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In the title compound, C13H13NO3, the central six-membered ring of the indolizine system adopts a sofa conformation. The conformation of the oxopyrrolidine ring is envelope. The crystal structure is stabilized by van der Waals forces.

Supporting information

cif

Crystallographic Information File (CIF) https://doi.org/10.1107/S1600536807017072/ci2358sup1.cif
Contains datablocks I, global

hkl

Structure factor file (CIF format) https://doi.org/10.1107/S1600536807017072/ci2358Isup2.hkl
Contains datablock I

CCDC reference: 647573

Key indicators

  • Single-crystal X-ray study
  • T = 298 K
  • Mean [sigma](C-C) = 0.003 Å
  • R factor = 0.031
  • wR factor = 0.087
  • Data-to-parameter ratio = 8.6

checkCIF/PLATON results

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Alert level G REFLT03_ALERT_4_G Please check that the estimate of the number of Friedel pairs is correct. If it is not, please give the correct count in the _publ_section_exptl_refinement section of the submitted CIF. From the CIF: _diffrn_reflns_theta_max 26.37 From the CIF: _reflns_number_total 1340 Count of symmetry unique reflns 1347 Completeness (_total/calc) 99.48% TEST3: Check Friedels for noncentro structure Estimate of Friedel pairs measured 0 Fraction of Friedel pairs measured 0.000 Are heavy atom types Z>Si present no PLAT791_ALERT_1_G Confirm the Absolute Configuration of C13 = . S
0 ALERT level A = In general: serious problem 0 ALERT level B = Potentially serious problem 0 ALERT level C = Check and explain 2 ALERT level G = General alerts; check 1 ALERT type 1 CIF construction/syntax error, inconsistent or missing data 0 ALERT type 2 Indicator that the structure model may be wrong or deficient 0 ALERT type 3 Indicator that the structure quality may be low 1 ALERT type 4 Improvement, methodology, query or suggestion 0 ALERT type 5 Informative message, check

Comment top

Isoquinolizine derivatives continue to attract the attention of organic and medicinal chemists because of their potential application as pharmaceutical drugs for the treatment of diabetes (Kubo et al., 2000). Benzoquinolizine derivatives are interesting as selective non-steroidal inhibitors of steroid 5α-reductase-1 (Guarna et al., 2001). Selective inhibition of 5αR-1 is currently investigated as a potential therapeutic tool for the treatment of dihydrotestosterone-related skin disorders, such as acne, alopecia, male baldness and hirsutism (Harris & Kozarich, 1997). The structural investigation of the title compound, (I), has been undertaken as part of our study of the conformational changes caused by different substituents on the indolizine ring system. The absolute configuration is known from the synthesis and is depicted in the scheme and figure.

The crystal structure of (I) (Fig. 1) is stabilized by van der Waals forces; the shortest intermolecular contacts are 3.395 (3) Å for C1···O3(-1 + x, y, z) and 3.350 (2) Å for C5···O3(-1/2 + x, 3/2 - y, 2 - z). The isoquinoline moiety is not completely planar, the central N-heterocyclic ring being distorted towards a sofa conformation (Nardelli, 1983), with atom N4 displaced by 0.485 (3) Å from the mean plane defined by atoms C11/C5/C13/C10/C12. Atom N4 is sp2-hybridized, as evidenced by the sum of the valence angles around it (359.7°). These data are consistent with conjugation of the lone-pair electrons on N4 with the adjacent carbonyl, similar to what is observed for amides. The oxopyrrolidine ring adopts a flat-envelope conformation, with C1 on

the flap; the deviation of atom C1 from the N4/C13/C2/C3 plane is 0.350 (1) Å.

The bond lengths of the carbonyl groups C10O2 and C3O3 are 1.217 (2) and 1.230 (2) Å, respectively, somewhat longer than typical carbonyl bonds. This may be due to the fact that atoms O2 and O3 participate in intermolecular van der Waals forces. Bond lengths and angles in the indolizine ring system are in good agreement with values from the literature (Camus et al., 2000, 2003; Lokaj et al., 1999).

Related literature top

For related literature, see: Camus et al. (2000, 2003); Guarna et al. (2001); Harris & Kozarich (1997); Kubo et al. (2000); Lokaj et al. (1999); Marchalín et al. (1998); Nardelli (1983).

