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Acta Crystallogr Sect E Struct Rep Online. 2009 February 1; 65(Pt 2): o394–o395.
Published online 2009 January 28. doi:  10.1107/S1600536809002839
PMCID: PMC2968123

3-(2,6-Dioxopiperidin-3-yl)-3-aza­bicyclo­[3.2.0]heptane-2,4-dione

Abstract

The title mol­ecule, C11H12N2O4, consists of a 3-aza­bicyclo­[3.2.0]heptane group containing a nearly planar cyclo­butane ring (r.m.s. deviation of fitted atoms is 0.0609 Å), fused to a pyrrolidine ring, bonded to a 2,6-dioxopiperidine ring at the 3-position. The angle between the mean planes of the cyclo­butane and fused pyrrolidine ring is 67.6 (6)°. The dihedral angles between the mean planes of the pyrrolidine and cyclo­butane rings and the dioxopiperidine ring are 73.9 (2) and 62.4 (4)°, respectively. The pyrrolidine and dioxopiperidine rings are twisted about the 3-yl group [torsion angles = −55.0 (1) and 115.0 (1)°] in a nearly perpendicular manner. Crystal packing is influenced by extensive inter­molecular C—H(...)O and N—H(...)O inter­actions between all four carbonyl O atoms and H atoms from the cyclo­butane and dioxopiperidine rings, as well as between the N atom and an H atom from the cyclo­butane ring. In addition, weak π-ring interactions also occur between H atoms from the cyclobutane ring and the five-membered pyrrolidine ring. As a result, mol­ecules are linked into infinite chains diagonally along the [101] plane of the unit cell in an alternate inverted pattern.

Related literature

For related structures, see: Muller & Man (2008 [triangle]); Yamamoto et al. (2008 [triangle]); Zeldis (2008 [triangle]). For related literature, see: Carson et al. (2004 [triangle]); Werbel et al. (1968 [triangle]); Cremer & Pople (1975 [triangle]); Schmidt & Polik (2007 [triangle]).

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Object name is e-65-0o394-scheme1.jpg

Experimental

Crystal data

  • C11H12N2O4
  • M r = 236.23
  • Monoclinic, An external file that holds a picture, illustration, etc.
Object name is e-65-0o394-efi1.jpg
  • a = 10.7332 (7) Å
  • b = 9.9358 (5) Å
  • c = 11.0753 (7) Å
  • β = 116.201 (8)°
  • V = 1059.75 (13) Å3
  • Z = 4
  • Mo Kα radiation
  • μ = 0.11 mm−1
  • T = 200 (2) K
  • 0.57 × 0.34 × 0.19 mm

Data collection

  • Oxford Diffraction Gemini diffractometer
  • Absorption correction: multi-scan (CrysAlis RED; Oxford Diffraction, 2007 [triangle]) T min = 0.866, T max = 0.975
  • 10798 measured reflections
  • 3496 independent reflections
  • 2193 reflections with I > 2σ(I)
  • R int = 0.025

Refinement

  • R[F 2 > 2σ(F 2)] = 0.039
  • wR(F 2) = 0.108
  • S = 0.99
  • 3496 reflections
  • 154 parameters
  • H-atom parameters constrained
  • Δρmax = 0.28 e Å−3
  • Δρmin = −0.25 e Å−3

Data collection: CrysAlisPro (Oxford Diffraction, 2007 [triangle]); cell refinement: CrysAlisPro; data reduction: CrysAlis RED; program(s) used to solve structure: SHELXS97 (Sheldrick, 2008 [triangle]); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008 [triangle]); molecular graphics: SHELXTL (Sheldrick, 2008 [triangle]); software used to prepare material for publication: SHELXTL.

