organic compounds\(\def\hfill{\hskip 5em}\def\hfil{\hskip 3em}\def\eqno#1{\hfil {#1}}\)

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ISSN: 2056-9890

Ethyl 2-hydr­­oxy-5,11-dioxo­pyrrolo[2,1-c][1,4]benzodiazepine-10-acetate

aLaboratoire de Chimie Organique Hétérocyclique, Pôle de Compétences Pharmacochimie, Université Mohammed V-Agdal, BP 1014 Avenue Ibn Batout, Rabat, Morocco, bCNRST, Division of UATRS Angle Allal Fassi/FAR, BP 8027 Hay Riad, 10000 Rabat, Morocco, and cDepartment of Chemistry, University of Malaya, 50603 Kuala Lumpur, Malaysia
*Correspondence e-mail: seikweng@um.edu.my

(Received 21 February 2010; accepted 23 February 2010; online 3 March 2010)

The title compound, C16H18N2O5, consists of a benzodiazepinedione system fused to a pyrrole system. The seven-membered ring adopts a boat-shaped conformation (with the methine C atom as the prow); the five-membered ring adopts an enveloped-shaped conformation (with the hydr­oxy-bearing C atom as the flap). The hydr­oxy group is hydrogen bonded to the carbonyl O atom of an adjacent mol­ecule generating a zigzag chain in the crystal structure.

Related literature

Pyrrolo[2,1-c][1,4]benzodiazepines are potent anti­biotics produced by Streptomyces species; see: Cargill et al. (1974[Cargill, C., Bachmann, E. & Zbinden, G. (1974). J. Natl. Cancer Inst. 53, 481- 486.]). For the design of DNA inter-strand cross-linking as well as of conjugate agents to enhance the sequence selectivity and selectivity for tumor cells, see: Gregson et al. (2004[Gregson, S. T., Howard, P. W., Gullick, D. R., Hamaguchi, A., Corcoran, K. E., Brooks, N. A., Hartley, J. A., Jenkins, T. C., Patel, S., Guille, M. J. & Thurston, D. E. (2004). J. Med. Chem. 47, 1161-1174.]).

[Scheme 1]

Experimental

Crystal data
  • C16H18N2O5

  • Mr = 318.32

  • Orthorhombic, P 21 21 21

  • a = 8.5503 (2) Å

  • b = 9.6580 (2) Å

  • c = 18.2734 (4) Å

  • V = 1509.00 (6) Å3

  • Z = 4

  • Mo Kα radiation

  • μ = 0.11 mm−1

  • T = 293 K

  • 0.3 × 0.3 × 0.3 mm

Data collection
  • Bruker APEXII diffractometer

  • 11809 measured reflections

  • 1907 independent reflections

  • 1765 reflections with I > 2σ(I)

  • Rint = 0.024

Refinement
  • R[F2 > 2σ(F2)] = 0.032

  • wR(F2) = 0.098

  • S = 1.04

  • 1907 reflections

  • 213 parameters

  • 1 restraint

  • H atoms treated by a mixture of independent and constrained refinement

  • Δρmax = 0.21 e Å−3

  • Δρmin = −0.17 e Å−3

Table 1
Hydrogen-bond geometry (Å, °)

D—H⋯A D—H H⋯A DA D—H⋯A
O3—H3⋯O1i 0.84 (1) 2.02 (2) 2.810 (2) 157 (4)
Symmetry code: (i) [-x, y+{\script{1\over 2}}, -z+{\script{1\over 2}}].

Data collection: APEX2 (Bruker, 2005[Bruker (2005). APEX2 and SAINT. Bruker AXS Inc., Madison, Wisconsin, USA.]); cell refinement: SAINT (Bruker, 2005[Bruker (2005). APEX2 and SAINT. Bruker AXS Inc., Madison, Wisconsin, USA.]); data reduction: SAINT; program(s) used to solve structure: SHELXS97 (Sheldrick, 2008[Sheldrick, G. M. (2008). Acta Cryst. A64, 112-122.]); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008[Sheldrick, G. M. (2008). Acta Cryst. A64, 112-122.]); molecular graphics: X-SEED (Barbour, 2001[Barbour, L. J. (2001). J. Supramol. Chem. 1, 189-191.]); software used to prepare material for publication: publCIF (Westrip, 2010[Westrip, S. P. (2010). publCIF. In preparation.]).

