(11aS)-7-Bromo-2,3,5,10,11,11a-hexa­hydro-1H-pyrrolo­[2,1-c][1,4]benzodiazepine-3,11-dione

Ma, C.; Wang, Z.-Z.; Pan, L.; Tian, Y.; Xiao, W.

doi:10.1107/S1600536811052962

organic compounds

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(11aS)-7-Bromo-2,3,5,10,11,11a-hexahydro-1H-pyrrolo[2,1-c][1,4]benzodiazepine-3,11-dione

Chao Ma,^a Zhen-Zhong Wang,^b Li Pan,^a Yu Tian ^a and Wei Xiao ^b ^*

^aSchool of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang 110016, People's Republic of China, and ^bJiangsu Kanion Pharmaceutical Co. Ltd, Lianyungang 222001, People's Republic of China
^*Correspondence e-mail: machao@syphu.edu.cn

(Received 5 December 2011; accepted 8 December 2011; online 14 December 2011)

The title compound, C₁₂H₁₁BrN₂O₂, was prepared by an intra-cyclization reaction of (S)-1-(5-bromo-2-nitrobenzyl)-5-oxopyrrolidine-2-carboxylic acid methyl ester in the presence of EtOH/Fe. The five-membered pyrrolidinone ring adopts an approximate envelope conformation, while the seven-membered diazepanone ring displays a twisted boat conformation. Intermolecular classical N—H⋯O hydrogen bonds and weak C—H⋯O interactions help to stabilize the crystal structure.

Related literature

For applications of pyrrolo[2,1-c][1,4]benzodiazepines, see: Bose et al. (1992 ); Hu et al. (2001 ); Jitendra et al. (2007 ); Kamal et al. (2002 ); Thurston & Bose (1994 ). For a related structure, see: Cheng et al. (2007 ).

Experimental

Crystal data

C₁₂H₁₁BrN₂O₂
M_r = 295.14
Orthorhombic, P 2₁ 2₁ 2₁
a = 4.3880 (4) Å
b = 13.1210 (11) Å
c = 19.8722 (16) Å
V = 1144.14 (17) Å³
Z = 4
Mo Kα radiation
μ = 3.58 mm⁻¹
T = 185 K
0.22 × 0.18 × 0.07 mm

Data collection

Bruker APEX CCD area-detector diffractometer
Absorption correction: multi-scan (SADABS; Bruker, 2001 ) T_min = 0.506, T_max = 0.788
7012 measured reflections
2244 independent reflections
2074 reflections with I > 2σ(I)
R_int = 0.021

Refinement

R[F² > 2σ(F²)] = 0.022
wR(F²) = 0.057
S = 1.02
2244 reflections
154 parameters
H-atom parameters constrained
Δρ_max = 0.49 e Å⁻³
Δρ_min = −0.21 e Å⁻³
Absolute structure: Flack (1983 ), 884 Friedel pairs
Flack parameter: −0.007 (9)

Table 1
Hydrogen-bond geometry (Å, °)

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A
N2—H2⋯O1ⁱ	0.88	2.00	2.864 (2)	169
C5—H5A⋯O2ⁱⁱ	0.99	2.38	3.328 (3)	160
Symmetry codes: (i) $[-x+2, y+{\script{1\over 2}}, -z+{\script{3\over 2}}]$ ; (ii) $[-x+2, y-{\script{1\over 2}}, -z+{\script{3\over 2}}]$ .

Data collection: SMART (Bruker, 2007 ); cell refinement: SAINT (Bruker, 2007); data reduction: SAINT; program(s) used to solve structure: SHELXTL (Sheldrick, 2008 ); program(s) used to refine structure: SHELXTL; molecular graphics: SHELXTL; software used to prepare material for publication: SHELXTL.