Table 1
Hydrogen-bond geometry (Å, °)

Supplementary Material

Crystal structure: contains datablocks global, I. DOI: 10.1107/S1600536809002839/cs2103sup1.cif

Structure factors: contains datablocks I. DOI: 10.1107/S1600536809002839/cs2103Isup2.hkl

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

Acknowledgments

RJB acknowledges the NSF MRI program (grant No. CHE-0619278) for funds to purchase an X-ray diffractometer.

supplementary crystallographic information

Comment

The synthesis and biological evaluation of the title compound, 3-(2,6-dioxopiperidine-3-yl)-3-azabicyclo[3.2.0]heptane-2,4-dione and its analogues is of interest to synthetic medicinal chemists. Specifically, piperidine 2,6-dione derivatives, including those of phthalimide, are important anti-angiogenic and immunomodulative agents used for the treatment of many diseases including multiple myeloma, (Muller & Man, 2008; Yamamoto et al., 2008; Zeldis, 2008), Chron's disease (Carson et al., 2004), and leprosy (Werbel et al., 1968). The title molecule, C11H12N2O4, a piperidine 2,6-dione derivative, consists of an azabicyclo[3.2.0]heptane group containing a nearly planar cyclobutane ring, fused to a pyrrolidine ring, bonded to a 2,6-dioxopiperidine ring at the 3 position. The six-membered dioxopiperidine ring (N2–C8–C7–C11–C10–C9) is a slightly distorted envelope, with Cremer & Pople (1975) puckering parameters Q, θ and [var phi] of 0.5187 (12) Å, 56.12 (13)° and 176.55 (16)°, respectively. The 5-membered pyrrolidine group (N1/C2–C6) has also a slightly distorted envelope conformation with puckering parameters Q(2)and [var phi](2) of 0.0940 (13) Å, 82.9 (7)° respectively. For an ideal envelope θ has a value of 0 or 180° and θ(2) has a value of 72. The angle between the mean planes of the cyclobutane and fused pyrrolidine ring is 67.6 (6)° (Fig. 1). The mean planes of the pyrrolidine and cyclobutane rings make an angle of 73.9 (2)° and 62.4 (4)° with the dihedral angle of the dioxopiperidine ring, respectively. The pyrrolidine and dioxopiperidine rings are twisted about the 3-yl group [torsion angles = -55.0 (1)° (C1—N1—C7—C8) and 115.0 (1)° (C6—N1—C7—C8)] in a nearly perpendicular manner.

Crystal packing is influenced by extensive intermolecular C–H···O hydrogen bonding between all four carbonyl oxygen atoms [O1, O2, O3, O4] and hydrogen atoms from the cyclobutane (H3A & H5A) and dioxopiperidine rings (H10B & H11B) as well as by N–H···O intermolecular interactions. As a result the molecules are linked into infinite chains diagonally along the [101] plane of the unit cell in an alternate inverted pattern (Fig. 2). In addition, weak C-H··· π-ring interactions also occur between hydrogen atoms from the cyclobutane ring [H3B] and the 5-membered pyrrolidine ring [C3–H3B···Cg2; H3B···Cg2 = 2.50 Å, C3–H3B···Cg2 = 64°, C3···Cg2–H3B = 2.2475 (13) Å, x,y,z, where Cg2 = center of gravity of the N1/C1/C2/C5/C6 ring].

After a MOPAC AMI calculation [Austin Model 1 approximation together with the Hartree-Fock closed-shell (restricted) wavefunction was used and minimizations were terminnated at an r.m.s. gradient of less than 0.01 kJ mol-1 Å-1] with WebMO Pro (Schmidt & Polik, 2007), the mean planes of the cyclopropane and pyrrolidine rings became completely planar in the local minimized structure and the dihedral angle between these rings became 64.3 (8)°. The angle between the mean planes of the pyrrolidine and cyclobutane rings and the dihedral angle of the dioxopiperidine ring became 73.9 (2)° and 62.4 (4)°, respectively. The twist of the pyrrolidine and dioxopiperidine rings about the 3-yl group became more perpendicuar to each other after this geometry minimization [torsion angles = -68.6 (6)° (C1—N1—C7—C8) and 100.4 (1)° (C6—N1—C7—C8)]. Thus it is apparent that the extensive hydrogen bonding and π-ring intermolecular interactions significantly influence crystal packing for this molecule.

