N-(4-Chloro-2-nitro­phen­yl)-5-methyl­isoxazole-4-carboxamide

Abstract

In the title compound, C₁₁H₈ClN₃O₄, the dihedral angle between benzene and isoxazole rings is 9.92 (1) °. The nitro group is almost coplanar with the benzene ring with an O—N—C—C torsion angle of 8.4 (3)°. The mol­ecular conformation is stabilized by an intra­molecular N—H⋯O hydrogen bond, closing a six-membered ring.

Related literature

For applications of leflunomide [systematic name: 5-methyl-N-[4-(trifluoro­meth­yl) phen­yl]-isoxazole-4-carboxamide] in the treatment of rheumatoid arthritis, see: Shaw et al. (2011 ▶); Schattenkirchner (2000 ▶). The title compound was synthesized as an immunomodulating leflunomide analog; for another immunomodulating leflunomide analog, see: Huang et al. (2003 ▶).

Experimental

Crystal data

• C₁₁H₈ClN₃O₄

• M _r = 281.65

• Monoclinic,

• a = 5.3870 (11) Å

• b = 23.537 (5) Å

• c = 9.4600 (19) Å

• β = 99.86 (3)°

• V = 1181.8 (4) ų

• Z = 4

• Mo Kα radiation

• μ = 0.34 mm⁻¹

• T = 293 K

• 0.30 × 0.20 × 0.10 mm

Data collection

• Enraf–Nonius CAD-4 diffractometer

• Absorption correction: ψ scan (North et al., 1968 ▶) T _min = 0.905, T _max = 0.967

• 4645 measured reflections

• 2121 independent reflections

• 1558 reflections with I > 2σ(I)

• R _int = 0.044

• 3 standard reflections every 200 reflections intensity decay: 1%

Refinement

• R[F ² > 2σ(F ²)] = 0.042

• wR(F ²) = 0.143

• S = 1.02

• 2121 reflections

• 174 parameters

• H-atom parameters constrained

• Δρ_max = 0.18 e Å⁻³

• Δρ_min = −0.22 e Å⁻³

Data collection: CAD-4 EXPRESS (Enraf–Nonius, 1994 ▶); cell refinement: CAD-4 EXPRESS; data reduction: XCAD4 (Harms & Wocadlo, 1995 ▶); 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

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⋯O2	0.86	1.94	2.629 (3)	136

supplementary crystallographic information

Comment

Leflunomide is one of the most effective isoxazole-containing disease-modifying drugs for treating rheumatoid arthritis(Shaw et al., 2011; Schattenkirchner, 2000). Many leflunomide analogs have been synthesized and exhibit potent immunomodulating effect (Huang, et al., 2003). The title compound, 5-methyl-N-(4-chloro-2-nitrophenyl)isoxazole-4-carboxamide (I), was synthesized as a novel and potent immunomodulating leflunomide analog. We report herein its crystal structure. The molecular structure of the title compound is shown in Fig. 1. The nitro group is approximately coplanar with the benzene ring, as indicated by the torsion angle O1—N1—C5—C4 of 8.4 (3)°. The amide group is also coplanar with the benzene and isoxazole rings [torsion angles N2—C7—C8—C9 and C7—N2—C6—C1 are -8.9 (4) and -3.1 (4)°], respectively. The molecular conformation is stabilized by an intra-molecular N—H···O hydrogen bond (Table 1). In the crystal, infinite zigzag chain are formed via short inter-molecular Cl···O contacts of 3.089 (3) Å.

Experimental

A solution of 0.05 mol of 5-methylisoxazole-4-carboxylic acid chloride (7.3 g) in 20 ml of acetonitrile was added dropwise, while stirring, to 0.1 mol of 4-chloro-2-nitroaniline (17.2 g), dissolved in 150 ml of acetonitrile, at room temperature. After stirring for 40 more minutes, the precipitated 4-chloro-2-nitroaniline hydrochloride was filtered off and washed with 100 ml portions of acetonitrile, and the combined filtrates were concentrated under reduced pressure. 9.6 g (65% of theory) of yellow crytalline 5-methyl-N-(4-Chloro-2-nitrophenyl)isoxazole-4-carboxamide were thus obtained. Crystals of (I) suitable for X-ray diffraction were obtained by slow evaporation of toluene solution.