Experimental top

The title compound was prepared by intramolecular Friedel–Crafts acylation of the chloride of the starting enantiopure 5-oxoproline derivative, which in turn was obtained from (S)-glutamic acid (Marchalín et al., 1998). A stirred solution of (S)-(+)-N-(2-methoxybenzyl)-5-oxoproline (2.5 g, 10 mmol)

in dry dichloromethane (30 ml) was treated rapidly with thionyl chloride (1.3 g, 11 mmol). After being refluxed overnight, the chilled solution was treated in portions over a period of 2 h with high-purity aluminium trichloride

(4.0 g, 31 mmol) with stirring and external cooling (268–273 K). The mixture was stirred with cooling for 1 h and then for 2 h at room temperature. The mixture was chilled with ice–water, and the reaction was quenched by cautious addition of ice chips and then diluted with water. Dichloromethane was added and the mixture was agitated thoroughly until all the solid dissolved. The phases were separated and the aqueous phase was extracted with dichloromethane (50 ml). The combined organic phase was washed with water and saturated brine, dried (MgSO4), filtered and concentrated in vacuo to give a solid residue. Colourless block-shaped single crystals were obtained by recrystallization from ethanol (yield 65%, 1.5 g; m.p. 447–449 K).

Refinement top

H atoms were placed in geometrically idealized positions and constrained to ride on their parent atoms, with C—H = 0.93–0.98 Å and Uiso(H) = 1.2Ueq(C) or 1.5Ueq(methyl C). The absolute configuration could not be reliably determined for this compound using Mo radiation, and has been assigned according to the synthesis. Friedel pairs have been merged.

Structure description top

Isoquinolizine derivatives continue to attract the attention of organic and medicinal chemists because of their potential application as pharmaceutical drugs for the treatment of diabetes (Kubo et al., 2000). Benzoquinolizine derivatives are interesting as selective non-steroidal inhibitors of steroid 5α-reductase-1 (Guarna et al., 2001). Selective inhibition of 5αR-1 is currently investigated as a potential therapeutic tool for the treatment of dihydrotestosterone-related skin disorders, such as acne, alopecia, male baldness and hirsutism (Harris & Kozarich, 1997). The structural investigation of the title compound, (I), has been undertaken as part of our study of the conformational changes caused by different substituents on the indolizine ring system. The absolute configuration is known from the synthesis and is depicted in the scheme and figure.

The crystal structure of (I) (Fig. 1) is stabilized by van der Waals forces; the shortest intermolecular contacts are 3.395 (3) Å for C1···O3(-1 + x, y, z) and 3.350 (2) Å for C5···O3(-1/2 + x, 3/2 - y, 2 - z). The isoquinoline moiety is not completely planar, the central N-heterocyclic ring being distorted towards a sofa conformation (Nardelli, 1983), with atom N4 displaced by 0.485 (3) Å from the mean plane defined by atoms C11/C5/C13/C10/C12. Atom N4 is sp2-hybridized, as evidenced by the sum of the valence angles around it (359.7°). These data are consistent with conjugation of the lone-pair electrons on N4 with the adjacent carbonyl, similar to what is observed for amides. The oxopyrrolidine ring adopts a flat-envelope conformation, with C1 on

the flap; the deviation of atom C1 from the N4/C13/C2/C3 plane is 0.350 (1) Å.

The bond lengths of the carbonyl groups C10O2 and C3O3 are 1.217 (2) and 1.230 (2) Å, respectively, somewhat longer than typical carbonyl bonds. This may be due to the fact that atoms O2 and O3 participate in intermolecular van der Waals forces. Bond lengths and angles in the indolizine ring system are in good agreement with values from the literature (Camus et al., 2000, 2003; Lokaj et al., 1999).

For related literature, see: Camus et al. (2000, 2003); Guarna et al. (2001); Harris & Kozarich (1997); Kubo et al. (2000); Lokaj et al. (1999); Marchalín et al. (1998); Nardelli (1983).

Computing details top

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, 1997); program(s) used to refine structure: SHELXL97 (Sheldrick, 1997); molecular graphics: DIAMOND (Brandenburg, 2002); software used to prepare material for publication: SHELXL97.