Experimental

The title compound was synthesized as follows: cis-1,2-cyclobutane dicarboxylic acid anhydride (0.1 g, 0.79 mmol), glutamic acid (0.12 g, 0.79 mmol), DMAP (0.02 g, 0.16 mmol), and ammonium chloride (NH4Cl) (0.04 g, 0.916 mmol) were mixed thoroughly in a CEM-sealed vial with a magnetic stirrer. The mixture was heated for 10 min at 423 K in a CEM Discover microwave powered at 150 W. It was then cooled rapidly to 313 K and dissolved in 15 ml of (1:1) ethyl acetate: acetone. The organic layer was washed with 2x (10 ml) distilled water and dried over sodium sulfate (anhydrous). The organic layer was concentrated under vacuum and precipitated with hexanes (30 ml) affording a white solid, recrystallized from methanol, (0.10 g, 54%). mp 476–478 K; 1H NMR (400 MHz, DMSO-d6), δ (p.p.m.): 11.06 (s, 1 H, NH), 4.95 (dd, 1 H, 12.5, 5.5 Hz), 2.84 (m, 2 H), 2.52 (m, 4 H,), 2.02 (m, 2 H), 1.92 (m, 2 H); 13C NMR (100 MHz, DMSO-d6) δ (p.p.m.): 179.0(C=O), 172.7(C=O), 169.4(C=O), 49.1(CH), 37.9(CH), 37.7(CH), 30.7(CH), 22.3(CH2), 22.0(CH2), 21.0(CH2); MS m/z 236 (M+) 208, 151, 106, 112, 96, 83, 55, 41; IR (nujol) (νmax, cm-1): 3207.48, 1702.55, 1729.09, 1771.79 (C=O).

Refinement

The H atoms were placed in their calculated positions and then refined using the riding model with C(N)—H = 0.88 to 1.00 Å, and with Uiso(H) = 1.18–1.21Ueq(C,N).

Figures

Fig. 1.
The molecular structure of C11H12N2O4, showing the atom numbering scheme and 50% probability displacement ellipsoids.
Fig. 2.
The molecular packing for C11H12N2O4 viewed down the b axis. Dashed lines indicate C–H···O and N–H···O intermolecular hydrogen bonds.

Crystal data

C11H12N2O4F(000) = 496
Mr = 236.23Dx = 1.481 Mg m3
Monoclinic, P21/aMo Kα radiation, λ = 0.71073 Å
Hall symbol: -P 2yabCell parameters from 4629 reflections
a = 10.7332 (7) Åθ = 4.9–32.6°
b = 9.9358 (5) ŵ = 0.11 mm1
c = 11.0753 (7) ÅT = 200 K
β = 116.201 (8)°Prism, colorless
V = 1059.75 (13) Å30.57 × 0.34 × 0.19 mm
Z = 4

Data collection

Oxford Diffraction Gemini diffractometer3496 independent reflections
Radiation source: fine-focus sealed tube2193 reflections with I > 2σ(I)
graphiteRint = 0.025
Detector resolution: 10.5081 pixels mm-1θmax = 32.5°, θmin = 4.9°
[var phi] and ω scansh = −14→16
Absorption correction: multi-scan (CrysAlis RED; Oxford Diffraction, 2007)k = −14→13
Tmin = 0.866, Tmax = 0.975l = −15→15
10798 measured reflections

Refinement

Refinement on F2Primary atom site location: structure-invariant direct methods
Least-squares matrix: fullSecondary atom site location: difference Fourier map
R[F2 > 2σ(F2)] = 0.039Hydrogen site location: inferred from neighbouring sites
wR(F2) = 0.108H-atom parameters constrained
S = 0.99w = 1/[σ2(Fo2) + (0.0607P)2] where P = (Fo2 + 2Fc2)/3
3496 reflections(Δ/σ)max < 0.001
154 parametersΔρmax = 0.28 e Å3
0 restraintsΔρmin = −0.25 e Å3

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.

