tmax = 0.992	l = −13→13
14552 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)] = 0.040	Hydrogen site location: inferred from neighbouring sites
wR(F2) = 0.120	H-atom parameters constrained
S = 1.03	w = 1/[σ2(Fo2) + (0.063P)2 + 0.130P] where P = (Fo2 + 2Fc2)/3
2213 reflections	(Δ/σ)max < 0.001
127 parameters	Δρmax = 0.20 e Å−3
0 restraints	Δρmin = −0.16 e Å−3

Special details

Experimental. face-indexed (Oxford Diffraction, 2006)

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
C2	1.15109 (18)	0.99636 (12)	0.67889 (14)	0.0438 (3)
C3	1.3182 (2)	1.01426 (13)	0.62848 (17)	0.0543 (4)
H3B	1.4237	1.0285	0.7068	0.065*
H3A	1.3015	1.0783	0.5647	0.065*
C4	1.3418 (2)	0.90534 (14)	0.55443 (18)	0.0584 (4)
H4B	1.4692	0.8843	0.5756	0.070*
H4A	1.2938	0.9134	0.4538	0.070*
C5	1.23351 (17)	0.81624 (11)	0.61138 (14)	0.0439 (3)
H5A	1.3159	0.7767	0.6906	0.053*
C6	1.13528 (19)	0.72915 (11)	0.50495 (14)	0.0456 (3)
C7	0.96776 (18)	0.69128 (11)	0.53212 (13)	0.0429 (3)
C8	0.7398 (2)	0.58131 (13)	0.53142 (16)	0.0539 (4)
H8A	0.6557	0.5223	0.5095	0.065*
C9	0.74188 (18)	0.66085 (12)	0.62999 (14)	0.0475 (3)
H9A	0.6623	0.6671	0.6858	0.057*
C10	0.89106 (17)	0.73291 (11)	0.63038 (13)	0.0408 (3)
C11	0.96560 (19)	0.83359 (13)	0.71747 (14)	0.0483 (3)
H11B	0.8692	0.8880	0.7146	0.058*
H11A	1.0172	0.8106	0.8140	0.058*
N1	1.10563 (14)	0.88532 (10)	0.66294 (11)	0.0425 (3)
O1	1.07083 (16)	1.06761 (9)	0.72905 (13)	0.0636 (3)
O2	1.19841 (17)	0.69185 (9)	0.41368 (12)	0.0654 (3)
O3	0.87461 (14)	0.59746 (9)	0.46802 (10)	0.0535 (3)

Atomic displacement parameters (Ų)

	U11	U22	U33	U12	U13	U23
C2	0.0435 (6)	0.0436 (7)	0.0472 (7)	0.0004 (5)	0.0176 (5)	0.0013 (5)
C3	0.0515 (8)	0.0506 (8)	0.0679 (9)	−0.0066 (6)	0.0282 (7)	0.0042 (7)
C4	0.0544 (8)	0.0586 (9)	0.0760 (10)	−0.0066 (7)	0.0412 (8)	−0.0008 (7)
C5	0.0412 (6)	0.0457 (7)	0.0519 (7)	0.0039 (5)	0.0249 (6)	0.0033 (6)
C6	0.0541 (7)	0.0405 (7)	0.0511 (7)	0.0077 (6)	0.0294 (6)	0.0049 (5)
C7	0.0476 (7)	0.0408 (7)	0.0437 (7)	0.0003 (5)	0.0180 (6)	−0.0004 (5)
C8	0.0480 (8)	0.0501 (8)	0.0624 (9)	−0.0075 (6)	0.0131 (7)	0.0025 (7)
C9	0.0428 (7)	0.0526 (8)	0.0495 (7)	−0.0036 (6)	0.0169 (6)	0.0068 (6)
C10	0.0419 (6)	0.0441 (7)	0.0392 (6)	−0.0003 (5)	0.0161 (5)	0.0044 (5)
C11	0.0504 (7)	0.0550 (8)	0.0492 (7)	−0.0092 (6)	0.0301 (6)	−0.0073 (6)
N1	0.0428 (6)	0.0440 (6)	0.0487 (6)	−0.0026 (5)	0.0263 (5)	−0.0035 (5)
O1	0.0681 (7)	0.0486 (6)	0.0852 (8)	0.0021 (5)	0.0396 (6)	−0.0122 (5)
O2	0.0849 (8)	0.0569 (6)	0.0742 (7)	0.0039 (6)	0.0552 (7)	−0.0080 (5)
O3	0.0584 (6)	0.0480 (6)	0.0559 (6)	−0.0029 (4)	0.0188 (5)	−0.0085 (4)