Figures top
[Figure 1] Fig. 1. The molecular structure of (I), with the atomic numbering scheme. Displacement ellipsoids are drawn at the 50% probability level.
(10aS)-6-Methoxy-1,10a-dihydropyrrolo[1,2-b]isoquinoline-3,10(2H,5H)-dione top
Crystal data top
C13H13NO3F(000) = 488
Mr = 231.24Dx = 1.377 Mg m3
Orthorhombic, P212121Mo Kα radiation, λ = 0.71073 Å
Hall symbol: P 2ac 2abCell parameters from 13309 reflections
a = 6.1806 (1) Åθ = 4.2–26.3°
b = 9.2755 (2) ŵ = 0.10 mm1
c = 19.4579 (4) ÅT = 298 K
V = 1115.49 (4) Å3Block, colourless
Z = 40.5 × 0.3 × 0.2 mm
Data collection top
Oxford Gemini R CCD area-detector
diffractometer
1340 independent reflections
Radiation source: fine-focus sealed tube1188 reflections with I > 2σ(I)
Graphite monochromatorRint = 0.017
Detector resolution: 10.4340 pixels mm-1θmax = 26.4°, θmin = 4.1°
ω and φ scansh = 77
Absorption correction: analytical
(Clark & Reid, 1995)
k = 911
Tmin = 0.948, Tmax = 0.978l = 2424
20403 measured reflections
Refinement top
Refinement on F2Secondary atom site location: difference Fourier map
Least-squares matrix: fullHydrogen site location: inferred from neighbouring sites
R[F2 > 2σ(F2)] = 0.031H-atom parameters constrained
wR(F2) = 0.087 w = 1/[σ2(Fo2) + (0.0428P)2 + 0.1859P]
where P = (Fo2 + 2Fc2)/3
S = 1.05(Δ/σ)max = 0.001
1340 reflectionsΔρmax = 0.12 e Å3
156 parametersΔρmin = 0.11 e Å3
0 restraintsExtinction correction: SHELXL97 (Sheldrick, 1997), Fc*=kFc[1+0.001xFc2λ3/sin(2θ)]-1/4
Primary atom site location: structure-invariant direct methodsExtinction coefficient: 0.021 (3)
Crystal data top
C13H13NO3V = 1115.49 (4) Å3
Mr = 231.24Z = 4
Orthorhombic, P212121Mo Kα radiation
a = 6.1806 (1) ŵ = 0.10 mm1
b = 9.2755 (2) ÅT = 298 K
c = 19.4579 (4) Å0.5 × 0.3 × 0.2 mm
Data collection top
Oxford Gemini R CCD area-detector
diffractometer
1340 independent reflections
Absorption correction: analytical
(Clark & Reid, 1995)
1188 reflections with I > 2σ(I)
Tmin = 0.948, Tmax = 0.978Rint = 0.017
20403 measured reflections
Refinement top
R[F2 > 2σ(F2)] = 0.0310 restraints
wR(F2) = 0.087H-atom parameters constrained
S = 1.05Δρmax = 0.12 e Å3
1340 reflectionsΔρmin = 0.11 e Å3
156 parameters
Special details top

Experimental. face-indexed (CrysAlis RED; Oxford Diffraction, 2006)