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å2)

xyzUiso*/Ueq
O10.32277 (8)0.13630 (8)0.42230 (7)0.0271 (2)
O20.04309 (9)0.50429 (9)0.26752 (8)0.0372 (2)
O30.02024 (7)0.12103 (8)0.39189 (7)0.02458 (19)
O40.16813 (8)0.16581 (9)0.83857 (8)0.0350 (2)
N10.18201 (8)0.32243 (9)0.37104 (8)0.0196 (2)
N20.10433 (9)0.14479 (9)0.61681 (8)0.0222 (2)
H2B0.06830.06600.61950.027*
C10.25634 (10)0.22276 (11)0.34235 (10)0.0211 (2)
C20.23146 (11)0.24120 (12)0.19918 (11)0.0258 (3)
H2A0.31540.23150.18270.031*
C30.09860 (12)0.16602 (13)0.09668 (11)0.0340 (3)
H3A0.11540.10760.03300.041*
H3B0.04870.11640.13960.041*
C40.03228 (13)0.30239 (14)0.03642 (11)0.0357 (3)
H4A−0.05940.31720.03550.043*
H4B0.02810.3205−0.05320.043*
C50.15349 (12)0.37539 (12)0.15340 (11)0.0278 (3)
H5A0.20190.44640.12590.033*
C60.11702 (11)0.41346 (11)0.26561 (10)0.0240 (2)
C70.15765 (10)0.31947 (11)0.49000 (10)0.0190 (2)
H7A0.09050.39310.48050.023*
C80.08854 (9)0.18701 (11)0.49330 (10)0.0188 (2)
C90.17118 (10)0.21274 (12)0.73885 (10)0.0234 (2)
C100.24295 (11)0.34041 (11)0.73556 (10)0.0249 (2)
H10A0.32600.35200.82280.030*
H10B0.17990.41720.72390.030*
C110.28713 (10)0.34228 (11)0.62276 (10)0.0220 (2)
H11A0.35610.27040.63690.026*
H11B0.33000.43000.62090.026*

Atomic displacement parameters (Å2)

U11U22U33U12U13U23
O10.0272 (4)0.0236 (4)0.0302 (4)0.0056 (3)0.0125 (3)0.0028 (3)
O20.0488 (5)0.0302 (5)0.0331 (4)0.0158 (4)0.0185 (4)0.0085 (4)
O30.0235 (4)0.0233 (4)0.0256 (4)−0.0044 (3)0.0096 (3)−0.0028 (3)
O40.0448 (5)0.0383 (5)0.0276 (4)−0.0018 (4)0.0211 (4)0.0041 (4)
N10.0226 (4)0.0176 (5)0.0209 (4)0.0009 (3)0.0117 (3)0.0022 (4)
N20.0252 (4)0.0186 (5)0.0252 (4)−0.0048 (3)0.0134 (4)0.0012 (4)
C10.0196 (5)0.0198 (5)0.0263 (5)−0.0028 (4)0.0124 (4)−0.0009 (4)
C20.0295 (6)0.0251 (6)0.0279 (5)−0.0016 (4)0.0174 (5)−0.0016 (5)
C30.0441 (7)0.0330 (7)0.0254 (6)−0.0064 (5)0.0158 (5)−0.0041 (5)
C40.0385 (7)0.0436 (8)0.0218 (5)0.0015 (6)0.0103 (5)0.0005 (5)
C50.0347 (6)0.0256 (6)0.0255 (5)−0.0027 (5)0.0155 (5)0.0034 (5)
C60.0265 (5)0.0203 (6)0.0238 (5)−0.0007 (4)0.0098 (4)0.0032 (4)
C70.0203 (5)0.0170 (5)0.0217 (5)0.0004 (4)0.0110 (4)0.0008 (4)
C80.0156 (4)0.0195 (5)0.0224 (5)0.0016 (4)0.0093 (4)0.0013 (4)
C90.0226 (5)0.0247 (6)0.0248 (5)0.0025 (4)0.0122 (4)0.0012 (5)
C100.0294 (5)0.0217 (6)0.0225 (5)−0.0019 (4)0.0105 (4)−0.0023 (4)
C110.0215 (5)0.0193 (5)0.0248 (5)−0.0030 (4)0.0099 (4)−0.0014 (4)

