Supporting information
Crystallographic Information File (CIF) https://doi.org/10.1107/S1600536807017072/ci2358sup1.cif | |
Structure factor file (CIF format) https://doi.org/10.1107/S1600536807017072/ci2358Isup2.hkl |
CCDC reference: 647573
Key indicators
- Single-crystal X-ray study
- T = 298 K
- Mean (C-C) = 0.003 Å
- R factor = 0.031
- wR factor = 0.087
- Data-to-parameter ratio = 8.6
checkCIF/PLATON results
No syntax errors found
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
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).
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.
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 C10═O2 and C3═O3 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).
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.
Fig. 1. The molecular structure of (I), with the atomic numbering scheme. Displacement ellipsoids are drawn at the 50% probability level. |
C13H13NO3 | F(000) = 488 |
Mr = 231.24 | Dx = 1.377 Mg m−3 |
Orthorhombic, P212121 | Mo Kα radiation, λ = 0.71073 Å |
Hall symbol: P 2ac 2ab | Cell parameters from 13309 reflections |
a = 6.1806 (1) Å | θ = 4.2–26.3° |
b = 9.2755 (2) Å | µ = 0.10 mm−1 |
c = 19.4579 (4) Å | T = 298 K |
V = 1115.49 (4) Å3 | Block, colourless |
Z = 4 | 0.5 × 0.3 × 0.2 mm |
Oxford Gemini R CCD area-detector diffractometer | 1340 independent reflections |
Radiation source: fine-focus sealed tube | 1188 reflections with I > 2σ(I) |
Graphite monochromator | Rint = 0.017 |
Detector resolution: 10.4340 pixels mm-1 | θmax = 26.4°, θmin = 4.1° |
ω and φ scans | h = −7→7 |
Absorption correction: analytical (Clark & Reid, 1995) | k = −9→11 |
Tmin = 0.948, Tmax = 0.978 | l = −24→24 |
20403 measured reflections |
Refinement on F2 | Secondary atom site location: difference Fourier map |
Least-squares matrix: full | Hydrogen site location: inferred from neighbouring sites |
R[F2 > 2σ(F2)] = 0.031 | H-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 reflections | Δρmax = 0.12 e Å−3 |
156 parameters | Δρmin = −0.11 e Å−3 |
0 restraints | Extinction correction: SHELXL97 (Sheldrick, 1997), Fc*=kFc[1+0.001xFc2λ3/sin(2θ)]-1/4 |
Primary atom site location: structure-invariant direct methods | Extinction coefficient: 0.021 (3) |
C13H13NO3 | V = 1115.49 (4) Å3 |
Mr = 231.24 | Z = 4 |
Orthorhombic, P212121 | Mo Kα radiation |
a = 6.1806 (1) Å | µ = 0.10 mm−1 |
b = 9.2755 (2) Å | T = 298 K |
c = 19.4579 (4) Å | 0.5 × 0.3 × 0.2 mm |
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 = 0.978 | Rint = 0.017 |
