5-(1H-Indol-3-yl)-3-(4-methyl­phen­yl)-4,5-dihydro­isoxazoline

The title compound, C₁₈H₁₆N₂O, was synthesized by the cyclo­condensation of 1-(1H-indol-3-yl)-3-(4-methyl­phen­yl)­prop-1-en-3-one with hydroxylamine hydro­chloride. The isoxazoline ring adopts an envelope conformation. Symmetry-related mol­ecules are linked via N—H...O hydrogen bonds into a chain along the a axis.

Key indicators

• Single-crystal X-ray study
• T = 294 K
• Mean [sigma](C-C) = 0.004 Å
• R factor = 0.039
• wR factor = 0.093
• Data-to-parameter ratio = 9.0

checkCIF/PLATON results

No syntax errors found



Alert level C
PLAT230_ALERT_2_C Hirshfeld Test Diff for    C1     -   C8      ..       5.33 su
PLAT230_ALERT_2_C Hirshfeld Test Diff for    C14    -   C15     ..       5.24 su

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           26.41
           From the CIF: _reflns_number_total               1747
           Count of symmetry unique reflns         1751
           Completeness (_total/calc)             99.77%
           TEST3: Check Friedels for noncentro structure
           Estimate of Friedel pairs measured         0
           Fraction of Friedel pairs measured     0.000
           Are heavy atom types Z>Si present         no

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

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

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S1. Comment

Indole skeletons play an important role as an intermediate for the design of many pharmacologically active compounds (Sundberg, 1996). Indole derivatives have been widely studied because of their biological activities, such as anti-inflammatory, antibacterial response etc. Isoxazole compounds demonstrate antiproliferative activity on tumor cells of different lineages and are able to induce erythroid differentiation and adipogenic conversion (Simoni et al., 1991). Isoxazoline derivatives act as inhibitors of Human Leukocyte Elastase (HLE) and cathepsin G (Cath G) (William et al., 1995). In view of these potential uses, we have recently focused our attention on the preparation of isoxazoline derivatives, using chalcone synthons (Darid et al., 1998). The title compound, (I), was synthesized by the cyclocondensation of 1–3'-indolyl-3-(4'-methyl)-phenyl-1-propene-3-one in the presence of oxammonium hydrochloride. An X-ray crystal structure determination of (I) was carried out to elucidate the structure, and the results are presented here.

In compound (I), the indole ring system is essentially planar (Fig. 1). The isoxazoline ring adopts an envelope conformation. Atom C9 deviates from the O1/N2/C10/C11 plane by 0.385 (4) Å. The N1/C1–C8 and C12–C17 planes form dihedral angles of 86.3 (1) and 14.8 (2)°, respectively, with the O1/N2/C10/C11 plane. Symmetry-related molecules are linked via N—H···O hydrogen bonds (Table 1) into a chain along the a axis.

S2. Experimental

A mixture of p-methylacetophenone (4.64 g, 35 mmol) and indole-3-aldehyde (2.00 g, 14 mmol) in MeOH (50 ml) was stirred and then 60% KOH aqueous solution (17 ml) was added dropwise at 298 K. The mixture was stirred for 42 h at 323–333 K and then cooled to room temperature and poured on water. The resulting precipitate was purified by preparative thin-layer chromatography (CH₂Cl₂/MeOH 18:1 as eluant) to give a yellow powder product, E-1-(3'-indolyl)-3-(4'-methyl)phenyl-1-propenone (0.593 g, m.p. 430–431 K, yield 16.5%). A mixture of E-1-(3'-indolyl)-3-(4'-methyl)phenyl-1-propenone (0.25 g, 1 mmol) and oxammonium hydrochloride (0.17 g, 2.5 mmol) in EtOH (30 ml) was stirred, and NaOH (0.04 mg, 1 mmol) and water (8 drops) were added. The mixture was refluxed for 42 h and then cooled to 298 K. The mixture was filtered, the filtrate was dried under pressure and the obtained solid was crystallized from EtOH to give a solid product (yield 54.3%). Single crystals of the title compound, suitable for X-ray diffraction study, were obtained by slow evaporation of a methanol solution (m.p. 440–442 K). ¹H NMR (CDCl ₃ , p.p.m.): 2.39 (s, 3H), 6.02 (dd, 1H, ₁J = 9.03 Hz, ₂J = 10.71 Hz), 3.52 (dd, 1H, ₁J = 10.86 Hz, ₂J = 16.56 Hz), 3.76 (dd, 1H, ₁J = 10.86 Hz, ₂J = 16.60 Hz), 7.09–7.64 (m, 9H), 8.15 (br s, 1H).