Geometric parameters (Å, °)

O1—C11.2136 (13)C3—H3B0.9900
O2—C61.2080 (13)C4—C51.5520 (16)
O3—C81.2253 (12)C4—H4A0.9900
O4—C91.2125 (13)C4—H4B0.9900
N1—C11.3936 (14)C5—C61.5069 (16)
N1—C61.3959 (13)C5—H5A1.0000
N1—C71.4523 (13)C7—C81.5191 (15)
N2—C81.3679 (13)C7—C111.5298 (13)
N2—C91.3933 (13)C7—H7A1.0000
N2—H2B0.8800C9—C101.4929 (16)
C1—C21.4984 (15)C10—C111.5195 (15)
C2—C51.5364 (17)C10—H10A0.9900
C2—C31.5654 (15)C10—H10B0.9900
C2—H2A1.0000C11—H11A0.9900
C3—C41.5390 (18)C11—H11B0.9900
C3—H3A0.9900
C1—N1—C6113.25 (9)C6—C5—H5A115.6
C1—N1—C7122.88 (8)C2—C5—H5A115.6
C6—N1—C7123.25 (9)C4—C5—H5A115.6
C8—N2—C9127.22 (9)O2—C6—N1123.98 (10)
C8—N2—H2B116.4O2—C6—C5127.86 (10)
C9—N2—H2B116.4N1—C6—C5108.14 (9)
O1—C1—N1123.21 (9)N1—C7—C8108.95 (8)
O1—C1—C2129.16 (10)N1—C7—C11114.71 (8)
N1—C1—C2107.57 (9)C8—C7—C11110.57 (8)
C1—C2—C5105.78 (9)N1—C7—H7A107.4
C1—C2—C3112.87 (9)C8—C7—H7A107.4
C5—C2—C389.18 (8)C11—C7—H7A107.4
C1—C2—H2A115.3O3—C8—N2120.82 (10)
C5—C2—H2A115.3O3—C8—C7122.84 (9)
C3—C2—H2A115.3N2—C8—C7116.33 (9)
C4—C3—C289.61 (9)O4—C9—N2119.20 (10)
C4—C3—H3A113.7O4—C9—C10124.80 (10)
C2—C3—H3A113.7N2—C9—C10116.00 (9)
C4—C3—H3B113.7C9—C10—C11112.47 (9)
C2—C3—H3B113.7C9—C10—H10A109.1
H3A—C3—H3B111.0C11—C10—H10A109.1
C3—C4—C589.58 (8)C9—C10—H10B109.1
C3—C4—H4A113.7C11—C10—H10B109.1
C5—C4—H4A113.7H10A—C10—H10B107.8
C3—C4—H4B113.7C10—C11—C7107.91 (9)
C5—C4—H4B113.7C10—C11—H11A110.1
H4A—C4—H4B111.0C7—C11—H11A110.1
C6—C5—C2104.34 (9)C10—C11—H11B110.1
C6—C5—C4112.24 (10)C7—C11—H11B110.1
C2—C5—C490.21 (9)H11A—C11—H11B108.4
C6—N1—C1—O1178.13 (10)C2—C5—C6—O2−171.68 (11)
C7—N1—C1—O1−10.65 (15)C4—C5—C6—O2−75.45 (15)
C6—N1—C1—C2−4.49 (11)C2—C5—C6—N17.10 (11)
C7—N1—C1—C2166.72 (9)C4—C5—C6—N1103.32 (11)
O1—C1—C2—C5−174.12 (11)C1—N1—C7—C8−55.34 (12)
N1—C1—C2—C58.72 (11)C6—N1—C7—C8115.01 (10)
O1—C1—C2—C389.96 (14)C1—N1—C7—C1169.19 (12)
N1—C1—C2—C3−87.20 (11)C6—N1—C7—C11−120.47 (10)
C1—C2—C3—C4115.83 (10)C9—N2—C8—O3−175.72 (9)
C5—C2—C3—C49.02 (9)C9—N2—C8—C73.25 (15)
C2—C3—C4—C5−8.93 (9)N1—C7—C8—O3−24.63 (13)
C1—C2—C5—C6−9.47 (11)C11—C7—C8—O3−151.56 (9)
C3—C2—C5—C6104.11 (9)N1—C7—C8—N2156.42 (9)
C1—C2—C5—C4−122.52 (9)C11—C7—C8—N229.49 (12)
C3—C2—C5—C4−8.94 (9)C8—N2—C9—O4174.97 (10)
C3—C4—C5—C6−96.51 (11)C8—N2—C9—C10−5.28 (15)
C3—C4—C5—C29.10 (9)O4—C9—C10—C11153.52 (11)
C1—N1—C6—O2177.01 (10)N2—C9—C10—C11−26.21 (13)
C7—N1—C6—O25.83 (16)C9—C10—C11—C756.95 (12)
C1—N1—C6—C5−1.83 (11)N1—C7—C11—C10178.27 (9)
C7—N1—C6—C5−173.01 (9)C8—C7—C11—C10−58.05 (11)