Supporting information

Crystal structure: contains datablocks I, global. DOI: 10.1107/S1600536811052962/xu5404sup1.cif

Structure factors: contains datablock I. DOI: 10.1107/S1600536811052962/xu5404Isup2.hkl

Supporting information file. DOI: 10.1107/S1600536811052962/xu5404Isup3.cml

checkCIF report

Comment top

Pyrrolo[2,1-c][1,4]benzodiazepines (PBDs) are of considerable interest because of their wide range of biological activities such as antitumor agents, gene regulators, DNA probes, and anti-ischemic agents (Bose et al., 1992; Hu et al., 2001; Jitendra et al.,2007; Kamal et al., 2002; Thurston & Bose, 1994). As PBDs compounds are of great pharmaceutical importance, we determined the title chiral compound's crystal structure. The molecular is shown in Fig. 1 and the bond lengths and angles are within normal ranges. PBD ring involes in a twisted conformation, similar to a related structure (Cheng et al., 2007). The seven-membered ring C5—C6—C7—N2—C8—C4—N1 (substituted diazepine) is far from planar, and its shape approximates to a twist boat. In this description applied to the title compound (Fig. 1), atoms C5, C8, N1 and N2 form the bottom of the boat (deviation from the mean N1/C5/N2/C8 plane = 0.138 (5) Å), C4 the prow, and C6 and C7 the stern [deviations from the C5/C8/N1/N2 mean plane = 0.641, 0.854, 0.952 Å, respectively]. The bond length of the carbonyl groups C8=O2 and C1=O1 of 1.221 (2) and 1.233 (3) Å, respectively, are somewhat longer than typical carbonyl bonds. This may be due to the fact that atoms O1 and O2 participate in intermolecular van der Waals forces. The five-membered ring N1—C1—C2—C3—C4 (substituted pyrrole) is non-planar and adopts nearly envelope conformation (deviation from the mean C4/N1/C1/C2 plane = 0.019 Å). The C3 atom is located above the plane [deviations from the C4/N1/C1/C2 mean plane = 0.322 Å]. Atom C4 of the title molecule is chiral: S configuration was assigned to this atom based on the known chirality of the equivalent atom in the starting material. In the crystal structure, intermolecular C—H···O and N—H···O hydrogen bonds link the molecules together (Table 1) and help to stabilize the structure.

Related literature top

For applications of pyrrolo[2,1-c][1,4]benzodiazepines, see: Bose et al. (1992); Hu et al. (2001); Jitendra et al. (2007); Kamal et al. (2002); Thurston & Bose (1994). For a related structure, see: Cheng et al. (2007).

Experimental top

(S)-1-(5-bromo-2-nitrobenzyl)-5-oxopyrrolidine-2-carboxylic acid methyl ester (10.68 g, 30 mmol) was dissolved in ethanol (200 ml). Fe (3.92 g, 70 mmol) was added and the solution was heated to reflux for 50 min. The mixture was filtered and the filtrate was concentrated under vacuum. The pure product was obtained through silica gel chromatography (eluant: petroleum ether/ethyl acetate, 2:1). Single crystals suitable for X-ray diffraction were obtained by slow evaporation of a dilute solution of the title compound in ethyl acetate at room temperature.

Computing details top

Data collection: SMART (Bruker, 2007); cell refinement: SAINT (Bruker, 2007); data reduction: SAINT (Bruker, 2007); program(s) used to solve structure: SHELXTL (Sheldrick, 2008); program(s) used to refine structure: SHELXTL (Sheldrick, 2008); molecular graphics: SHELXTL (Sheldrick, 2008); software used to prepare material for publication: SHELXTL (Sheldrick, 2008).

Figures top

	Fig. 1. The structure of the title compound, showing 30% probability displacement ellipsoids and the atom-numbering scheme.
	Fig. 2. The molecular packing of the title compound.

(11aS)-7-Bromo-2,3,5,10,11,11a-hexahydro-1H- pyrrolo[2,1-c][1,4]benzodiazepine-3,11-dione top

Crystal data top

C₁₂H₁₁BrN₂O₂	F(000) = 592
M_r = 295.14	D_x = 1.713 Mg m⁻³
Orthorhombic, P2₁2₁2₁	Mo Kα radiation, λ = 0.71073 Å
Hall symbol: P 2ac 2ab	Cell parameters from 3967 reflections
a = 4.3880 (4) Å	θ = 2.6–26.0°
b = 13.1210 (11) Å	µ = 3.58 mm⁻¹
c = 19.8722 (16) Å	T = 185 K
V = 1144.14 (17) Å³	Plate, colorless
Z = 4	0.22 × 0.18 × 0.07 mm

Data collection top

Bruker APEX CCD area-detector diffractometer	2244 independent reflections
Radiation source: fine-focus sealed tube	2074 reflections with I > 2σ(I)
Graphite monochromator	R_int = 0.021
ϕ and ω scans	θ_max = 26.0°, θ_min = 1.9°
Absorption correction: multi-scan (SADABS; Bruker, 2001)	h = −5→5
T_min = 0.506, T_max = 0.788	k = −14→16
7012 measured reflections	l = −23→24

