(S)-Methyl 2-(4,5-dibromo-1H-pyrrole-2-carboxamido)-3-methyl­butanoate

Zeng, X.-C.

doi:10.1107/S1600536805040547

(S)-Methyl 2-(4,5-dibromo-1H-pyrrole-2-carboxamido)-3-methylbutanoate

The title compound, C₁₁H₁₄Br₂N₂O₃, was synthesized by condensation of methyl l-2-amino-3-methylbutanoate with 4,5-dibromo-2-trichloroacetylpyrrole at room temperature. In the crystal structure, intermolecular N—H

O hydrogen-bonding interactions link the molecules, forming extended chains parallel to [010]. Bioactivity tests show that the title compound inhibits bacteria and also exhibits cytotoxicity.

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Supporting information

	Crystallographic Information File (CIF) https://doi.org/10.1107/S1600536805040547/bd6020sup1.cif Contains datablocks I, global
	Structure factor file (CIF format) https://doi.org/10.1107/S1600536805040547/bd6020Isup2.hkl Contains datablock I

CCDC reference: 296519

checkCIF report

Key indicators

Single-crystal X-ray study
T = 293 K
Mean (C-C) = 0.005 Å
R factor = 0.033
wR factor = 0.075
Data-to-parameter ratio = 19.1

checkCIF/PLATON results

No syntax errors found



Alert level C
PLAT066_ALERT_1_C Predicted and Reported Transmissions Identical .          ?
PLAT125_ALERT_4_C No _symmetry_space_group_name_Hall Given .......          ?
PLAT199_ALERT_1_C Check the Reported _cell_measurement_temperature        293 K
PLAT200_ALERT_1_C Check the Reported _diffrn_ambient_temperature .        293 K
PLAT220_ALERT_2_C Large Non-Solvent    C     Ueq(max)/Ueq(min) ...       2.68 Ratio
PLAT222_ALERT_3_C Large Non-Solvent    H     Ueq(max)/Ueq(min) ...       3.08 Ratio

Alert level G
REFLT03_ALERT_4_G Please check that the estimate of the number of Friedel pairs is
            correct. If it is not, please give the correct count in the
            _publ_section_exptl_refinement section of the submitted CIF.
           From the CIF: _diffrn_reflns_theta_max           27.01
           From the CIF: _reflns_number_total               3112
           Count of symmetry unique reflns         1799
           Completeness (_total/calc)            172.98%
           TEST3: Check Friedels for noncentro structure
           Estimate of Friedel pairs measured      1313
           Fraction of Friedel pairs measured     0.730
           Are heavy atom types Z>Si present        yes

   0 ALERT level A = In general: serious problem
   0 ALERT level B = Potentially serious problem
   6 ALERT level C = Check and explain
   1 ALERT level G = General alerts; check

   3 ALERT type 1 CIF construction/syntax error, inconsistent or missing data
   1 ALERT type 2 Indicator that the structure model may be wrong or deficient
   1 ALERT type 3 Indicator that the structure quality may be low
   2 ALERT type 4 Improvement, methodology, query or suggestion

Comment top

Pyrrole derivatives are well known in many marine organisms (Faulkner, 2001), and some are known to be bioactive (Tasdemir et al., 2002). In our search for bioactive compounds, a series of brominated pyrrole(2-carbonyl)-amino acid esters, including the title compound, (I), has been synthesized by the reaction of amino acid esters with brominated 2-trichloroacetylpyrrole or with brominated 1-methyl-2-trichloroacetylpyrrole. Here we report the crystal structure of (I) and its bioactivity in pharmacological studies.

Bond lengths and angles are unexceptional and are in good agreement with the corresponding values in 4,5-dibromo-1-methyl-1H-pyrrole-2-carbonyl-amino-acetic acid methyl ester (Zeng et al., 2004) and in (s)-methyl-4-methyl-2-(1H-pyrrole-2-carboxamido)pentanoate (Zeng et al., 2005).

In the crystal structure of the title compound there are two kinds of intermolecular hydrogen bonds (Table 1). Each molecule is connected to two other molecules by N—H···O hydrogen-bonded interactions, forming extended chains parallel to [010] (Fig. 2). This packing mode is dissimilar to that in the crystal structure of (s)-methyl-4-methyl-2-(1H-pyrrole-2-carboxamido)pentanoate (MMP) which contains four unique intermolecular hydrogen bonds.