S3. Refinement

Atom H1A was located in a difference map and refined isotropically. The other H atoms were positioned geometrically (C—H = 0.93–0.97 Å) and constrained to ride on their parent atoms, with U_iso(H) values of 1.5U_eq(carrier atom) for methyl and 1.2U_eq(C) for the remaining H atoms. The methyl group was allowed to rotate freely about the C—C bond. In the absence of significant anomalous dispersion effects, Friedel pairs were merged before the final refinement.

Computing details

Data collection: SMART (Bruker, 1997); cell refinement: SAINT (Bruker, 1997); data reduction: SAINT; program(s) used to solve structure: SHELXS97 (Sheldrick, 1997); program(s) used to refine structure: SHELXL97 (Sheldrick, 1997); molecular graphics: SHELXTL (Bruker, 1997); software used to prepare material for publication: SHELXTL.

Figures

Fig. 1. A view of (I), showing the atom-labelling scheme. Displacement ellipsoids are drawn at the 30% probability level.

5-(1H-Indol-3-yl)-3-(4-methylphenyl)-4,5-dihydroisoxazoline

Crystal data

C18H16N2O	Dx = 1.238 Mg m^−3
Mr = 276.33	Melting point: 441 K
Orthorhombic, P212121	Mo Kα radiation, λ = 0.71073 Å
Hall symbol: P 2ac 2ab	Cell parameters from 1772 reflections
a = 8.1881 (19) Å	θ = 2.9–21.2°
b = 12.713 (3) Å	µ = 0.08 mm^−1
c = 14.239 (3) Å	T = 294 K
V = 1482.3 (6) Å^3	Block, purple
Z = 4	0.30 × 0.24 × 0.12 mm
F(000) = 584

Data collection

Bruker SMART CCD area-detector diffractometer	1747 independent reflections
Radiation source: fine-focus sealed tube	1120 reflections with I > 2σ(I)
Graphite monochromator	Rint = 0.050
ϕ and ω scans	θmax = 26.4°, θmin = 2.2°
Absorption correction: multi-scan (SADABS; Sheldrick, 1996)	h = −9→10
Tmin = 0.968, Tmax = 0.991	k = −12→15
8368 measured reflections	l = −17→15