Supporting information


Related literature top

Pyrrolo[2,1-c][1,4]benzodiazepines are potent antibiotics produced by Streptomyces species; see: Cargill et al. (1974). For the design of DNA inter-strand cross-linking as well as of conjugate agents to enhance the sequence selectivity and selectivity for tumor cells, see: Gregson et al. (2004).

Experimental top

2-Hydroxy- pyrrolo[2,1-c][1,4]benzodiazepine-5,11-dione (0.5 g, 2.15 mmol), ethyl bromoacetate (0.45 ml, 4.3 mmol), potassium carbonate (0.6 g, 4.3 mmol) along with a catalytic amount of tetra-n-butyl ammonium bromide were stirred in N,N-dimethylformamide (20 ml) for 24 h. After the completion of the reaction (monitored by TLC), the solid material was removed by filtration and the solvent evaporated under vacuum. Dichloromethane (20 ml) was added and the solution filtered. The solvent was removed and the product purified by recrystallization from ethanol to afford colorless crystals in 80% yield.

Refinement top

Carbon-bound H-atoms were placed in calculated positions (C—H 0.93-0.98 Å) and were included in the refinement in the riding model approximation, with U(H) set to 1.2–1.5U(C). The oxygen-bound H-atom was located in a difference Fourier map, and was refined isotropically with a distance restraint of O–H = 0.84±0.01 Å. Due to the absence of anomalous scatterers Friedel pairs were merged and the absolute configuration was arbitrarily set.

Computing details top

Data collection: APEX2 (Bruker, 2005); cell refinement: SAINT (Bruker, 2005); data reduction: SAINT (Bruker, 2005); program(s) used to solve structure: SHELXS97 (Sheldrick, 2008); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008); molecular graphics: X-SEED (Barbour, 2001); software used to prepare material for publication: publCIF (Westrip, 2010).

Figures top
[Figure 1] Fig. 1. Anisotropic displacement ellipsoid plot (Barbour, 2001) of C16H18N2O5 at the 50% probability level; hydrogen atoms are drawn as arbitrary radius.
Ethyl 2-hydroxy-5,11-dioxopyrrolo[2,1-c][1,4]benzodiazepine-10-acetate top
Crystal data top
C16H18N2O5F(000) = 672
Mr = 318.32Dx = 1.401 Mg m3
Orthorhombic, P212121Mo Kα radiation, λ = 0.71073 Å
Hall symbol: P 2ac 2abCell parameters from 6127 reflections
a = 8.5503 (2) Åθ = 2.2–32.7°
b = 9.6580 (2) ŵ = 0.11 mm1
c = 18.2734 (4) ÅT = 293 K
V = 1509.00 (6) Å3Block, colorless
Z = 40.3 × 0.3 × 0.3 mm
Data collection top
Bruker APEXII
diffractometer
1765 reflections with I > 2σ(I)
Radiation source: fine-focus sealed tubeRint = 0.024
Graphite monochromatorθmax = 27.5°, θmin = 3.1°
ϕ and ω scansh = 109
11809 measured reflectionsk = 1212
1907 independent reflectionsl = 2323
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)] = 0.032Hydrogen site location: inferred from neighbouring sites
wR(F2) = 0.098H atoms treated by a mixture of independent and constrained refinement
S = 1.04 w = 1/[σ2(Fo2) + (0.0709P)2 + 0.1392P]
where P = (Fo2 + 2Fc2)/3
1907 reflections(Δ/σ)max = 0.001
213 parametersΔρmax = 0.21 e Å3
1 restraintΔρmin = 0.17 e Å3
Crystal data top
C16H18N2O5V = 1509.00 (6) Å3
Mr = 318.32Z = 4
Orthorhombic, P212121Mo Kα radiation
a = 8.5503 (2) ŵ = 0.11 mm1
b = 9.6580 (2) ÅT = 293 K
c = 18.2734 (4) Å0.3 × 0.3 × 0.3 mm
Data collection top
Bruker APEXII
diffractometer
1765 reflections with I > 2σ(I)
11809 measured reflectionsRint = 0.024
1907 independent reflections
Refinement top
R[F2 > 2σ(F2)] = 0.0321 restraint
wR(F2) = 0.098H atoms treated by a mixture of independent and constrained refinement
S = 1.04Δρmax = 0.21 e Å3
1907 reflectionsΔρmin = 0.17 e Å3
213 parameters
Special details top