Refinement

Carbon- and nitrogen-bound H atoms were placed in calculated positions and were treated as riding on the parent C or N atoms with C—H = 0.96 (methyl), 0.97 (methylene) and N—H = 0.86 Å, U_iso(H) = 1.2 U_eq(C, N). The positions of methyl hydrogens were optimized rotationally with U_iso(H) = 1.5 U_eq(C).

Figures

Fig. 1.

The structure of the title compound, showing the atomic numbering scheme. Non-H atoms are shown with 30% probability displacement ellipsoids.

Crystal data

C11H8ClN3O4	F(000) = 576
Mr = 281.65	Dx = 1.583 Mg m−3
Monoclinic, P21/c	Mo Kα radiation, λ = 0.71073 Å
Hall symbol: -P 2ybc	Cell parameters from 25 reflections
a = 5.3870 (11) Å	θ = 9–13°
b = 23.537 (5) Å	µ = 0.34 mm−1
c = 9.4600 (19) Å	T = 293 K
β = 99.86 (3)°	Block, white
V = 1181.8 (4) Å3	0.30 × 0.20 × 0.10 mm
Z = 4

Data collection

Enraf–Nonius CAD-4 diffractometer	1558 reflections with I > 2σ(I)
Radiation source: fine-focus sealed tube	Rint = 0.044
graphite	θmax = 25.2°, θmin = 1.7°
ω/2θ scans	h = 0→6
Absorption correction: ψ scan (North et al., 1968)	k = −28→28
Tmin = 0.905, Tmax = 0.967	l = −11→11
4645 measured reflections	3 standard reflections every 200 reflections
2121 independent reflections	intensity decay: 1%

Refinement

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)] = 0.042	H-atom parameters constrained
wR(F2) = 0.143	w = 1/[σ2(Fo2) + (0.090P)2] where P = (Fo2 + 2Fc2)/3
S = 1.02	(Δ/σ)max < 0.001
2121 reflections	Δρmax = 0.18 e Å−3
174 parameters	Δρmin = −0.22 e Å−3
0 restraints	Extinction correction: SHELXL, Fc*=kFc[1+0.001xFc2λ3/sin(2θ)]-1/4
Primary atom site location: structure-invariant direct methods	Extinction coefficient: 0.010 (3)

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.

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 (Ų)

	x	y	z	Uiso*/Ueq
Cl	1.14810 (15)	0.27507 (3)	0.51209 (9)	0.0712 (3)
N1	0.5249 (4)	0.33771 (10)	0.8313 (2)	0.0534 (6)
C1	0.8613 (5)	0.42551 (11)	0.5906 (3)	0.0476 (6)
H1A	0.8768	0.4628	0.5606	0.057*
O1	0.5463 (5)	0.28905 (9)	0.8742 (3)	0.0868 (8)
O2	0.3751 (4)	0.37087 (9)	0.8716 (2)	0.0611 (5)
C2	0.9988 (5)	0.38350 (11)	0.5390 (3)	0.0507 (6)
H2A	1.1070	0.3927	0.4757	0.061*
N2	0.5564 (4)	0.45566 (9)	0.7398 (2)	0.0469 (5)
H2B	0.4559	0.4440	0.7951	0.056*
N3	0.0876 (5)	0.56302 (12)	0.9317 (3)	0.0656 (7)
O3	0.6784 (4)	0.53680 (8)	0.6379 (2)	0.0586 (5)
C3	0.9774 (5)	0.32777 (11)	0.5806 (3)	0.0475 (6)
O4	0.1878 (4)	0.61421 (9)	0.8857 (2)	0.0658 (6)
C4	0.8225 (5)	0.31427 (11)	0.6765 (3)	0.0501 (6)
H4A	0.8099	0.2768	0.7060	0.060*
C5	0.6850 (5)	0.35645 (10)	0.7294 (2)	0.0434 (6)
C6	0.6978 (4)	0.41348 (10)	0.6875 (2)	0.0406 (5)
C7	0.5541 (5)	0.51330 (10)	0.7158 (2)	0.0433 (6)
C8	0.3842 (4)	0.54381 (11)	0.7965 (2)	0.0444 (6)
C9	0.2056 (5)	0.52340 (12)	0.8774 (3)	0.0555 (7)
H9A	0.1763	0.4850	0.8901	0.067*
C10	0.3644 (5)	0.60153 (11)	0.8058 (3)	0.0522 (7)
C11	0.4990 (7)	0.65000 (12)	0.7545 (4)	0.0731 (9)
H11A	0.4181	0.6848	0.7737	0.110*
H11B	0.4958	0.6464	0.6532	0.110*
H11C	0.6705	0.6503	0.8035	0.110*