Preliminary antibiotic tests performed in vitro and determined by the agar dilution method (Feng, 2000) indicate that the title compound inhibits five bacteria. Antibiotic activities against these bacteria (determined as minimum inhibitory concentration (mg ml⁻¹) values) are as the following: Streptococcus faecalis, 0.078; Salmonella choleraesu, 0.156; Micrococcus luteus, 0.156; Staphylococcus aureus, 0.156; and Escherichia coli, 0.156. The bioactivities are promising and warrant further studies of this type of compound.

Experimental top

A hydrochloride salt of l-valine methyl ester (0.84 g, 5 mmol) and 4,5-dibromo-2-trichloroacetylpyrrole (1.85 g, 5 mmol) were added to 12 ml acetonitrile, followed by the dropwise addition of triethylamine (1.4 ml). The mixture was stirred at room temperature for 8 h and then poured into water. After filtration, the precipitate was collected as a pale yellow solid. The impure product was dissolved in ethanol at room temperature. Colorless plate suitable for X-ray analysis (m. p. 179°C, in 80.9% yield) crystallized over a period of 7 days. ¹H NMR (DMSO-d₆, 300 Hz): 11.13 (brs, 1H), 6.65 (d, 1H), 6.44 (d, 1H), 4.74–4.70 (m, 1H), 3.70 (s, 3H), 2.24–2.13 (m, 1H), 0.94–0.88 (m, 6H); IR(KBr): 3378, 3277, 3116, 1724, 1635, 1559, 1518, 1319, 1216, 1150; Elemental analysis calculated for C₁₁H₁₄Br₂N₂O₃: C 34.58, H 3.69, N 7.33%; found: C 34.35, H 3.77, N 7.52%.

Computing details top

Data collection: SMART (Bruker,1999); cell refinement: SAINT-Plus (Bruker, 1999); data reduction: SAINT-Plus; program(s) used to solve structure: SHELXTL (Bruker,1997); program(s) used to refine structure: SHELXTL; molecular graphics: SHELXTL; software used to prepare material for publication: SHELXTL.

Figures top

	Fig. 1. The molecular structure of (I), showing the atomic numbering scheme. Displacement ellipsoids are shown at the 30% probability level.
	Fig. 2. The packing of (I), showing the hydrogen-bonded chains (dashed lines).

(S)-Methyl 2-(4,5-dibromo-1H-pyrrole-2-carboxamido)-3-methylbutanoate top

Crystal data top

C₁₁H₁₄Br₂N₂O₃	D_x = 1.773 Mg m⁻³
M_r = 382.04	Melting point: 452 K
Orthorhombic, P2₁2₁2₁	Mo Kα radiation, λ = 0.71073 Å
a = 9.196 (3) Å	Cell parameters from 905 reflections
b = 10.928 (3) Å	θ = 2.6–24.8°
c = 14.244 (4) Å	µ = 5.66 mm⁻¹
V = 1431.5 (7) Å³	T = 293 K
Z = 4	Plate, colorless
F(000) = 752	0.47 × 0.41 × 0.18 mm

Data collection top

Bruker SMART 1K CCD area-detector diffractometer	3112 independent reflections
Radiation source: fine-focus sealed tube	2519 reflections with I > 2σ(I)
Graphite monochromator	R_int = 0.033
ϕ and ω scans	θ_max = 27.0°, θ_min = 2.4°
Absorption correction: multi-scan (SADABS; Sheldrick, 1996)	h = −11→11
T_min = 0.087, T_max = 0.361	k = −13→13
8925 measured reflections	l = −15→18

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)] = 0.033	H-atom parameters constrained
wR(F²) = 0.075	w = 1/[σ²(F_o²) + (0.0245P)² + 0.4813P] where P = (F_o² + 2F_c²)/3
S = 1.04	(Δ/σ)_max = 0.001
3112 reflections	Δρ_max = 0.47 e Å⁻³
163 parameters	Δρ_min = −0.61 e Å⁻³
0 restraints	Absolute structure: Flack (1983)
Primary atom site location: structure-invariant direct methods	Absolute structure parameter: 0.020 (12)