Geometry. All esds (except the esd in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell esds are taken into account individually in the estimation of esds in distances, angles and torsion angles; correlations between esds in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell esds is used for estimating esds involving l.s. planes.

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å2) top
xyzUiso*/Ueq
O10.0674 (2)1.16444 (16)0.01855 (9)0.0502 (4)
O20.1577 (2)1.04456 (15)0.23744 (7)0.0480 (4)
O30.2180 (2)1.50177 (16)0.09188 (10)0.0577 (5)
H30.277 (3)1.452 (3)0.0664 (16)0.077 (10)*
O40.25606 (19)0.66847 (14)0.26892 (8)0.0426 (4)
O50.4250 (2)0.8107 (2)0.21372 (11)0.0677 (6)
N10.0805 (2)1.20584 (14)0.08027 (8)0.0306 (4)
N20.1825 (2)0.92800 (14)0.13177 (7)0.0299 (3)
C10.2136 (2)0.92042 (17)0.05498 (9)0.0275 (4)
C20.3094 (3)0.81259 (19)0.03067 (10)0.0386 (4)
H20.36050.75670.06450.046*
C30.3287 (3)0.7885 (2)0.04302 (12)0.0478 (6)
H3A0.39320.71680.05860.057*
C40.2530 (3)0.8699 (2)0.09410 (11)0.0495 (6)
H40.26380.85170.14380.059*
C50.1614 (3)0.9784 (2)0.07053 (9)0.0395 (5)
H50.11161.03380.10500.047*
C60.1411 (2)1.00772 (17)0.00397 (8)0.0289 (4)
C70.0428 (2)1.13048 (18)0.02157 (9)0.0325 (4)
C80.0024 (3)1.33736 (19)0.09788 (12)0.0403 (4)
H8A0.08901.32190.12820.048*
H8B0.02921.38550.05370.048*
C90.1259 (3)1.41889 (18)0.13900 (11)0.0385 (5)
H90.07471.47840.17520.046*
C100.2186 (3)1.30721 (18)0.17856 (11)0.0383 (4)
H10A0.17171.28690.22570.046*
H10B0.32561.33710.18630.046*
C110.2141 (2)1.17906 (16)0.12901 (9)0.0270 (3)
H110.31111.17110.10080.032*
C120.1830 (2)1.04664 (17)0.17179 (8)0.0292 (4)
C130.1586 (3)0.79979 (17)0.17246 (10)0.0333 (4)
H13A0.13980.72490.13820.040*
H13B0.06630.80920.20290.040*
C140.2970 (3)0.76303 (19)0.22022 (10)0.0353 (4)
C150.3801 (3)0.6167 (3)0.31610 (14)0.0548 (6)
H15A0.42800.69290.34250.066*
H15B0.46020.57180.28690.066*
C160.3116 (4)0.5171 (3)0.36799 (15)0.0711 (9)
H16A0.39330.47650.39700.107*
H16B0.25800.44570.34140.107*
H16C0.23900.56410.39940.107*
Atomic displacement parameters (Å2) top
U11U22U33U12U13U23
O10.0530 (10)0.0443 (7)0.0533 (8)0.0063 (8)0.0280 (8)0.0017 (7)
O20.0756 (12)0.0458 (7)0.0226 (6)0.0069 (8)0.0034 (6)0.0001 (5)
O30.0718 (13)0.0293 (6)0.0720 (11)0.0031 (8)0.0311 (10)0.0004 (7)