Atomic displacement parameters (Ų)

	U11	U22	U33	U12	U13	U23
Cl	0.0730 (5)	0.0583 (5)	0.0884 (6)	0.0099 (4)	0.0308 (4)	−0.0103 (4)
N1	0.0613 (14)	0.0467 (13)	0.0561 (12)	−0.0111 (11)	0.0211 (11)	0.0031 (10)
C1	0.0504 (14)	0.0448 (14)	0.0502 (13)	−0.0018 (12)	0.0158 (11)	0.0077 (11)
O1	0.121 (2)	0.0491 (13)	0.1062 (18)	−0.0060 (12)	0.0648 (16)	0.0174 (11)
O2	0.0612 (12)	0.0607 (12)	0.0687 (12)	−0.0006 (10)	0.0320 (10)	0.0094 (9)
C2	0.0515 (15)	0.0515 (16)	0.0530 (14)	−0.0043 (12)	0.0199 (12)	0.0013 (11)
N2	0.0524 (12)	0.0432 (12)	0.0493 (11)	−0.0006 (9)	0.0210 (10)	0.0049 (9)
N3	0.0568 (14)	0.0717 (18)	0.0722 (15)	0.0055 (12)	0.0221 (12)	−0.0037 (12)
O3	0.0713 (13)	0.0431 (11)	0.0691 (11)	−0.0025 (9)	0.0335 (10)	0.0048 (8)
C3	0.0449 (13)	0.0467 (15)	0.0520 (14)	0.0003 (11)	0.0112 (11)	−0.0044 (11)
O4	0.0620 (12)	0.0666 (14)	0.0703 (12)	0.0135 (10)	0.0152 (10)	−0.0107 (10)
C4	0.0541 (15)	0.0379 (14)	0.0587 (15)	−0.0039 (11)	0.0107 (13)	0.0027 (11)
C5	0.0434 (13)	0.0429 (14)	0.0454 (13)	−0.0068 (11)	0.0123 (11)	0.0015 (10)
C6	0.0430 (13)	0.0411 (13)	0.0377 (11)	−0.0023 (10)	0.0069 (10)	0.0009 (9)
C7	0.0459 (13)	0.0408 (13)	0.0431 (13)	−0.0014 (11)	0.0069 (11)	0.0017 (10)
C8	0.0433 (13)	0.0464 (15)	0.0428 (12)	0.0017 (11)	0.0053 (10)	−0.0003 (10)
C9	0.0513 (15)	0.0590 (18)	0.0577 (15)	−0.0006 (13)	0.0140 (13)	−0.0033 (13)
C10	0.0521 (15)	0.0536 (16)	0.0506 (14)	0.0088 (13)	0.0080 (12)	−0.0030 (12)
C11	0.089 (2)	0.0471 (17)	0.086 (2)	0.0019 (16)	0.0222 (18)	−0.0016 (15)

Geometric parameters (Å, °)

