5-Benzoyl­amino-3-bromo-4-(4-methoxy­phenyl)-4,5-di­hydro­isoxazole-5-carboxyl­ic acid

The title compound, C₁₈H₁₅BrN₂O₅, a promising N-protected α-amino acid, was synthesized directly from an unusual bromo dipole and a 4-(aryl­methyl­ene)­oxazolone. The crystal packing of the title compound is a racemic mixture. Peculiar graph-set motifs driven by the most important hydrogen bonds are described.

S1. Comment

As part of a search for biologically active heterocyclic compounds, the α-amino acid (I) was prepared from bromonitrile oxide, (1), and (Z)-4-Arylmethylene-1,3-oxazol-5-one, (2) (Foti et al., 2004). The reaction appeared to proceed through complete substrate-controlled diastereoselectivity and the unexpected amino acid, (I), was directly isolated after the opening of the fragile oxazolone ring (scheme 1).

Compound (I) is an isoxazoline substituted with (i) a Br atom, (ii) a para-methoxy-phenyl group, (iii) a benzoylamine group and (iv) a carboxylic acid group. The molecule in the asymmetric unit contains two chiral C atoms, C2 and C3, whose configurations are S and R (Fig. 1). Since the compound crystallizes in the centrosymmetric space group P2₁/c, in the solid state it is a racemic mixture. Despite the sp³ hybridization of these C atoms, the isoxazoline ring looks flat [the maximum deviation from the plane is 0.108 (5) Å for atom C2] because of the extended π conjugation over the other sp²-hybridized C atom and the heteroatoms (see the geometrical parameters for atoms O3 and N2 in Table 1). The amide linkage is found in the usual trans conformation [C2—N1—C12—C13 = 179.3 (4)°]; the benzamide moiety, as usual, does not deviate from planarity, allowing an extended π conjugation on atoms C12, N1 and O5. Bond distances and angles of the benzamide fragment are in good agreement with the corresponding values reported in related compounds (Bunuel et al., 1996; Bunuel et al., 1997). Early studies (Domiano et al., 1979) have already reported a large asymmetry in the methoxy-ring angles for anisole moieties. This asymmetry has been ascribed to some degree of conjugation between the O atom and the phenyl ring; we have found evidence to support this interpretation, by analysing the electron density of structures concerning compounds of pharmacological interest and by running theoretical calculations (Bruno et al., 1999; Bruno et al., 2001). In this case, the asymmetry is noticeable for the C7—C8—O4 [124.4 (5)°] and C9—C8—O4 [115.7 (4)°] angles, as well as in the planarity of the methoxy group with respect to the phenyl ring [C7—C8—O4—C11 = −5.1 (8)°], all of which are determined by conjugation effects. Evident conformational freedom generates disorder for the terminal carboxylic acid and para-methoxyphenyl groups, as evidenced by the displacement parameters and structural resolution warnings. The crystal packing is essentially governed by intermolecular hydrogen bonds. The most important interaction links two enantiomeric molecules related by an inversion centre. The other noteworthy hydrogen-bonding interaction develops chains along the [101] direction. In summary, the first level graph-set definition (Bernstein et al., 1995) for this arrangement is C(10)R₂²(10). The three-dimensional packing takes the form of linear coupled strands running along the [101] axis (Fig. 2).

S2. Experimental

Scheme 2 reports the reaction in tetrahydrofurane (THF) leading to (I) as described by Foti et al. (2004). After purification, suitable crystals were obtained by slow evaporation from acetone solutions.

S3. Refinement

H atoms were located in a difference Fourier map, and were then placed in idealized positions and included in the refinement using a riding model.

Computing details

Data collection: XSCANS (Siemens, 1989); cell refinement: XSCANS; data reduction: XPREPW (Bruker, 1997); program(s) used to solve structure: SIR97 (Altomare et al., 1994); program(s) used to refine structure: SHELXL97 (Sheldrick, 1997); molecular graphics: XPW (Bruker, 1997); software used to prepare material for publication: 'PARST97 (Nardelli, 1995) and WinGX-PC (Farrugia, 1999)'.