Refinement

Refinement on F^2	Primary atom site location: structure-invariant direct methods
Least-squares matrix: full	Secondary atom site location: difference Fourier map
R[F^2 > 2σ(F^2)] = 0.039	Hydrogen site location: inferred from neighbouring sites
wR(F^2) = 0.093	H atoms treated by a mixture of independent and constrained refinement
S = 1.02	w = 1/[σ^2(Fo^2) + (0.0374P)^2 + 0.1511P] where P = (Fo^2 + 2Fc^2)/3
1747 reflections	(Δ/σ)max = 0.001
195 parameters	Δρmax = 0.11 e Å^−3
0 restraints	Δρmin = −0.13 e Å^−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
O1	1.0214 (3)	−0.03619 (14)	0.58725 (13)	0.0585 (6)
N1	0.7346 (4)	−0.2791 (2)	0.4315 (2)	0.0720 (9)
H1A	0.686 (6)	−0.335 (3)	0.424 (3)	0.125 (17)*
N2	1.0613 (3)	0.06924 (18)	0.61107 (15)	0.0537 (6)
C1	0.8258 (4)	−0.1266 (2)	0.4900 (2)	0.0512 (7)
C2	0.8890 (3)	−0.1382 (2)	0.39596 (19)	0.0506 (7)
C3	0.9899 (4)	−0.0790 (3)	0.3374 (2)	0.0676 (9)
H3	1.0326	−0.0151	0.3577	0.081*
C4	1.0255 (5)	−0.1167 (3)	0.2486 (2)	0.0878 (11)
H4	1.0924	−0.0774	0.2092	0.105*
C5	0.9634 (5)	−0.2120 (4)	0.2172 (3)	0.0971 (13)
H5	0.9896	−0.2352	0.1571	0.117*
C6	0.8643 (5)	−0.2726 (3)	0.2727 (3)	0.0831 (11)
H6	0.8230	−0.3366	0.2517	0.100*
C7	0.8282 (4)	−0.2347 (2)	0.3618 (2)	0.0603 (9)
C8	0.7342 (4)	−0.2139 (2)	0.5070 (3)	0.0670 (9)
H8	0.6787	−0.2270	0.5628	0.080*
C9	0.8496 (4)	−0.0396 (2)	0.5576 (2)	0.0573 (8)
H9	0.7820	−0.0536	0.6130	0.069*
C10	0.8191 (4)	0.0732 (2)	0.5261 (2)	0.0588 (8)
H10A	0.8329	0.0812	0.4588	0.071*
H10B	0.7110	0.0973	0.5439	0.071*
C11	0.9497 (4)	0.1296 (2)	0.57947 (17)	0.0465 (6)
C12	0.9562 (4)	0.2435 (2)	0.59429 (17)	0.0459 (7)
C13	1.0595 (4)	0.2882 (2)	0.66125 (19)	0.0539 (7)
H13	1.1280	0.2452	0.6965	0.065*
C14	1.0607 (4)	0.3958 (2)	0.67571 (19)	0.0579 (8)
H14	1.1309	0.4240	0.7204	0.070*
C15	0.9599 (4)	0.4624 (2)	0.62517 (19)	0.0519 (7)
C16	0.8611 (4)	0.4184 (2)	0.5577 (2)	0.0574 (8)
H16	0.7948	0.4617	0.5214	0.069*
C17	0.8587 (4)	0.3108 (2)	0.54274 (19)	0.0533 (7)
H17	0.7899	0.2832	0.4970	0.064*
C18	0.9587 (4)	0.5789 (2)	0.6439 (2)	0.0702 (9)
H18A	0.9517	0.6162	0.5854	0.105*
H18B	1.0574	0.5984	0.6758	0.105*
H18C	0.8663	0.5963	0.6823	0.105*