Cl—C3	1.734 (3)	O3—C7	1.210 (3)
N1—O1	1.214 (3)	C3—C4	1.371 (4)
N1—O2	1.230 (3)	O4—C10	1.346 (3)
N1—C5	1.467 (3)	C4—C5	1.382 (3)
C1—C2	1.374 (4)	C4—H4A	0.9300
C1—C6	1.405 (3)	C5—C6	1.405 (3)
C1—H1A	0.9300	C7—C8	1.475 (3)
C2—C3	1.380 (4)	C8—C10	1.367 (4)
C2—H2A	0.9300	C8—C9	1.412 (4)
N2—C7	1.375 (3)	C9—H9A	0.9300
N2—C6	1.393 (3)	C10—C11	1.477 (4)
N2—H2B	0.8600	C11—H11A	0.9600
N3—C9	1.285 (3)	C11—H11B	0.9600
N3—O4	1.419 (3)	C11—H11C	0.9600
O1—N1—O2	121.7 (2)	C6—C5—N1	122.4 (2)
O1—N1—C5	118.0 (2)	N2—C6—C1	122.0 (2)
O2—N1—C5	120.3 (2)	N2—C6—C5	121.6 (2)
C2—C1—C6	121.5 (2)	C1—C6—C5	116.3 (2)
C2—C1—H1A	119.2	O3—C7—N2	124.1 (2)
C6—C1—H1A	119.2	O3—C7—C8	123.3 (2)
C1—C2—C3	120.4 (2)	N2—C7—C8	112.5 (2)
C1—C2—H2A	119.8	C10—C8—C9	103.6 (2)
C3—C2—H2A	119.8	C10—C8—C7	125.4 (2)
C7—N2—C6	129.4 (2)	C9—C8—C7	131.0 (2)
C7—N2—H2B	115.3	N3—C9—C8	113.6 (3)
C6—N2—H2B	115.3	N3—C9—H9A	123.2
C9—N3—O4	104.7 (2)	C8—C9—H9A	123.2
C4—C3—C2	119.9 (2)	O4—C10—C8	109.1 (2)
C4—C3—Cl	120.2 (2)	O4—C10—C11	116.5 (3)
C2—C3—Cl	119.8 (2)	C8—C10—C11	134.3 (3)
C10—O4—N3	109.1 (2)	C10—C11—H11A	109.5
C3—C4—C5	119.8 (2)	C10—C11—H11B	109.5
C3—C4—H4A	120.1	H11A—C11—H11B	109.5
C5—C4—H4A	120.1	C10—C11—H11C	109.5
C4—C5—C6	121.9 (2)	H11A—C11—H11C	109.5
C4—C5—N1	115.7 (2)	H11B—C11—H11C	109.5
C6—C1—C2—C3	0.7 (4)	C4—C5—C6—C1	−1.0 (3)
C1—C2—C3—C4	−1.5 (4)	N1—C5—C6—C1	179.2 (2)
C1—C2—C3—Cl	178.87 (19)	C6—N2—C7—O3	2.0 (4)
C9—N3—O4—C10	−0.4 (3)	C6—N2—C7—C8	−177.5 (2)
C2—C3—C4—C5	1.1 (4)	O3—C7—C8—C10	−7.0 (4)
Cl—C3—C4—C5	−179.31 (19)	N2—C7—C8—C10	172.5 (2)
C3—C4—C5—C6	0.2 (4)	O3—C7—C8—C9	171.5 (2)
C3—C4—C5—N1	180.0 (2)	N2—C7—C8—C9	−8.9 (4)
O1—N1—C5—C4	8.4 (3)	O4—N3—C9—C8	0.4 (3)
O2—N1—C5—C4	−171.8 (2)	C10—C8—C9—N3	−0.2 (3)
O1—N1—C5—C6	−171.8 (2)	C7—C8—C9—N3	−179.0 (2)
O2—N1—C5—C6	7.9 (4)	N3—O4—C10—C8	0.3 (3)
C7—N2—C6—C1	−3.1 (4)	N3—O4—C10—C11	−177.0 (2)
C7—N2—C6—C5	176.7 (2)	C9—C8—C10—O4	−0.1 (3)
C2—C1—C6—N2	−179.6 (2)	C7—C8—C10—O4	178.8 (2)
C2—C1—C6—C5	0.6 (3)	C9—C8—C10—C11	176.5 (3)
C4—C5—C6—N2	179.2 (2)	C7—C8—C10—C11	−4.6 (5)
N1—C5—C6—N2	−0.6 (4)

Hydrogen-bond geometry (Å, °)

D—H···A	D—H	H···A	D···A	D—H···A
N2—H2B···O2	0.86	1.94	2.629 (3)	136.