Refinement top

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)] = 0.022	H-atom parameters constrained
wR(F²) = 0.057	w = 1/[σ²(F_o²) + (0.0236P)²] where P = (F_o² + 2F_c²)/3
S = 1.02	(Δ/σ)_max = 0.001
2244 reflections	Δρ_max = 0.49 e Å⁻³
154 parameters	Δρ_min = −0.21 e Å⁻³
0 restraints	Absolute structure: Flack (1983), 884 Friedel pairs
Primary atom site location: structure-invariant direct methods	Absolute structure parameter: −0.007 (9)

Crystal data top

C₁₂H₁₁BrN₂O₂	V = 1144.14 (17) Å³
M_r = 295.14	Z = 4
Orthorhombic, P2₁2₁2₁	Mo Kα radiation
a = 4.3880 (4) Å	µ = 3.58 mm⁻¹
b = 13.1210 (11) Å	T = 185 K
c = 19.8722 (16) Å	0.22 × 0.18 × 0.07 mm

Data collection top

Bruker APEX CCD area-detector diffractometer	2244 independent reflections
Absorption correction: multi-scan (SADABS; Bruker, 2001)	2074 reflections with I > 2σ(I)
T_min = 0.506, T_max = 0.788	R_int = 0.021
7012 measured reflections

Refinement top

R[F² > 2σ(F²)] = 0.022	H-atom parameters constrained
wR(F²) = 0.057	Δρ_max = 0.49 e Å⁻³
S = 1.02	Δρ_min = −0.21 e Å⁻³
2244 reflections	Absolute structure: Flack (1983), 884 Friedel pairs
154 parameters	Absolute structure parameter: −0.007 (9)
0 restraints

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.

Refinement. Refinement of F² against ALL reflections. The weighted R-factor wR and goodness of fit S are based on F², conventional R-factors R are based on F, with F set to zero for negative F². The threshold expression of F² > σ(F²) is used only for calculating R-factors(gt) etc. and is not relevant to the choice of reflections for refinement. R-factors based on F² are statistically about twice as large as those based on F, and R- factors based on ALL data will be even larger.

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

	x	y	z	U_iso*/U_eq
Br1	0.25401 (6)	0.050666 (16)	0.521650 (10)	0.04269 (9)
O1	1.0495 (4)	0.02986 (12)	0.85625 (8)	0.0421 (4)
O2	0.9421 (4)	0.41192 (12)	0.82097 (8)	0.0443 (4)
N1	0.8206 (4)	0.16602 (12)	0.80547 (8)	0.0238 (4)
N2	0.7499 (5)	0.35871 (11)	0.72148 (7)	0.0275 (3)
H2	0.8076	0.4163	0.7027	0.033*
C1	0.8919 (5)	0.10757 (16)	0.85843 (11)	0.0301 (5)
C2	0.7399 (7)	0.15233 (16)	0.92027 (10)	0.0388 (5)
H2A	0.8826	0.1537	0.9588	0.047*
H2B	0.5574	0.1123	0.9329	0.047*
C3	0.6517 (5)	0.26009 (17)	0.89928 (10)	0.0322 (5)
H3A	0.8033	0.3101	0.9157	0.039*
H3B	0.4489	0.2785	0.9175	0.039*
C4	0.6457 (4)	0.25772 (15)	0.82215 (10)	0.0253 (5)
H4	0.4310	0.2502	0.8060	0.030*
C5	0.9226 (5)	0.14577 (17)	0.73654 (10)	0.0249 (4)
H5A	0.9572	0.0717	0.7312	0.030*
H5B	1.1195	0.1808	0.7289	0.030*
C6	0.6986 (4)	0.18057 (14)	0.68438 (9)	0.0214 (4)
C7	0.6198 (5)	0.28407 (15)	0.67832 (10)	0.0240 (4)
C8	0.7940 (5)	0.35007 (14)	0.78876 (10)	0.0276 (4)
C9	0.5797 (5)	0.11109 (15)	0.63852 (10)	0.0233 (4)
H9	0.6271	0.0407	0.6424	0.028*
C10	0.3923 (5)	0.14489 (17)	0.58721 (10)	0.0267 (4)
C11	0.3113 (5)	0.24598 (17)	0.58081 (10)	0.0295 (5)
H11	0.1805	0.2676	0.5455	0.035*
C12	0.4250 (5)	0.31536 (17)	0.62704 (11)	0.0291 (5)
H12	0.3692	0.3851	0.6237	0.035*