Figures

	Fig. 1. A view of (I), with 30% probability displacement ellipsoids and the atom-numbering scheme.
	Fig. 2. The crystal packing of (I), showing intermolecular interactions as dashed lines.

5-Benzoylamino-3-bromo-4-(4-methoxy-phenyl)-4,5-dihydro-isoxazole- 5-carboxylic acid

Crystal data

C18H15BrN2O5	F(000) = 848
Mr = 419.23	Dx = 1.541 Mg m^−3
Monoclinic, P21/c	Mo Kα radiation, λ = 0.71073 Å
Hall symbol: -P 2ybc	Cell parameters from 39 reflections
a = 9.9280 (8) Å	θ = 5.2–13.9°
b = 19.9509 (17) Å	µ = 2.31 mm^−1
c = 9.5841 (14) Å	T = 298 K
β = 107.875 (9)°	Irregular, colourless
V = 1806.7 (4) Å^3	0.5 × 0.38 × 0.3 mm
Z = 4

Data collection

Bruker P4 diffractometer	Rint = 0.021
ω scans	θmax = 25.0°, θmin = 2.0°
Absorption correction: integration (XPREPW; Bruker, 1997)	h = −11→11
Tmin = 0.305, Tmax = 0.579	k = −1→23
3980 measured reflections	l = −1→11
3157 independent reflections	3 standard reflections every 197 reflections
1773 reflections with I > 2σ(I)	intensity decay: none

Refinement

Refinement on F^2	H-atom parameters constrained
Least-squares matrix: full	w = 1/[σ^2(Fo^2) + (0.0481P)^2 + 3.8612P] where P = (Fo^2 + 2Fc^2)/3
R[F^2 > 2σ(F^2)] = 0.059	(Δ/σ)max = 0.001
wR(F^2) = 0.149	Δρmax = 0.65 e Å^−3
S = 1.02	Δρmin = −0.86 e Å^−3
3157 reflections	Extinction correction: SHELXL97, Fc^*=kFc[1+0.001xFc^2λ^3/sin(2θ)]^-1/4
237 parameters	Extinction coefficient: 0.0040 (7)
0 restraints

Special details

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 (Ų)

	x	y	z	Uiso*/Ueq
Br1	0.22027 (9)	0.72836 (4)	0.17025 (11)	0.1073 (5)
N2	0.2661 (5)	0.6082 (3)	0.3096 (6)	0.0641 (14)
N1	0.3490 (4)	0.47665 (19)	0.1148 (4)	0.0386 (10)
H1	0.3048	0.4771	0.0224	0.046*
O1	0.6249 (4)	0.53704 (19)	0.1837 (4)	0.0494 (9)
O2	0.5964 (5)	0.5553 (2)	0.4069 (4)	0.0762 (13)
H2	0.6831	0.5565	0.4345	0.114*
O3	0.3179 (4)	0.54213 (18)	0.3046 (4)	0.0527 (10)
O4	−0.0749 (4)	0.5737 (2)	−0.4601 (4)	0.0617 (11)
O5	0.4433 (4)	0.41504 (18)	0.3180 (4)	0.0541 (10)
C1	0.5501 (5)	0.5421 (2)	0.2631 (5)	0.0373 (12)
C2	0.3885 (5)	0.5383 (2)	0.1914 (5)	0.0369 (12)
C3	0.3374 (5)	0.6016 (2)	0.0965 (6)	0.0465 (14)
H3A	0.4195	0.6255	0.0848	0.056*
C4	0.2802 (6)	0.6393 (3)	0.2005 (7)	0.0578 (17)
C5	0.2280 (5)	0.5928 (2)	−0.0522 (6)	0.0425 (13)
C6	0.2624 (5)	0.6071 (3)	−0.1774 (6)	0.0487 (14)
H6A	0.3539	0.6213	−0.1685	0.058*
C7	0.1663 (5)	0.6011 (3)	−0.3164 (6)	0.0482 (14)
H7A	0.1932	0.6102	−0.3993	0.058*
C8	0.0304 (5)	0.5813 (3)	−0.3293 (6)	0.0462 (13)
C9	−0.0067 (5)	0.5661 (3)	−0.2047 (6)	0.0537 (15)
H9A	−0.0979	0.5516	−0.2134	0.064*
C10	0.0909 (5)	0.5724 (3)	−0.0691 (6)	0.0513 (14)
H10A	0.0643	0.5627	0.0137	0.062*
C11	−0.0421 (7)	0.5928 (4)	−0.5889 (6)	0.083 (2)
H11A	−0.1242	0.5872	−0.6728	0.124*
H11B	0.0333	0.5652	−0.5996	0.124*
H11C	−0.0131	0.6389	−0.5812	0.124*
C12	0.3805 (5)	0.4171 (3)	0.1863 (6)	0.0402 (12)
C13	0.3348 (5)	0.3547 (2)	0.1004 (6)	0.0401 (12)
C14	0.3989 (7)	0.2960 (3)	0.1602 (8)	0.0690 (18)
H14A	0.4689	0.2967	0.2506	0.083*
C15	0.3609 (9)	0.2362 (3)	0.0882 (10)	0.095 (3)
H15A	0.4064	0.197	0.1294	0.115*
C16	0.2575 (10)	0.2340 (4)	−0.0424 (10)	0.093 (2)
H16A	0.2333	0.1934	−0.0916	0.111*
C17	0.1887 (9)	0.2917 (4)	−0.1019 (8)	0.089 (2)
H17A	0.1152	0.29	−0.1897	0.107*
C18	0.2284 (7)	0.3527 (3)	−0.0318 (6)	0.0626 (17)
H18A	0.1835	0.392	−0.0737	0.075*

