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

Yousef M Hijji; Ellis Benjamin; Earl Benjamin; Ray J Butcher; Jerry P Jasinski

doi:10.1107/S1600536809002839

. 2009 Jan 28;65(Pt 2):o394–o395. doi: 10.1107/S1600536809002839

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

Yousef M Hijji ^a, Ellis Benjamin ^b, Earl Benjamin ^b, Ray J Butcher ^c,^*, Jerry P Jasinski ^d

PMCID: PMC2968123 PMID: 21581989

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

Experimental

Crystal data

C₁₁H₁₂N₂O₄
M _r = 236.23
Monoclinic,
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 ▶) 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
Δρ_max = 0.28 e Å⁻³
Δρ_min = −0.25 e Å⁻³

Data collection: CrysAlisPro (Oxford Diffraction, 2007 ▶); cell refinement: CrysAlisPro; data reduction: CrysAlis RED; 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.

Supplementary Material

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

e-65-0o394-sup1.cif^{(17.2KB, cif)}

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

e-65-0o394-Isup2.hkl^{(171.5KB, hkl)}

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

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

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A
N2—H2B⋯O3ⁱ	0.88	2.06	2.9426 (12)	175
C5—H5A⋯O4ⁱⁱ	1.00	2.52	3.4424 (15)	153
C10—H10B⋯O2ⁱⁱⁱ	0.99	2.56	3.4228 (14)	146
C11—H11B⋯O3ⁱⁱ	0.99	2.53	3.5026 (13)	167
C11—H11B⋯O1ⁱⁱ	0.99	2.53	3.1072 (14)	117
C3—H3A⋯O4^iv	0.99	2.52	3.2577 (15)	131

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Symmetry codes: (i) Inline graphic ; (ii) ; (iii) ; (iv) .

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 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.

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) (ν_max, cm^-1): 3207.48, 1702.55, 1729.09, 1771.79 (C=O).