Atomic displacement parameters (Å²) top

	U¹¹	U²²	U³³	U¹²	U¹³	U²³
Br1	0.06219 (16)	0.03517 (14)	0.03072 (13)	0.00004 (16)	−0.01668 (12)	−0.00718 (8)
O1	0.0678 (12)	0.0294 (9)	0.0292 (9)	0.0169 (9)	−0.0064 (8)	0.0009 (7)
O2	0.0671 (12)	0.0285 (9)	0.0374 (10)	−0.0143 (9)	−0.0088 (9)	−0.0034 (7)
N1	0.0321 (10)	0.0195 (8)	0.0199 (8)	0.0021 (7)	0.0005 (7)	−0.0026 (6)
N2	0.0391 (9)	0.0173 (7)	0.0262 (8)	−0.0044 (10)	0.0027 (9)	−0.0003 (6)
C1	0.0400 (12)	0.0244 (11)	0.0261 (12)	−0.0031 (10)	−0.0012 (10)	−0.0022 (9)
C2	0.0597 (13)	0.0332 (11)	0.0235 (10)	0.0038 (16)	0.0059 (14)	0.0014 (8)
C3	0.0411 (13)	0.0314 (12)	0.0241 (11)	0.0036 (9)	0.0040 (9)	−0.0054 (9)
C4	0.0293 (11)	0.0230 (10)	0.0236 (10)	0.0028 (8)	0.0022 (8)	−0.0028 (8)
C5	0.0268 (11)	0.0250 (10)	0.0229 (10)	0.0004 (9)	0.0013 (8)	−0.0031 (9)
C6	0.0230 (11)	0.0221 (9)	0.0190 (9)	0.0013 (8)	0.0077 (8)	0.0005 (7)
C7	0.0288 (10)	0.0202 (10)	0.0231 (10)	−0.0035 (8)	0.0048 (9)	0.0011 (8)
C8	0.0316 (12)	0.0195 (9)	0.0318 (11)	0.0024 (10)	0.0010 (9)	−0.0039 (8)
C9	0.0273 (10)	0.0202 (10)	0.0226 (10)	−0.0005 (8)	0.0028 (9)	−0.0010 (8)
C10	0.0313 (10)	0.0271 (11)	0.0218 (11)	−0.0033 (9)	0.0014 (9)	−0.0043 (9)
C11	0.0359 (13)	0.0320 (11)	0.0205 (10)	0.0047 (10)	−0.0015 (9)	0.0051 (8)
C12	0.0383 (12)	0.0219 (11)	0.0271 (12)	0.0035 (9)	0.0050 (10)	0.0029 (9)

Geometric parameters (Å, º) top

Br1—C10	1.896 (2)	C3—H3B	0.9900
O1—C1	1.233 (3)	C4—C8	1.527 (3)
O2—C8	1.221 (2)	C4—H4	1.0000
N1—C1	1.339 (3)	C5—C6	1.500 (3)
N1—C4	1.465 (2)	C5—H5A	0.9900
N1—C5	1.465 (3)	C5—H5B	0.9900
N2—C8	1.356 (2)	C6—C9	1.391 (3)
N2—C7	1.422 (3)	C6—C7	1.406 (3)
N2—H2	0.8800	C7—C12	1.392 (3)
C1—C2	1.517 (3)	C9—C10	1.383 (3)
C2—C3	1.524 (3)	C9—H9	0.9500
C2—H2A	0.9900	C10—C11	1.379 (3)
C2—H2B	0.9900	C11—C12	1.386 (3)
C3—C4	1.533 (3)	C11—H11	0.9500
C3—H3A	0.9900	C12—H12	0.9500