Crystal data top

C₁₁H₁₄Br₂N₂O₃	V = 1431.5 (7) Å³
M_r = 382.04	Z = 4
Orthorhombic, P2₁2₁2₁	Mo Kα radiation
a = 9.196 (3) Å	µ = 5.66 mm⁻¹
b = 10.928 (3) Å	T = 293 K
c = 14.244 (4) Å	0.47 × 0.41 × 0.18 mm

Data collection top

Bruker SMART 1K CCD area-detector diffractometer	3112 independent reflections
Absorption correction: multi-scan (SADABS; Sheldrick, 1996)	2519 reflections with I > 2σ(I)
T_min = 0.087, T_max = 0.361	R_int = 0.033
8925 measured reflections

Refinement top

R[F² > 2σ(F²)] = 0.033	H-atom parameters constrained
wR(F²) = 0.075	Δρ_max = 0.47 e Å⁻³
S = 1.04	Δρ_min = −0.61 e Å⁻³
3112 reflections	Absolute structure: Flack (1983)
163 parameters	Absolute structure parameter: 0.020 (12)
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	0.10111 (5)	0.86539 (4)	0.53610 (3)	0.05906 (14)
Br2	0.11594 (5)	0.55203 (4)	0.45728 (4)	0.06917 (16)
O1	0.5194 (3)	0.4819 (2)	0.73898 (19)	0.0440 (6)
C4	0.3822 (3)	0.6391 (3)	0.6695 (2)	0.0298 (7)
N1	0.3194 (3)	0.5608 (2)	0.60666 (19)	0.0331 (6)
H1A	0.3393	0.4843	0.6010	0.040*
N2	0.5749 (3)	0.6783 (3)	0.77767 (19)	0.0354 (7)
H2A	0.5530	0.7542	0.7702	0.042*
C1	0.2209 (3)	0.6229 (3)	0.5548 (2)	0.0357 (8)
C3	0.3219 (3)	0.7528 (3)	0.6573 (2)	0.0321 (7)
H3A	0.3446	0.8235	0.6905	0.039*
C6	0.6943 (4)	0.6464 (3)	0.8398 (2)	0.0350 (8)
H6A	0.6879	0.5584	0.8525	0.042*
C2	0.2187 (3)	0.7413 (3)	0.5846 (2)	0.0356 (8)
C5	0.4975 (3)	0.5930 (3)	0.7315 (2)	0.0321 (8)
C8	0.8462 (4)	0.6718 (4)	0.7977 (3)	0.0458 (9)
H8A	0.9185	0.6473	0.8447	0.055*
C7	0.6779 (4)	0.7126 (3)	0.9324 (2)	0.0344 (8)
O2	0.6126 (3)	0.8072 (2)	0.94335 (18)	0.0496 (6)
O3	0.7497 (3)	0.6556 (3)	0.99927 (18)	0.0505 (7)
C9	0.7482 (5)	0.7098 (4)	1.0923 (3)	0.0562 (11)
H9A	0.8042	0.6600	1.1344	0.084*
H9B	0.6498	0.7149	1.1145	0.084*
H9C	0.7895	0.7904	1.0896	0.084*
C11	0.8700 (5)	0.5922 (5)	0.7115 (4)	0.0799 (16)
H11A	0.9648	0.6081	0.6860	0.120*
H11B	0.7973	0.6108	0.6653	0.120*
H11C	0.8630	0.5075	0.7289	0.120*
C10	0.8706 (5)	0.8050 (5)	0.7768 (4)	0.0689 (13)
H10A	0.9662	0.8160	0.7511	0.103*
H10B	0.8617	0.8516	0.8336	0.103*
H10C	0.7994	0.8325	0.7322	0.103*