Hydrogen-bond geometry (Å, °)

D—H···AD—HH···AD···AD—H···A
N2—H2B···O3i0.882.062.9426 (12)175
C5—H5A···O4ii1.002.523.4424 (15)153
C10—H10B···O2iii0.992.563.4228 (14)146
C11—H11B···O3ii0.992.533.5026 (13)167
C11—H11B···O1ii0.992.533.1072 (14)117
C3—H3A···O4iv0.992.523.2577 (15)131

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

Footnotes

Supplementary data and figures for this paper are available from the IUCr electronic archives (Reference: CS2103).

References

  • Carson, K. G., Jaffee, B. D. & Harriman, G. C. B. (2004). Annu. Rep. Med. Chem.39, 149–158.
  • Cremer, D. & Pople, J. A. (1975). J. Am. Chem. Soc.97, 1354–1358.
  • Muller, G. W. & Man, H.-W. (2008). PCT Int. Appl. PIXXD2 WO 2008039489 A2 20080403.
  • Oxford Diffraction (2007). CrysAlis Pro and CrysAlis RED Oxford Diffraction Ltd, Abingdon, Oxfordshire, England.
  • Schmidt, J. R. & Polik, W. F. (2007). WebMO Pro WebMO, LLC, Holland, Michigan, USA, 2007. http://www.webmo.net
  • Sheldrick, G. M. (2008). Acta Cryst. A64, 112–122. [PubMed]
  • Werbel, L. M., Elslager, E. F., Fisher, M. W., Gavrilis, Z. B. & Phillips, A. A. (1968). J. Med. Chem.11, 411–419. [PubMed]
  • Yamamoto, T., Shibata, N., Takashima, M., Nakamura, S., Toru, T., Matsunaga, N. & Hara, H. (2008). Org. Biomol. Chem.6, 1540–1543. [PubMed]
  • Zeldis, J. B. (2008). PCT Int. Appl. PIXXD2. WO 2008019065, A1 20080214, CAN 148:230111, AN 2008:191687.

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