Geometric parameters (Å, °)

C2—O1	1.2211 (16)	C6—C7	1.4472 (18)
C2—N1	1.3492 (18)	C7—C10	1.3578 (17)
C2—C3	1.5062 (18)	C7—O3	1.3717 (16)
C3—C4	1.512 (2)	C8—C9	1.350 (2)
C3—H3B	0.9700	C8—O3	1.3579 (18)
C3—H3A	0.9700	C8—H8A	0.9300
C4—C5	1.5345 (19)	C9—C10	1.4188 (18)
C4—H4B	0.9700	C9—H9A	0.9300
C4—H4A	0.9700	C10—C11	1.4848 (19)
C5—N1	1.4651 (15)	C11—N1	1.4562 (15)
C5—C6	1.515 (2)	C11—H11B	0.9700
C5—H5A	0.9800	C11—H11A	0.9700
C6—O2	1.2176 (16)
O1—C2—N1	124.75 (12)	C7—C6—C5	111.91 (10)
O1—C2—C3	127.14 (13)	C10—C7—O3	110.64 (11)
N1—C2—C3	108.08 (11)	C10—C7—C6	126.76 (13)
C2—C3—C4	105.48 (12)	O3—C7—C6	122.29 (11)
C2—C3—H3B	110.6	C9—C8—O3	112.18 (12)
C4—C3—H3B	110.6	C9—C8—H8A	123.9
C2—C3—H3A	110.6	O3—C8—H8A	123.9
C4—C3—H3A	110.6	C8—C9—C10	105.49 (12)
H3B—C3—H3A	108.8	C8—C9—H9A	127.3
C3—C4—C5	104.60 (11)	C10—C9—H9A	127.3
C3—C4—H4B	110.8	C7—C10—C9	106.58 (12)
C5—C4—H4B	110.8	C7—C10—C11	122.24 (11)
C3—C4—H4A	110.8	C9—C10—C11	131.16 (11)
C5—C4—H4A	110.8	N1—C11—C10	108.71 (10)
H4B—C4—H4A	108.9	N1—C11—H11B	109.9
N1—C5—C6	111.56 (10)	C10—C11—H11B	109.9
N1—C5—C4	103.12 (11)	N1—C11—H11A	109.9
C6—C5—C4	114.77 (12)	C10—C11—H11A	109.9
N1—C5—H5A	109.1	H11B—C11—H11A	108.3
C6—C5—H5A	109.1	C2—N1—C11	123.51 (10)
C4—C5—H5A	109.1	C2—N1—C5	113.76 (10)
O2—C6—C7	125.20 (14)	C11—N1—C5	121.64 (11)
O2—C6—C5	122.74 (13)	C8—O3—C7	105.10 (10)
O1—C2—C3—C4	−170.54 (15)	C8—C9—C10—C7	−0.07 (15)
N1—C2—C3—C4	11.15 (17)	C8—C9—C10—C11	−178.40 (15)
C2—C3—C4—C5	−20.30 (17)	C7—C10—C11—N1	9.17 (19)
C3—C4—C5—N1	21.70 (16)	C9—C10—C11—N1	−172.72 (13)
C3—C4—C5—C6	143.24 (13)	O1—C2—N1—C11	−6.8 (2)
N1—C5—C6—O2	152.99 (13)	C3—C2—N1—C11	171.60 (12)
C4—C5—C6—O2	36.17 (19)	O1—C2—N1—C5	−174.95 (14)
N1—C5—C6—C7	−31.17 (16)	C3—C2—N1—C5	3.41 (16)
C4—C5—C6—C7	−147.98 (12)	C10—C11—N1—C2	153.77 (12)
O2—C6—C7—C10	−178.15 (14)	C10—C11—N1—C5	−38.95 (17)
C5—C6—C7—C10	6.1 (2)	C6—C5—N1—C2	−139.84 (12)
O2—C6—C7—O3	9.0 (2)	C4—C5—N1—C2	−16.15 (16)
C5—C6—C7—O3	−166.75 (11)	C6—C5—N1—C11	51.73 (16)
O3—C8—C9—C10	−0.56 (16)	C4—C5—N1—C11	175.42 (12)
O3—C7—C10—C9	0.67 (15)	C9—C8—O3—C7	0.96 (16)
C6—C7—C10—C9	−172.91 (13)	C10—C7—O3—C8	−0.99 (15)
O3—C7—C10—C11	179.19 (12)	C6—C7—O3—C8	172.92 (13)
C6—C7—C10—C11	5.6 (2)