20403 measured reflections |
R[F2 > 2σ(F2)] = 0.031 | 0 restraints |
wR(F2) = 0.087 | H-atom parameters constrained |
S = 1.05 | Δρmax = 0.12 e Å−3 |
1340 reflections | Δρmin = −0.11 e Å−3 |
156 parameters |
x | y | z | Uiso*/Ueq | ||
C1 | 0.1338 (3) | 0.9055 (2) | 0.86422 (11) | 0.0599 (6) | |
H1A | 0.1529 | 0.9140 | 0.8149 | 0.072* | |
H1B | −0.0130 | 0.9332 | 0.8760 | 0.072* | |
C2 | 0.2964 (4) | 0.9972 (2) | 0.90225 (12) | 0.0600 (5) | |
H2A | 0.3516 | 1.0731 | 0.8727 | 0.072* | |
H2B | 0.2308 | 1.0409 | 0.9425 | 0.072* | |
C3 | 0.4738 (3) | 0.8963 (2) | 0.92269 (10) | 0.0501 (5) | |
C5 | 0.5222 (3) | 0.6327 (2) | 0.93118 (10) | 0.0517 (5) | |
H5A | 0.4716 | 0.5969 | 0.9752 | 0.062* | |
H5B | 0.6746 | 0.6558 | 0.9357 | 0.062* | |
C6 | 0.6387 (3) | 0.4031 (2) | 0.87544 (10) | 0.0520 (5) | |
C7 | 0.6177 (4) | 0.2969 (2) | 0.82579 (11) | 0.0647 (6) | |
H7 | 0.7170 | 0.2217 | 0.8237 | 0.078* | |
C8 | 0.4488 (5) | 0.3033 (3) | 0.77955 (11) | 0.0700 (7) | |
H8 | 0.4342 | 0.2313 | 0.7466 | 0.084* | |
C9 | 0.3036 (4) | 0.4131 (2) | 0.78132 (10) | 0.0631 (6) | |
H9 | 0.1907 | 0.4159 | 0.7498 | 0.076* | |
C10 | 0.1595 (3) | 0.6372 (2) | 0.83345 (10) | 0.0547 (5) | |
C11 | 0.4937 (3) | 0.5179 (2) | 0.87746 (9) | 0.0450 (4) | |
C12 | 0.3240 (3) | 0.5219 (2) | 0.83063 (9) | 0.0486 (4) | |
C13 | 0.1826 (3) | 0.7511 (2) | 0.88860 (10) | 0.0492 (5) | |
H13 | 0.0872 | 0.7272 | 0.9272 | 0.059* | |
C14 | 0.9445 (4) | 0.2899 (3) | 0.92832 (15) | 0.0789 (7) | |
H14A | 1.0217 | 0.2821 | 0.8857 | 0.118* | |
H14B | 0.8668 | 0.2021 | 0.9368 | 0.118* | |
H14C | 1.0451 | 0.3067 | 0.9650 | 0.118* | |
N4 | 0.4035 (3) | 0.76077 (17) | 0.91305 (8) | 0.0475 (4) | |
O1 | 0.7955 (3) | 0.40722 (15) | 0.92447 (8) | 0.0673 (4) | |
O2 | 0.0057 (3) | 0.6414 (2) | 0.79442 (9) | 0.0842 (6) | |
O3 | 0.6514 (2) | 0.92868 (17) | 0.94671 (9) | 0.0706 (5) |
U11 | U22 | U33 | U12 | U13 | U23 | |
C1 | 0.0507 (11) | 0.0656 (13) | 0.0635 (11) | 0.0183 (11) | −0.0045 (10) | 0.0036 (10) |
C2 | 0.0583 (12) | 0.0506 (10) | 0.0710 (12) | 0.0064 (10) | 0.0026 (11) | 0.0103 (10) |
C3 | 0.0451 (10) | 0.0492 (10) | 0.0561 (10) | 0.0004 (9) | 0.0030 (9) | −0.0012 (8) |
C5 | 0.0499 (11) | 0.0500 (10) | 0.0553 (10) | 0.0111 (9) | −0.0132 (9) | −0.0048 (8) |
C6 | 0.0557 (11) | 0.0477 (10) | 0.0527 (9) | 0.0046 (10) | 0.0047 (9) | 0.0021 (8) |
C7 | 0.0797 (15) | 0.0491 (11) | 0.0653 (12) | 0.0053 (12) | 0.0153 (13) | −0.0075 (10) |
C8 | 0.0928 (18) | 0.0597 (13) | 0.0574 (11) | −0.0107 (14) | 0.0065 (13) | −0.0164 (10) |