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å2) top
xyzUiso*/Ueq
C10.1338 (3)0.9055 (2)0.86422 (11)0.0599 (6)
H1A0.15290.91400.81490.072*
H1B0.01300.93320.87600.072*
C20.2964 (4)0.9972 (2)0.90225 (12)0.0600 (5)
H2A0.35161.07310.87270.072*
H2B0.23081.04090.94250.072*
C30.4738 (3)0.8963 (2)0.92269 (10)0.0501 (5)
C50.5222 (3)0.6327 (2)0.93118 (10)0.0517 (5)
H5A0.47160.59690.97520.062*
H5B0.67460.65580.93570.062*
C60.6387 (3)0.4031 (2)0.87544 (10)0.0520 (5)
C70.6177 (4)0.2969 (2)0.82579 (11)0.0647 (6)
H70.71700.22170.82370.078*
C80.4488 (5)0.3033 (3)0.77955 (11)0.0700 (7)
H80.43420.23130.74660.084*
C90.3036 (4)0.4131 (2)0.78132 (10)0.0631 (6)
H90.19070.41590.74980.076*
C100.1595 (3)0.6372 (2)0.83345 (10)0.0547 (5)
C110.4937 (3)0.5179 (2)0.87746 (9)0.0450 (4)
C120.3240 (3)0.5219 (2)0.83063 (9)0.0486 (4)
C130.1826 (3)0.7511 (2)0.88860 (10)0.0492 (5)
H130.08720.72720.92720.059*
C140.9445 (4)0.2899 (3)0.92832 (15)0.0789 (7)
H14A1.02170.28210.88570.118*
H14B0.86680.20210.93680.118*
H14C1.04510.30670.96500.118*
N40.4035 (3)0.76077 (17)0.91305 (8)0.0475 (4)
O10.7955 (3)0.40722 (15)0.92447 (8)0.0673 (4)
O20.0057 (3)0.6414 (2)0.79442 (9)0.0842 (6)
O30.6514 (2)0.92868 (17)0.94671 (9)0.0706 (5)
Atomic displacement parameters (Å2) top
U11U22U33U12U13U23
C10.0507 (11)0.0656 (13)0.0635 (11)0.0183 (11)0.0045 (10)0.0036 (10)
C20.0583 (12)0.0506 (10)0.0710 (12)0.0064 (10)0.0026 (11)0.0103 (10)
C30.0451 (10)0.0492 (10)0.0561 (10)0.0004 (9)0.0030 (9)0.0012 (8)
C50.0499 (11)0.0500 (10)0.0553 (10)0.0111 (9)0.0132 (9)0.0048 (8)
C60.0557 (11)0.0477 (10)0.0527 (9)0.0046 (10)0.0047 (9)0.0021 (8)
C70.0797 (15)0.0491 (11)0.0653 (12)0.0053 (12)0.0153 (13)0.0075 (10)
C80.0928 (18)0.0597 (13)0.0574 (11)0.0107 (14)0.0065 (13)0.0164 (10)
C90.0737 (14)0.0660 (13)0.0496 (10)0.0143 (13)0.0063 (11)0.0057 (10)
C100.0480 (10)0.0632 (11)0.0528 (10)0.0051 (10)0.0089 (9)0.0056 (9)
C110.0480 (10)0.0425 (9)0.0444 (8)0.0029 (9)0.0014 (8)0.0014 (7)
C120.0524 (10)0.0485 (9)0.0450 (9)0.0079 (9)0.0022 (9)0.0034 (8)
C130.0364 (9)0.0594 (11)0.0517 (10)0.0041 (9)0.0029 (8)0.0031 (9)
C140.0712 (15)0.0642 (14)0.1013 (17)0.0284 (13)0.0037 (15)0.0095 (13)
N40.0400 (8)0.0454 (8)0.0571 (8)0.0054 (7)0.0098 (7)0.0033 (7)
O10.0679 (9)0.0569 (8)0.0769 (9)0.0250 (8)0.0132 (8)0.0062 (8)
O20.0711 (11)0.0890 (12)0.0924 (11)0.0036 (10)0.0415 (10)0.0081 (10)
O30.0513 (8)0.0622 (9)0.0984 (12)0.0056 (8)0.0119 (8)0.0093 (9)
Geometric parameters (Å, º) top
C1—C21.510 (3)C7—C81.379 (3)
C1—C131.539 (3)C7—H70.93
C1—H1A0.97C8—C91.358 (3)
C1—H1B0.97C8—H80.93
C2—C31.496 (3)C9—C121.398 (3)
C2—H2A0.97C9—H90.93
C2—H2B0.97C10—O21.217 (2)
C3—O31.230 (2)C10—C121.477 (3)
C3—N41.344 (3)C10—C131.512 (3)
C5—N41.441 (2)C11—C121.390 (3)
C5—C111.502 (2)C13—N41.449 (3)
C5—H5A0.97C13—H130.98
C5—H5B0.97C14—O11.427 (3)
C6—O11.361 (2)C14—H14A0.96
C6—C71.386 (3)C14—H14B0.96
C6—C111.393 (3)C14—H14C0.96
C2—C1—C13104.08 (16)C7—C8—H8119.5
C2—C1—H1A110.9C8—C9—C12119.9 (2)
C13—C1—H1A110.9C8—C9—H9120.0
C2—C1—H1B110.9C12—C9—H9120.0
C13—C1—H1B110.9O2—C10—C12122.5 (2)
H1A—C1—H1B109.0O2—C10—C13119.6 (2)
C3—C2—C1105.39 (17)C12—C10—C13117.86 (16)
C3—C2—H2A110.7C12—C11—C6119.16 (17)
C1—C2—H2A110.7C12—C11—C5121.76 (16)
C3—C2—H2B110.7C6—C11—C5119.07 (16)
C1—C2—H2B110.7C11—C12—C9119.9 (2)
H2A—C2—H2B108.8C11—C12—C10120.94 (16)
O3—C3—N4124.73 (19)C9—C12—C10119.10 (19)
O3—C3—C2127.1 (2)N4—C13—C10111.43 (16)
N4—C3—C2108.15 (17)N4—C13—C1103.18 (17)
N4—C5—C11110.74 (14)C10—C13—C1114.39 (16)
N4—C5—H5A109.5N4—C13—H13109.2
C11—C5—H5A109.5C10—C13—H13109.2
N4—C5—H5B109.5C1—C13—H13109.2
C11—C5—H5B109.5O1—C14—H14A109.5
H5A—C5—H5B108.1O1—C14—H14B109.5
O1—C6—C7125.15 (19)H14A—C14—H14B109.5
O1—C6—C11114.64 (16)O1—C14—H14C109.5
C7—C6—C11120.2 (2)H14A—C14—H14C109.5
C8—C7—C6119.7 (2)H14B—C14—H14C109.5
C8—C7—H7120.2C3—N4—C5124.97 (16)
C6—C7—H7120.2C3—N4—C13114.13 (16)
C9—C8—C7121.1 (2)C5—N4—C13120.61 (16)
C9—C8—H8119.5C6—O1—C14118.34 (18)
C13—C1—C2—C321.1 (2)O2—C10—C12—C90.1 (3)
C1—C2—C3—O3169.8 (2)C13—C10—C12—C9178.36 (18)
C1—C2—C3—N412.8 (2)O2—C10—C13—N4159.6 (2)
O1—C6—C7—C8178.8 (2)C12—C10—C13—N422.1 (2)
C11—C6—C7—C81.8 (3)O2—C10—C13—C143.0 (3)
C6—C7—C8—C90.8 (3)C12—C10—C13—C1138.68 (18)
C7—C8—C9—C120.0 (3)C2—C1—C13—N421.6 (2)
O1—C6—C11—C12178.38 (17)C2—C1—C13—C10142.78 (17)
C7—C6—C11—C122.2 (3)O3—C3—N4—C51.9 (3)
O1—C6—C11—C50.4 (3)C2—C3—N4—C5175.59 (18)
C7—C6—C11—C5179.08 (19)O3—C3—N4—C13175.80 (19)
N4—C5—C11—C1218.7 (3)C2—C3—N4—C131.7 (2)
N4—C5—C11—C6162.57 (16)C11—C5—N4—C3140.97 (19)
C6—C11—C12—C91.5 (3)C11—C5—N4—C1345.5 (2)
C5—C11—C12—C9179.83 (19)C10—C13—N4—C3138.26 (18)
C6—C11—C12—C10176.51 (17)C1—C13—N4—C315.1 (2)
C5—C11—C12—C102.2 (3)C10—C13—N4—C547.6 (2)
C8—C9—C12—C110.4 (3)C1—C13—N4—C5170.79 (17)
C8—C9—C12—C10177.60 (19)C7—C6—O1—C143.7 (3)
O2—C10—C12—C11177.9 (2)C11—C6—O1—C14176.89 (18)
C13—C10—C12—C110.4 (3)

