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Acta Cryst. (2009). E65, o394-o395    [ doi:10.1107/S1600536809002839 ]

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

Y. M. Hijji, E. Benjamin, E. Benjamin, R. J. Butcher and J. P. Jasinski

Abstract top

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 [pi]-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.

Comment top

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 φ 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 φ(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.

Related literature top

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

Experimental top

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 top

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).

Computing details top

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

Figures top
[Figure 1] Fig. 1. The molecular structure of C11H12N2O4, showing the atom numbering scheme and 50% probability displacement ellipsoids.
[Figure 2] 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.
3-(2,6-Dioxopiperidin-3-yl)-3-azabicyclo[3.2.0]heptane-2,4-dione top
Crystal data top
C11H12N2O4F(000) = 496
Mr = 236.23Dx = 1.481 Mg m−3
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 mm−1
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 top
Oxford Diffraction Gemini
diffractometer		3496 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°
φ 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 top
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 = 0.99 w = 1/[σ2(Fo2) + (0.0607P)2]
where P = (Fo2 + 2Fc2)/3
3496 reflections(Δ/σ)max < 0.001
154 parametersΔρmax = 0.28 e Å−3
0 restraintsΔρmin = −0.25 e Å−3
Crystal data top
C11H12N2O4V = 1059.75 (13) Å3
Mr = 236.23Z = 4
Monoclinic, P21/aMo Kα radiation
a = 10.7332 (7) ŵ = 0.11 mm−1
b = 9.9358 (5) ÅT = 200 K
c = 11.0753 (7) Å0.57 × 0.34 × 0.19 mm
β = 116.201 (8)°
Data collection top
Oxford Diffraction Gemini
diffractometer		3496 independent reflections
Absorption correction: multi-scan
(CrysAlis RED; Oxford Diffraction, 2007)		2193 reflections with I > 2σ(I)
Tmin = 0.866, Tmax = 0.975Rint = 0.025
10798 measured reflectionsθmax = 32.5°
Refinement top
R[F2 > 2σ(F2)] = 0.039H-atom parameters constrained
wR(F2) = 0.108Δρmax = 0.28 e Å−3
S = 0.99Δρmin = −0.25 e Å−3
3496 reflectionsAbsolute structure: ?
154 parametersFlack parameter: ?
0 restraintsRogers parameter: ?
Special details top

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) top
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) top
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, °) top
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, °) top
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.
Table 1
Hydrogen-bond geometry (Å, °) top
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.
Acknowledgements top

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

references
References top

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