C1—N1—C4	114.51 (16)	N1—C5—C6	113.00 (16)
C1—N1—C5	124.01 (17)	N1—C5—H5A	109.0
C4—N1—C5	121.36 (15)	C6—C5—H5A	109.0
C8—N2—C7	126.49 (16)	N1—C5—H5B	109.0
C8—N2—H2	116.8	C6—C5—H5B	109.0
C7—N2—H2	116.8	H5A—C5—H5B	107.8
O1—C1—N1	125.2 (2)	C9—C6—C7	118.99 (18)
O1—C1—C2	126.5 (2)	C9—C6—C5	119.95 (17)
N1—C1—C2	108.19 (18)	C7—C6—C5	120.95 (18)
C1—C2—C3	104.43 (17)	C12—C7—C6	119.90 (19)
C1—C2—H2A	110.9	C12—C7—N2	119.02 (18)
C3—C2—H2A	110.9	C6—C7—N2	120.98 (18)
C1—C2—H2B	110.9	O2—C8—N2	122.50 (19)
C3—C2—H2B	110.9	O2—C8—C4	121.76 (18)
H2A—C2—H2B	108.9	N2—C8—C4	115.73 (17)
C2—C3—C4	105.02 (17)	C10—C9—C6	119.74 (19)
C2—C3—H3A	110.7	C10—C9—H9	120.1
C4—C3—H3A	110.7	C6—C9—H9	120.1
C2—C3—H3B	110.7	C11—C10—C9	121.97 (19)
C4—C3—H3B	110.7	C11—C10—Br1	118.79 (15)
H3A—C3—H3B	108.8	C9—C10—Br1	119.20 (16)
N1—C4—C8	109.27 (16)	C10—C11—C12	118.56 (19)
N1—C4—C3	103.52 (16)	C10—C11—H11	120.7
C8—C4—C3	114.27 (17)	C12—C11—H11	120.7
N1—C4—H4	109.9	C11—C12—C7	120.8 (2)
C8—C4—H4	109.9	C11—C12—H12	119.6
C3—C4—H4	109.9	C7—C12—H12	119.6

Hydrogen-bond geometry (Å, º) top

D—H···A	D—H	H···A	D···A	D—H···A
N2—H2···O1ⁱ	0.88	2.00	2.864 (2)	169
C5—H5A···O2ⁱⁱ	0.99	2.38	3.328 (3)	160

Symmetry codes: (i) −x+2, y+1/2, −z+3/2; (ii) −x+2, y−1/2, −z+3/2.

Experimental details

Crystal data
Chemical formula	C₁₂H₁₁BrN₂O₂
M_r	295.14
Crystal system, space group	Orthorhombic, P2₁2₁2₁
Temperature (K)	185
a, b, c (Å)	4.3880 (4), 13.1210 (11), 19.8722 (16)
V (Å³)	1144.14 (17)
Z	4
Radiation type	Mo Kα
µ (mm⁻¹)	3.58
Crystal size (mm)	0.22 × 0.18 × 0.07

Data collection
Diffractometer	Bruker APEX CCD area-detector diffractometer
Absorption correction	Multi-scan (SADABS; Bruker, 2001)
T_min, T_max	0.506, 0.788
No. of measured, independent and observed [I > 2σ(I)] reflections	7012, 2244, 2074
R_int	0.021
(sin θ/λ)_max (Å⁻¹)	0.617

Refinement
R[F² > 2σ(F²)], wR(F²), S	0.022, 0.057, 1.02
No. of reflections	2244
No. of parameters	154
H-atom treatment	H-atom parameters constrained
Δρ_max, Δρ_min (e Å⁻³)	0.49, −0.21
Absolute structure	Flack (1983), 884 Friedel pairs
Absolute structure parameter	−0.007 (9)

Computer programs: SMART (Bruker, 2007), SAINT (Bruker, 2007), SHELXTL (Sheldrick, 2008).

Hydrogen-bond geometry (Å, º) top

D—H···A	D—H	H···A	D···A	D—H···A
N2—H2···O1ⁱ	0.88	2.00	2.864 (2)	168.6
C5—H5A···O2ⁱⁱ	0.99	2.38	3.328 (3)	160.1

Symmetry codes: (i) −x+2, y+1/2, −z+3/2; (ii) −x+2, y−1/2, −z+3/2.

Acknowledgements

The work was supported by grants from the National Natural Science Foundation of China (No. 30973613) and the National Science Foundation for Post-doctoral Scientists of China (No. 2011M500578).

References

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(11aS)-7-Bromo-2,3,5,10,11,11a-hexa­hydro-1H-pyrrolo­[2,1-c][1,4]benzodiazepine-3,11-dione

Related literature

Experimental

Crystal data

Data collection

Refinement

Supporting information

Acknowledgements

References

organic compounds

(11aS)-7-Bromo-2,3,5,10,11,11a-hexahydro-1H-pyrrolo[2,1-c][1,4]benzodiazepine-3,11-dione