Experimental details

Crystal data
Chemical formulaC13H13NO3
Mr231.24
Crystal system, space groupOrthorhombic, P212121
Temperature (K)298
a, b, c (Å)6.1806 (1), 9.2755 (2), 19.4579 (4)
V3)1115.49 (4)
Z4
Radiation typeMo Kα
µ (mm1)0.10
Crystal size (mm)0.5 × 0.3 × 0.2
Data collection
DiffractometerOxford Gemini R CCD area-detector
Absorption correctionAnalytical
(Clark & Reid, 1995)
Tmin, Tmax0.948, 0.978
No. of measured, independent and
observed [I > 2σ(I)] reflections
20403, 1340, 1188
Rint0.017
(sin θ/λ)max1)0.625
Refinement
R[F2 > 2σ(F2)], wR(F2), S 0.031, 0.087, 1.05
No. of reflections1340
No. of parameters156
H-atom treatmentH-atom parameters constrained
Δρmax, Δρmin (e Å3)0.12, 0.11

Computer programs: CrysAlis CCD (Oxford Diffraction, 2006), CrysAlis RED (Oxford Diffraction, 2006), CrysAlis RED, SHELXS97 (Sheldrick, 1997), SHELXL97 (Sheldrick, 1997), DIAMOND (Brandenburg, 2002), SHELXL97.

 

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