C9 | 0.0737 (14) | 0.0660 (13) | 0.0496 (10) | −0.0143 (13) | −0.0063 (11) | −0.0057 (10) |
C10 | 0.0480 (10) | 0.0632 (11) | 0.0528 (10) | −0.0051 (10) | −0.0089 (9) | 0.0056 (9) |
C11 | 0.0480 (10) | 0.0425 (9) | 0.0444 (8) | −0.0029 (9) | 0.0014 (8) | 0.0014 (7) |
C12 | 0.0524 (10) | 0.0485 (9) | 0.0450 (9) | −0.0079 (9) | −0.0022 (9) | 0.0034 (8) |
C13 | 0.0364 (9) | 0.0594 (11) | 0.0517 (10) | 0.0041 (9) | −0.0029 (8) | 0.0031 (9) |
C14 | 0.0712 (15) | 0.0642 (14) | 0.1013 (17) | 0.0284 (13) | 0.0037 (15) | 0.0095 (13) |
N4 | 0.0400 (8) | 0.0454 (8) | 0.0571 (8) | 0.0054 (7) | −0.0098 (7) | −0.0033 (7) |
O1 | 0.0679 (9) | 0.0569 (8) | 0.0769 (9) | 0.0250 (8) | −0.0132 (8) | −0.0062 (8) |
O2 | 0.0711 (11) | 0.0890 (12) | 0.0924 (11) | 0.0036 (10) | −0.0415 (10) | −0.0081 (10) |
O3 | 0.0513 (8) | 0.0622 (9) | 0.0984 (12) | −0.0056 (8) | −0.0119 (8) | −0.0093 (9) |
C1—C2 | 1.510 (3) | C7—C8 | 1.379 (3) |
C1—C13 | 1.539 (3) | C7—H7 | 0.93 |
C1—H1A | 0.97 | C8—C9 | 1.358 (3) |
C1—H1B | 0.97 | C8—H8 | 0.93 |
C2—C3 | 1.496 (3) | C9—C12 | 1.398 (3) |
C2—H2A | 0.97 | C9—H9 | 0.93 |
C2—H2B | 0.97 | C10—O2 | 1.217 (2) |
C3—O3 | 1.230 (2) | C10—C12 | 1.477 (3) |
C3—N4 | 1.344 (3) | C10—C13 | 1.512 (3) |
C5—N4 | 1.441 (2) | C11—C12 | 1.390 (3) |
C5—C11 | 1.502 (2) | C13—N4 | 1.449 (3) |
C5—H5A | 0.97 | C13—H13 | 0.98 |
C5—H5B | 0.97 | C14—O1 | 1.427 (3) |
C6—O1 | 1.361 (2) | C14—H14A | 0.96 |
C6—C7 | 1.386 (3) | C14—H14B | 0.96 |
C6—C11 | 1.393 (3) | C14—H14C | 0.96 |
C2—C1—C13 | 104.08 (16) | C7—C8—H8 | 119.5 |
C2—C1—H1A | 110.9 | C8—C9—C12 | 119.9 (2) |
C13—C1—H1A | 110.9 | C8—C9—H9 | 120.0 |
C2—C1—H1B | 110.9 | C12—C9—H9 | 120.0 |
C13—C1—H1B | 110.9 | O2—C10—C12 | 122.5 (2) |
H1A—C1—H1B | 109.0 | O2—C10—C13 | 119.6 (2) |
C3—C2—C1 | 105.39 (17) | C12—C10—C13 | 117.86 (16) |
C3—C2—H2A | 110.7 | C12—C11—C6 | 119.16 (17) |
C1—C2—H2A | 110.7 | C12—C11—C5 | 121.76 (16) |
C3—C2—H2B | 110.7 | C6—C11—C5 | 119.07 (16) |
C1—C2—H2B | 110.7 | C11—C12—C9 | 119.9 (2) |
H2A—C2—H2B | 108.8 | C11—C12—C10 | 120.94 (16) |
O3—C3—N4 | 124.73 (19) | C9—C12—C10 | 119.10 (19) |
O3—C3—C2 | 127.1 (2) | N4—C13—C10 | 111.43 (16) |
N4—C3—C2 | 108.15 (17) | N4—C13—C1 | 103.18 (17) |
N4—C5—C11 | 110.74 (14) | C10—C13—C1 | 114.39 (16) |
N4—C5—H5A | 109.5 | N4—C13—H13 | 109.2 |
C11—C5—H5A | 109.5 | C10—C13—H13 | 109.2 |
N4—C5—H5B | 109.5 | C1—C13—H13 | 109.2 |
C11—C5—H5B | 109.5 | O1—C14—H14A | 109.5 |
H5A—C5—H5B | 108.1 | O1—C14—H14B | 109.5 |