Atomic displacement parameters (Å²) top

	U¹¹	U²²	U³³	U¹²	U¹³	U²³
Br1	0.0689 (3)	0.0505 (2)	0.0577 (3)	0.0140 (2)	−0.0253 (2)	0.0038 (2)
Br2	0.0760 (3)	0.0601 (3)	0.0714 (3)	−0.0006 (2)	−0.0432 (3)	−0.0173 (2)
O1	0.0522 (15)	0.0333 (14)	0.0465 (15)	−0.0012 (11)	−0.0147 (13)	0.0021 (11)
C4	0.0315 (15)	0.0356 (17)	0.0224 (16)	−0.0059 (15)	0.0007 (14)	0.0006 (13)
N1	0.0360 (13)	0.0293 (14)	0.0340 (16)	−0.0042 (12)	−0.0093 (13)	−0.0003 (12)
N2	0.0360 (15)	0.0345 (14)	0.0357 (16)	0.0004 (12)	−0.0118 (13)	0.0003 (12)
C1	0.0367 (16)	0.0389 (19)	0.0315 (19)	−0.0052 (14)	−0.0106 (15)	0.0025 (16)
C3	0.0366 (17)	0.0341 (18)	0.0256 (17)	−0.0041 (15)	−0.0031 (14)	−0.0005 (13)
C6	0.0372 (17)	0.0326 (18)	0.0353 (19)	−0.0014 (15)	−0.0110 (15)	0.0020 (15)
C2	0.0356 (17)	0.040 (2)	0.0313 (19)	−0.0004 (15)	−0.0041 (15)	0.0048 (15)
C5	0.0326 (17)	0.040 (2)	0.0236 (19)	−0.0037 (14)	−0.0004 (14)	0.0013 (14)
C8	0.0379 (19)	0.052 (2)	0.048 (2)	0.0006 (16)	−0.0040 (17)	−0.0022 (18)
C7	0.0331 (16)	0.0377 (19)	0.0323 (19)	−0.0044 (15)	−0.0065 (15)	0.0063 (15)
O2	0.0647 (15)	0.0447 (14)	0.0394 (16)	0.0128 (13)	−0.0089 (14)	0.0002 (12)
O3	0.0640 (17)	0.0498 (17)	0.0378 (15)	0.0137 (14)	−0.0195 (13)	0.0042 (12)
C9	0.063 (2)	0.077 (3)	0.028 (2)	−0.002 (2)	−0.009 (2)	−0.001 (2)
C11	0.068 (3)	0.092 (4)	0.079 (4)	−0.006 (3)	0.021 (3)	−0.027 (3)
C10	0.050 (2)	0.069 (3)	0.087 (4)	−0.013 (2)	0.014 (3)	0.009 (3)

Geometric parameters (Å, º) top

Br1—C2	1.867 (3)	C6—H6A	0.9800
Br2—C1	1.860 (3)	C8—C10	1.503 (6)
O1—C5	1.236 (4)	C8—C11	1.520 (6)
C4—N1	1.366 (4)	C8—H8A	0.9800
C4—C3	1.371 (5)	C7—O2	1.205 (4)
C4—C5	1.469 (4)	C7—O3	1.316 (4)
N1—C1	1.351 (4)	O3—C9	1.452 (4)
N1—H1A	0.8600	C9—H9A	0.9600
N2—C5	1.345 (4)	C9—H9B	0.9600
N2—C6	1.454 (4)	C9—H9C	0.9600
N2—H2A	0.8600	C11—H11A	0.9600
C1—C2	1.362 (5)	C11—H11B	0.9600
C3—C2	1.410 (4)	C11—H11C	0.9600
C3—H3A	0.9300	C10—H10A	0.9600
C6—C7	1.512 (5)	C10—H10B	0.9600
C6—C8	1.545 (5)	C10—H10C	0.9600

N1—C4—C3	108.3 (3)	C10—C8—C6	112.7 (3)
N1—C4—C5	119.0 (3)	C11—C8—C6	109.9 (3)
C3—C4—C5	132.7 (3)	C10—C8—H8A	107.4
C1—N1—C4	109.1 (3)	C11—C8—H8A	107.4
C1—N1—H1A	125.5	C6—C8—H8A	107.4
C4—N1—H1A	125.5	O2—C7—O3	124.3 (3)
C5—N2—C6	122.1 (3)	O2—C7—C6	124.9 (3)
C5—N2—H2A	119.0	O3—C7—C6	110.7 (3)
C6—N2—H2A	119.0	C7—O3—C9	117.5 (3)
N1—C1—C2	108.4 (3)	O3—C9—H9A	109.5
N1—C1—Br2	123.2 (2)	O3—C9—H9B	109.5
C2—C1—Br2	128.4 (3)	H9A—C9—H9B	109.5
C4—C3—C2	106.5 (3)	O3—C9—H9C	109.5
C4—C3—H3A	126.7	H9A—C9—H9C	109.5
C2—C3—H3A	126.7	H9B—C9—H9C	109.5
N2—C6—C7	109.9 (3)	C8—C11—H11A	109.5
N2—C6—C8	113.8 (3)	C8—C11—H11B	109.5
C7—C6—C8	110.0 (3)	H11A—C11—H11B	109.5
N2—C6—H6A	107.6	C8—C11—H11C	109.5
C7—C6—H6A	107.6	H11A—C11—H11C	109.5
C8—C6—H6A	107.6	H11B—C11—H11C	109.5
C1—C2—C3	107.7 (3)	C8—C10—H10A	109.5
C1—C2—Br1	125.7 (3)	C8—C10—H10B	109.5
C3—C2—Br1	126.6 (3)	H10A—C10—H10B	109.5
O1—C5—N2	123.5 (3)	C8—C10—H10C	109.5
O1—C5—C4	120.5 (3)	H10A—C10—H10C	109.5
N2—C5—C4	116.0 (3)	H10B—C10—H10C	109.5
C10—C8—C11	111.8 (4)