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
Br1	0.0908 (6)	0.0532 (4)	0.1516 (9)	0.0195 (4)	−0.0015 (5)	−0.0267 (5)
N2	0.056 (3)	0.063 (3)	0.077 (4)	−0.004 (3)	0.024 (3)	−0.029 (3)
N1	0.045 (2)	0.038 (2)	0.029 (2)	−0.0034 (19)	0.0048 (19)	−0.002 (2)
O1	0.044 (2)	0.071 (3)	0.0335 (19)	−0.0023 (19)	0.0125 (17)	−0.0019 (19)
O2	0.082 (3)	0.079 (3)	0.057 (3)	−0.013 (2)	0.007 (2)	−0.004 (2)
O3	0.058 (2)	0.052 (2)	0.057 (2)	−0.0050 (19)	0.032 (2)	−0.011 (2)
O4	0.047 (2)	0.086 (3)	0.045 (2)	−0.008 (2)	0.0050 (19)	0.009 (2)
O5	0.073 (3)	0.051 (2)	0.034 (2)	−0.0021 (19)	0.009 (2)	0.0034 (18)
C1	0.047 (3)	0.035 (3)	0.026 (3)	−0.006 (2)	0.005 (2)	0.000 (2)
C2	0.042 (3)	0.037 (3)	0.033 (3)	−0.007 (2)	0.014 (2)	−0.003 (2)
C3	0.039 (3)	0.039 (3)	0.055 (3)	−0.006 (2)	0.003 (3)	0.002 (3)
C4	0.050 (3)	0.042 (3)	0.070 (4)	0.004 (3)	0.000 (3)	−0.023 (3)
C5	0.041 (3)	0.035 (3)	0.046 (3)	−0.001 (2)	0.005 (3)	0.005 (3)
C6	0.031 (3)	0.045 (3)	0.067 (4)	−0.004 (2)	0.010 (3)	0.009 (3)
C7	0.043 (3)	0.054 (3)	0.050 (3)	−0.002 (3)	0.019 (3)	0.010 (3)
C8	0.037 (3)	0.049 (3)	0.048 (3)	0.000 (2)	0.007 (3)	0.008 (3)
C9	0.033 (3)	0.071 (4)	0.056 (4)	−0.014 (3)	0.012 (3)	0.002 (3)
C10	0.040 (3)	0.062 (4)	0.052 (3)	−0.008 (3)	0.015 (3)	0.005 (3)
C11	0.080 (5)	0.114 (6)	0.046 (4)	−0.016 (4)	0.006 (3)	0.014 (4)
C12	0.041 (3)	0.043 (3)	0.038 (3)	−0.001 (2)	0.015 (2)	0.008 (3)
C13	0.049 (3)	0.036 (3)	0.039 (3)	−0.005 (2)	0.019 (3)	0.002 (2)
C14	0.075 (4)	0.047 (4)	0.078 (5)	−0.003 (3)	0.014 (4)	−0.002 (3)
C15	0.115 (6)	0.043 (4)	0.121 (7)	0.007 (4)	0.025 (6)	−0.005 (5)
C16	0.138 (7)	0.050 (4)	0.095 (6)	−0.031 (5)	0.042 (6)	−0.023 (5)
C17	0.125 (6)	0.067 (5)	0.061 (4)	−0.032 (5)	0.005 (4)	−0.013 (4)
C18	0.086 (4)	0.046 (3)	0.047 (4)	−0.015 (3)	0.007 (3)	−0.002 (3)