O40.0435 (9)0.0418 (7)0.0425 (7)0.0019 (7)0.0044 (6)0.0179 (6)
O50.0443 (10)0.0727 (12)0.0861 (13)0.0162 (10)0.0148 (9)0.0430 (10)
N10.0319 (9)0.0271 (7)0.0328 (7)0.0039 (6)0.0047 (6)0.0007 (5)
N20.0402 (10)0.0256 (6)0.0240 (6)0.0003 (6)0.0007 (6)0.0043 (5)
C10.0333 (10)0.0243 (7)0.0250 (7)0.0037 (7)0.0014 (6)0.0006 (6)
C20.0468 (13)0.0303 (8)0.0387 (9)0.0031 (9)0.0036 (9)0.0004 (7)
C30.0591 (16)0.0382 (9)0.0462 (11)0.0012 (10)0.0159 (11)0.0116 (8)
C40.0744 (17)0.0461 (10)0.0279 (8)0.0115 (11)0.0115 (10)0.0091 (8)
C50.0553 (14)0.0376 (9)0.0255 (8)0.0098 (9)0.0031 (8)0.0026 (7)
C60.0348 (10)0.0267 (7)0.0250 (7)0.0057 (7)0.0024 (7)0.0008 (6)
C70.0371 (11)0.0287 (8)0.0316 (8)0.0007 (7)0.0070 (7)0.0061 (6)
C80.0391 (12)0.0301 (8)0.0516 (10)0.0083 (8)0.0007 (9)0.0006 (8)
C90.0464 (13)0.0264 (8)0.0428 (10)0.0008 (8)0.0135 (9)0.0059 (7)
C100.0432 (12)0.0319 (8)0.0398 (9)0.0016 (8)0.0003 (9)0.0115 (7)
C110.0292 (10)0.0258 (7)0.0259 (7)0.0001 (7)0.0024 (6)0.0019 (6)
C120.0322 (10)0.0314 (7)0.0239 (7)0.0010 (7)0.0028 (7)0.0007 (6)
C130.0387 (11)0.0300 (8)0.0311 (8)0.0042 (7)0.0018 (7)0.0077 (6)
C140.0365 (12)0.0328 (8)0.0366 (9)0.0016 (8)0.0015 (8)0.0095 (7)
C150.0501 (15)0.0564 (12)0.0579 (13)0.0070 (12)0.0091 (11)0.0248 (11)
C160.080 (2)0.0770 (17)0.0566 (14)0.0242 (17)0.0073 (14)0.0332 (13)
Geometric parameters (Å, º) top
O1—C71.238 (2)C5—H50.9300
O2—C121.219 (2)C6—C71.489 (3)
O3—C91.415 (2)C8—C91.517 (3)
O3—H30.841 (10)C8—H8A0.9700
O4—C141.322 (2)C8—H8B0.9700
O4—C151.455 (3)C9—C101.521 (3)
O5—C141.193 (3)C9—H90.9800
N1—C71.336 (2)C10—C111.534 (2)
N1—C111.471 (2)C10—H10A0.9700
N1—C81.471 (2)C10—H10B0.9700
N2—C121.359 (2)C11—C121.522 (2)
N2—C11.430 (2)C11—H110.9800
N2—C131.459 (2)C13—C141.513 (3)
C1—C21.397 (3)C13—H13A0.9700
C1—C61.402 (2)C13—H13B0.9700
C2—C31.376 (3)C15—C161.472 (3)
C2—H20.9300C15—H15A0.9700
C3—C41.381 (3)C15—H15B0.9700
C3—H3A0.9300C16—H16A0.9600
C4—C51.377 (3)C16—H16B0.9600
C4—H40.9300C16—H16C0.9600
C5—C61.401 (2)
C9—O3—H3110 (2)C8—C9—H9109.1
C14—O4—C15116.28 (18)C10—C9—H9109.1
C7—N1—C11125.27 (15)C9—C10—C11106.17 (15)
C7—N1—C8122.48 (16)C9—C10—H10A110.5
C11—N1—C8111.83 (14)C11—C10—H10A110.5
C12—N2—C1124.78 (13)C9—C10—H10B110.5
C12—N2—C13116.22 (13)C11—C10—H10B110.5
C1—N2—C13118.86 (13)H10A—C10—H10B108.7
C2—C1—C6119.74 (15)N1—C11—C12108.85 (15)