C3—C4—N1—C1	0.2 (4)	C6—N2—C5—C4	−178.6 (3)
C5—C4—N1—C1	−177.7 (3)	N1—C4—C5—O1	−12.9 (5)
C4—N1—C1—C2	−0.6 (4)	C3—C4—C5—O1	169.8 (3)
C4—N1—C1—Br2	177.3 (2)	N1—C4—C5—N2	167.0 (3)
N1—C4—C3—C2	0.2 (4)	C3—C4—C5—N2	−10.3 (5)
C5—C4—C3—C2	177.7 (3)	N2—C6—C8—C10	61.9 (5)
C5—N2—C6—C7	−131.2 (3)	C7—C6—C8—C10	−61.9 (4)
C5—N2—C6—C8	104.8 (4)	N2—C6—C8—C11	−63.5 (4)
N1—C1—C2—C3	0.7 (4)	C7—C6—C8—C11	172.6 (4)
Br2—C1—C2—C3	−177.0 (3)	N2—C6—C7—O2	−24.8 (5)
N1—C1—C2—Br1	−179.9 (2)	C8—C6—C7—O2	101.3 (4)
Br2—C1—C2—Br1	2.3 (5)	N2—C6—C7—O3	157.7 (3)
C4—C3—C2—C1	−0.6 (4)	C8—C6—C7—O3	−76.2 (4)
C4—C3—C2—Br1	−180.0 (2)	O2—C7—O3—C9	0.8 (5)
C6—N2—C5—O1	1.2 (5)	C6—C7—O3—C9	178.3 (3)

Hydrogen-bond geometry (Å, º) top

D—H···A	D—H	H···A	D···A	D—H···A
N2—H2A···O1ⁱ	0.86	2.58	3.437 (4)	176
N1—H1A···O2ⁱⁱ	0.86	2.08	2.929 (4)	168

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

Experimental details

Crystal data
Chemical formula	C₁₁H₁₄Br₂N₂O₃
M_r	382.04
Crystal system, space group	Orthorhombic, P2₁2₁2₁
Temperature (K)	293
a, b, c (Å)	9.196 (3), 10.928 (3), 14.244 (4)
V (Å³)	1431.5 (7)
Z	4
Radiation type	Mo Kα
µ (mm⁻¹)	5.66
Crystal size (mm)	0.47 × 0.41 × 0.18

Data collection
Diffractometer	Bruker SMART 1K CCD area-detector diffractometer
Absorption correction	Multi-scan (SADABS; Sheldrick, 1996)
T_min, T_max	0.087, 0.361
No. of measured, independent and observed [I > 2σ(I)] reflections	8925, 3112, 2519
R_int	0.033
(sin θ/λ)_max (Å⁻¹)	0.639

Refinement
R[F² > 2σ(F²)], wR(F²), S	0.033, 0.075, 1.04
No. of reflections	3112
No. of parameters	163
H-atom treatment	H-atom parameters constrained
Δρ_max, Δρ_min (e Å⁻³)	0.47, −0.61
Absolute structure	Flack (1983)
Absolute structure parameter	0.020 (12)

Computer programs: SMART (Bruker,1999), SAINT-Plus (Bruker, 1999), SAINT-Plus, SHELXTL (Bruker,1997), SHELXTL.