Geometric parameters (Å, º)

Br1—C4	1.868 (6)	C7—C8	1.374 (7)
N2—C4	1.260 (8)	C7—H7A	0.93
N2—O3	1.421 (6)	C8—C9	1.387 (7)
N1—C12	1.360 (6)	C9—C10	1.367 (7)
N1—C2	1.424 (6)	C9—H9A	0.93
N1—H1	0.86	C10—H10A	0.93
O1—C1	1.220 (6)	C11—H11A	0.96
O2—C1	1.338 (6)	C11—H11B	0.96
O2—H2	0.82	C11—H11C	0.96
O3—C2	1.463 (5)	C12—C13	1.484 (7)
O4—C8	1.373 (6)	C13—C14	1.373 (7)
O4—C11	1.422 (7)	C13—C18	1.378 (7)
O5—C12	1.224 (6)	C14—C15	1.370 (9)
C1—C2	1.541 (7)	C14—H14A	0.93
C2—C3	1.548 (7)	C15—C16	1.355 (10)
C3—C4	1.493 (8)	C15—H15A	0.93
C3—C5	1.514 (7)	C16—C17	1.371 (10)
C3—H3A	0.98	C16—H16A	0.93
C5—C6	1.375 (7)	C17—C18	1.387 (8)
C5—C10	1.382 (7)	C17—H17A	0.93
C6—C7	1.385 (7)	C18—H18A	0.93
C6—H6A	0.93
C4—N2—O3	107.2 (5)	O4—C8—C9	115.7 (4)
C12—N1—C2	120.7 (4)	C7—C8—C9	119.9 (5)
C12—N1—H1	119.6	C10—C9—C8	120.0 (5)
C2—N1—H1	119.6	C10—C9—H9A	120
C1—O2—H2	109.5	C8—C9—H9A	120
N2—O3—C2	109.5 (4)	C9—C10—C5	121.5 (5)
C8—O4—C11	116.7 (4)	C9—C10—H10A	119.2
O1—C1—O2	125.2 (5)	C5—C10—H10A	119.2
O1—C1—C2	117.9 (4)	O4—C11—H11A	109.5
O2—C1—C2	116.8 (4)	O4—C11—H11B	109.5
N1—C2—O3	108.0 (4)	H11A—C11—H11B	109.5
N1—C2—C1	110.9 (4)	O4—C11—H11C	109.5
O3—C2—C1	109.7 (4)	H11A—C11—H11C	109.5
N1—C2—C3	114.4 (4)	H11B—C11—H11C	109.5
O3—C2—C3	104.4 (4)	O5—C12—N1	120.9 (5)
C1—C2—C3	109.3 (4)	O5—C12—C13	121.1 (5)
C4—C3—C5	112.1 (4)	N1—C12—C13	118.0 (4)
C4—C3—C2	98.2 (4)	C14—C13—C18	119.0 (5)
C5—C3—C2	118.0 (4)	C14—C13—C12	117.4 (5)
C4—C3—H3A	109.3	C18—C13—C12	123.6 (5)
C5—C3—H3A	109.3	C15—C14—C13	120.8 (7)
C2—C3—H3A	109.3	C15—C14—H14A	119.6
N2—C4—C3	117.9 (5)	C13—C14—H14A	119.6
N2—C4—Br1	119.1 (5)	C16—C15—C14	120.5 (7)
C3—C4—Br1	123.0 (5)	C16—C15—H15A	119.7
C6—C5—C10	117.3 (5)	C14—C15—H15A	119.7
C6—C5—C3	119.9 (5)	C15—C16—C17	119.7 (7)