C2—C1—N2117.34 (16)N1—C11—C10103.58 (14)
C6—C1—N2122.65 (16)C12—C11—C10112.28 (13)
C3—C2—C1120.47 (19)N1—C11—H11110.6
C3—C2—H2119.8C12—C11—H11110.6
C1—C2—H2119.8C10—C11—H11110.6
C4—C3—C2120.6 (2)O2—C12—N2120.99 (15)
C4—C3—H3A119.7O2—C12—C11123.37 (15)
C2—C3—H3A119.7N2—C12—C11115.62 (13)
C3—C4—C5119.21 (18)N2—C13—C14112.56 (16)
C3—C4—H4120.4N2—C13—H13A109.1
C5—C4—H4120.4C14—C13—H13A109.1
C4—C5—C6121.87 (19)N2—C13—H13B109.1
C4—C5—H5119.1C14—C13—H13B109.1
C6—C5—H5119.1H13A—C13—H13B107.8
C5—C6—C1118.02 (17)O5—C14—O4125.18 (19)
C5—C6—C7116.15 (16)O5—C14—C13124.73 (17)
C1—C6—C7125.82 (14)O4—C14—C13110.08 (18)
O1—C7—N1120.98 (18)O4—C15—C16108.4 (2)
O1—C7—C6120.85 (16)O4—C15—H15A110.0
N1—C7—C6118.12 (16)C16—C15—H15A110.0
N1—C8—C9103.94 (16)O4—C15—H15B110.0
N1—C8—H8A111.0C16—C15—H15B110.0
C9—C8—H8A111.0H15A—C15—H15B108.4
N1—C8—H8B111.0C15—C16—H16A109.5
C9—C8—H8B111.0C15—C16—H16B109.5
H8A—C8—H8B109.0H16A—C16—H16B109.5
O3—C9—C8112.32 (18)C15—C16—H16C109.5
O3—C9—C10113.62 (19)H16A—C16—H16C109.5
C8—C9—C10103.30 (14)H16B—C16—H16C109.5
O3—C9—H9109.1
C12—N2—C1—C2137.2 (2)N1—C8—C9—O390.74 (19)
C13—N2—C1—C238.4 (3)N1—C8—C9—C1032.09 (19)
C12—N2—C1—C648.8 (3)O3—C9—C10—C1190.0 (2)
C13—N2—C1—C6135.63 (19)C8—C9—C10—C1132.0 (2)
C6—C1—C2—C32.3 (3)C7—N1—C11—C1269.2 (2)
N2—C1—C2—C3171.88 (19)C8—N1—C11—C12118.12 (16)
C1—C2—C3—C40.4 (3)C7—N1—C11—C10171.13 (18)
C2—C3—C4—C51.9 (4)C8—N1—C11—C101.53 (19)
C3—C4—C5—C60.8 (3)C9—C10—C11—N119.1 (2)
C4—C5—C6—C11.8 (3)C9—C10—C11—C12136.39 (17)
C4—C5—C6—C7178.27 (19)C1—N2—C12—O2178.8 (2)
C2—C1—C6—C53.3 (3)C13—N2—C12—O23.2 (3)
N2—C1—C6—C5170.55 (18)C1—N2—C12—C112.2 (3)
C2—C1—C6—C7176.78 (18)C13—N2—C12—C11177.84 (17)
N2—C1—C6—C79.4 (3)N1—C11—C12—O2111.0 (2)
C11—N1—C7—O1176.41 (17)C10—C11—C12—O23.1 (3)
C8—N1—C7—O14.5 (3)N1—C11—C12—N268.0 (2)
C11—N1—C7—C61.1 (3)C10—C11—C12—N2177.93 (18)
C8—N1—C7—C6173.01 (16)C12—N2—C13—C1469.9 (2)
C5—C6—C7—O132.0 (3)C1—N2—C13—C14106.03 (19)
C1—C6—C7—O1147.9 (2)C15—O4—C14—O52.1 (3)
C5—C6—C7—N1145.53 (19)C15—O4—C14—C13176.49 (19)
C1—C6—C7—N134.6 (3)N2—C13—C14—O517.2 (3)
C7—N1—C8—C9151.47 (18)N2—C13—C14—O4164.23 (16)
C11—N1—C8—C921.4 (2)C14—O4—C15—C16177.9 (2)
Hydrogen-bond geometry (Å, º) top
D—H···AD—HH···AD···AD—H···A
O3—H3···O1i0.84 (1)1.95 (1)2.782 (2)173 (4)
Symmetry code: (i) x+1/2, y+5/2, z.