O1—C6—C7 | 125.15 (19) | H14A—C14—H14B | 109.5 |
O1—C6—C11 | 114.64 (16) | O1—C14—H14C | 109.5 |
C7—C6—C11 | 120.2 (2) | H14A—C14—H14C | 109.5 |
C8—C7—C6 | 119.7 (2) | H14B—C14—H14C | 109.5 |
C8—C7—H7 | 120.2 | C3—N4—C5 | 124.97 (16) |
C6—C7—H7 | 120.2 | C3—N4—C13 | 114.13 (16) |
C9—C8—C7 | 121.1 (2) | C5—N4—C13 | 120.61 (16) |
C9—C8—H8 | 119.5 | C6—O1—C14 | 118.34 (18) |
C13—C1—C2—C3 | 21.1 (2) | O2—C10—C12—C9 | 0.1 (3) |
C1—C2—C3—O3 | 169.8 (2) | C13—C10—C12—C9 | 178.36 (18) |
C1—C2—C3—N4 | −12.8 (2) | O2—C10—C13—N4 | −159.6 (2) |
O1—C6—C7—C8 | 178.8 (2) | C12—C10—C13—N4 | 22.1 (2) |
C11—C6—C7—C8 | −1.8 (3) | O2—C10—C13—C1 | −43.0 (3) |
C6—C7—C8—C9 | 0.8 (3) | C12—C10—C13—C1 | 138.68 (18) |
C7—C8—C9—C12 | 0.0 (3) | C2—C1—C13—N4 | −21.6 (2) |
O1—C6—C11—C12 | −178.38 (17) | C2—C1—C13—C10 | −142.78 (17) |
C7—C6—C11—C12 | 2.2 (3) | O3—C3—N4—C5 | 1.9 (3) |
O1—C6—C11—C5 | 0.4 (3) | C2—C3—N4—C5 | −175.59 (18) |
C7—C6—C11—C5 | −179.08 (19) | O3—C3—N4—C13 | 175.80 (19) |
N4—C5—C11—C12 | −18.7 (3) | C2—C3—N4—C13 | −1.7 (2) |
N4—C5—C11—C6 | 162.57 (16) | C11—C5—N4—C3 | −140.97 (19) |
C6—C11—C12—C9 | −1.5 (3) | C11—C5—N4—C13 | 45.5 (2) |
C5—C11—C12—C9 | 179.83 (19) | C10—C13—N4—C3 | 138.26 (18) |
C6—C11—C12—C10 | 176.51 (17) | C1—C13—N4—C3 | 15.1 (2) |
C5—C11—C12—C10 | −2.2 (3) | C10—C13—N4—C5 | −47.6 (2) |
C8—C9—C12—C11 | 0.4 (3) | C1—C13—N4—C5 | −170.79 (17) |
C8—C9—C12—C10 | −177.60 (19) | C7—C6—O1—C14 | −3.7 (3) |
O2—C10—C12—C11 | −177.9 (2) | C11—C6—O1—C14 | 176.89 (18) |
C13—C10—C12—C11 | 0.4 (3) |
Experimental details
Crystal data | |
Chemical formula | C13H13NO3 |
Mr | 231.24 |
Crystal system, space group | Orthorhombic, P212121 |
Temperature (K) | 298 |
a, b, c (Å) | 6.1806 (1), 9.2755 (2), 19.4579 (4) |
V (Å3) | 1115.49 (4) |
Z | 4 |
Radiation type | Mo Kα |
µ (mm−1) | 0.10 |
Crystal size (mm) | 0.5 × 0.3 × 0.2 |
Data collection | |
Diffractometer | Oxford Gemini R CCD area-detector |
Absorption correction | Analytical (Clark & Reid, 1995) |
Tmin, Tmax | 0.948, 0.978 |
No. of measured, independent and observed [I > 2σ(I)] reflections | 20403, 1340, 1188 |
Rint | 0.017 |
(sin θ/λ)max (Å−1) | 0.625 |
Refinement | |
R[F2 > 2σ(F2)], wR(F2), S | 0.031, 0.087, 1.05 |
No. of reflections | 1340 |
No. of parameters | 156 |
H-atom treatment | H-atom parameters constrained |
Δρmax, Δρmin (e Å−3) | 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.
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 C10═O2 and C3═O3 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).