C10—C5—C3	122.7 (5)	C15—C16—H16A	120.1
C5—C6—C7	122.6 (5)	C17—C16—H16A	120.1
C5—C6—H6A	118.7	C16—C17—C18	120.3 (7)
C7—C6—H6A	118.7	C16—C17—H17A	119.9
C8—C7—C6	118.6 (5)	C18—C17—H17A	119.9
C8—C7—H7A	120.7	C13—C18—C17	119.7 (6)
C6—C7—H7A	120.7	C13—C18—H18A	120.2
O4—C8—C7	124.4 (5)	C17—C18—H18A	120.2
C4—N2—O3—C2	9.3 (6)	C2—C3—C5—C10	66.9 (7)
C12—N1—C2—O3	−60.9 (5)	C10—C5—C6—C7	−0.7 (8)
C12—N1—C2—C1	59.3 (5)	C3—C5—C6—C7	−178.9 (5)
C12—N1—C2—C3	−176.6 (4)	C5—C6—C7—C8	1.3 (8)
N2—O3—C2—N1	−138.4 (4)	C11—O4—C8—C7	−5.1 (8)
N2—O3—C2—C1	100.7 (4)	C11—O4—C8—C9	176.4 (5)
N2—O3—C2—C3	−16.3 (5)	C6—C7—C8—O4	179.7 (5)
O1—C1—C2—N1	58.1 (6)	C6—C7—C8—C9	−1.8 (8)
O2—C1—C2—N1	−126.3 (5)	O4—C8—C9—C10	−179.7 (5)
O1—C1—C2—O3	177.3 (4)	C7—C8—C9—C10	1.6 (9)
O2—C1—C2—O3	−7.1 (6)	C8—C9—C10—C5	−1.0 (9)
O1—C1—C2—C3	−68.9 (6)	C6—C5—C10—C9	0.5 (8)
O2—C1—C2—C3	106.8 (5)	C3—C5—C10—C9	178.7 (5)
N1—C2—C3—C4	133.4 (4)	C2—N1—C12—O5	0.1 (7)
O3—C2—C3—C4	15.7 (4)	C2—N1—C12—C13	179.3 (4)
C1—C2—C3—C4	−101.6 (4)	O5—C12—C13—C14	−18.6 (7)
N1—C2—C3—C5	12.9 (6)	N1—C12—C13—C14	162.3 (5)
O3—C2—C3—C5	−104.8 (5)	O5—C12—C13—C18	158.6 (5)
C1—C2—C3—C5	137.9 (5)	N1—C12—C13—C18	−20.6 (7)
O3—N2—C4—C3	2.4 (7)	C18—C13—C14—C15	1.8 (10)
O3—N2—C4—Br1	179.2 (3)	C12—C13—C14—C15	179.1 (6)
C5—C3—C4—N2	112.9 (6)	C13—C14—C15—C16	−1.1 (12)
C2—C3—C4—N2	−11.9 (6)	C14—C15—C16—C17	−1.1 (13)
C5—C3—C4—Br1	−63.8 (6)	C15—C16—C17—C18	2.6 (12)
C2—C3—C4—Br1	171.4 (4)	C14—C13—C18—C17	−0.3 (9)
C4—C3—C5—C6	132.0 (5)	C12—C13—C18—C17	−177.5 (6)
C2—C3—C5—C6	−115.0 (5)	C16—C17—C18—C13	−1.9 (11)
C4—C3—C5—C10	−46.1 (7)

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
N1—H1···O1^i	0.86	2.31	2.963 (5)	133
O2—H2···O4^ii	0.82	2.33	3.139 (6)	170

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