Experimental details

Crystal data
Chemical formulaC16H18N2O5
Mr318.32
Crystal system, space groupOrthorhombic, P212121
Temperature (K)293
a, b, c (Å)8.5503 (2), 9.6580 (2), 18.2734 (4)
V3)1509.00 (6)
Z4
Radiation typeMo Kα
µ (mm1)0.11
Crystal size (mm)0.3 × 0.3 × 0.3
Data collection
DiffractometerBruker APEXII
diffractometer
Absorption correction
No. of measured, independent and
observed [I > 2σ(I)] reflections
11809, 1907, 1765
Rint0.024
(sin θ/λ)max1)0.649
Refinement
R[F2 > 2σ(F2)], wR(F2), S 0.032, 0.098, 1.04
No. of reflections1907
No. of parameters213
No. of restraints1
H-atom treatmentH atoms treated by a mixture of independent and constrained refinement
Δρmax, Δρmin (e Å3)0.21, 0.17

Computer programs: APEX2 (Bruker, 2005), SAINT (Bruker, 2005), SHELXS97 (Sheldrick, 2008), SHELXL97 (Sheldrick, 2008), X-SEED (Barbour, 2001), publCIF (Westrip, 2010).

Hydrogen-bond geometry (Å, º) top
D—H···AD—HH···AD···AD—H···A
O3—H3···O1i0.84 (1)1.95 (1)2.782 (2)173 (4)
Symmetry code: (i) x+1/2, y+5/2, z.
 

Acknowledgements

We thank Université Mohammed V-Agdaland the University of Malaya for supporting this study.

References

First citationBarbour, L. J. (2001). J. Supramol. Chem. 1, 189–191.  CrossRef CAS Google Scholar
First citationBruker (2005). APEX2 and SAINT. Bruker AXS Inc., Madison, Wisconsin, USA.  Google Scholar
First citationCargill, C., Bachmann, E. & Zbinden, G. (1974). J. Natl. Cancer Inst. 53, 481– 486.  CAS PubMed Web of Science Google Scholar
First citationGregson, S. T., Howard, P. W., Gullick, D. R., Hamaguchi, A., Corcoran, K. E., Brooks, N. A., Hartley, J. A., Jenkins, T. C., Patel, S., Guille, M. J. & Thurston, D. E. (2004). J. Med. Chem. 47, 1161–1174.  Web of Science CrossRef PubMed CAS Google Scholar
First citationSheldrick, G. M. (2008). Acta Cryst. A64, 112–122.  Web of Science CrossRef CAS IUCr Journals Google Scholar
First citationWestrip, S. P. (2010). publCIF. In preparation.  Google Scholar

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