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
O1	0.0610 (13)	0.0443 (11)	0.0703 (13)	0.0098 (10)	−0.0141 (11)	−0.0086 (10)
N1	0.071 (2)	0.0399 (15)	0.105 (2)	−0.0066 (15)	−0.0145 (18)	−0.0076 (17)
N2	0.0581 (16)	0.0495 (15)	0.0536 (13)	0.0066 (13)	−0.0051 (13)	−0.0096 (11)
C1	0.0511 (18)	0.0375 (16)	0.0651 (18)	−0.0016 (14)	−0.0046 (15)	0.0014 (15)
C2	0.0450 (16)	0.0459 (16)	0.0611 (17)	−0.0019 (14)	−0.0081 (14)	−0.0055 (15)
C3	0.056 (2)	0.074 (2)	0.072 (2)	−0.0112 (18)	−0.0038 (17)	−0.0008 (19)
C4	0.071 (3)	0.126 (3)	0.067 (2)	−0.008 (3)	0.0053 (19)	−0.002 (2)
C5	0.076 (3)	0.139 (4)	0.076 (2)	0.012 (3)	−0.005 (2)	−0.032 (3)
C6	0.071 (2)	0.081 (3)	0.096 (3)	0.015 (2)	−0.024 (2)	−0.043 (2)
C7	0.0524 (19)	0.0495 (19)	0.079 (2)	0.0024 (16)	−0.0130 (18)	−0.0109 (17)
C8	0.072 (2)	0.0520 (19)	0.077 (2)	−0.0011 (18)	0.0023 (18)	0.0069 (19)
C9	0.0527 (19)	0.0526 (18)	0.0667 (19)	0.0008 (15)	0.0005 (16)	−0.0039 (16)
C10	0.0540 (19)	0.0516 (18)	0.0708 (19)	0.0048 (16)	−0.0092 (16)	−0.0135 (16)
C11	0.0431 (15)	0.0491 (16)	0.0474 (15)	0.0046 (15)	−0.0002 (14)	−0.0055 (13)
C12	0.0447 (16)	0.0479 (16)	0.0451 (14)	0.0029 (14)	0.0016 (15)	−0.0047 (13)
C13	0.0591 (18)	0.0523 (18)	0.0503 (15)	−0.0005 (16)	−0.0043 (16)	−0.0001 (14)
C14	0.065 (2)	0.0589 (19)	0.0501 (16)	−0.0112 (17)	−0.0004 (16)	−0.0085 (15)
C15	0.0539 (18)	0.0484 (17)	0.0533 (16)	−0.0012 (16)	0.0079 (16)	−0.0023 (14)
C16	0.0563 (19)	0.0533 (19)	0.0626 (18)	0.0111 (16)	−0.0048 (16)	−0.0018 (15)
C17	0.0501 (18)	0.0534 (18)	0.0563 (17)	0.0065 (15)	−0.0087 (15)	−0.0090 (15)
C18	0.077 (2)	0.0535 (19)	0.080 (2)	−0.0043 (19)	0.008 (2)	−0.0075 (16)

Geometric parameters (Å, º)

O1—N2	1.421 (3)	C9—C10	1.524 (4)
O1—C9	1.469 (4)	C9—H9	0.98
N1—C8	1.358 (4)	C10—C11	1.495 (4)
N1—C7	1.375 (4)	C10—H10A	0.97
N1—H1A	0.82 (4)	C10—H10B	0.97
N2—C11	1.275 (3)	C11—C12	1.464 (3)
C1—C8	1.361 (4)	C12—C17	1.382 (3)
C1—C2	1.443 (4)	C12—C13	1.395 (4)
C1—C9	1.479 (4)	C13—C14	1.383 (4)
C2—C3	1.395 (4)	C13—H13	0.93
C2—C7	1.410 (4)	C14—C15	1.384 (4)
C3—C4	1.383 (5)	C14—H14	0.93
C3—H3	0.93	C15—C16	1.375 (4)
C4—C5	1.388 (5)	C15—C18	1.505 (4)
C4—H4	0.93	C16—C17	1.385 (4)
C5—C6	1.370 (5)	C16—H16	0.93
C5—H5	0.93	C17—H17	0.93
C6—C7	1.389 (4)	C18—H18A	0.96
C6—H6	0.93	C18—H18B	0.96
C8—H8	0.93	C18—H18C	0.96
N2—O1—C9	108.48 (19)	C10—C9—H9	108.3
C8—N1—C7	108.7 (3)	C11—C10—C9	100.6 (2)
C8—N1—H1A	129 (3)	C11—C10—H10A	111.7
C7—N1—H1A	122 (3)	C9—C10—H10A	111.7
C11—N2—O1	108.6 (2)	C11—C10—H10B	111.7
C8—C1—C2	106.2 (3)	C9—C10—H10B	111.7
C8—C1—C9	124.5 (3)	H10A—C10—H10B	109.4
C2—C1—C9	129.3 (3)	N2—C11—C12	121.2 (3)
C3—C2—C7	118.2 (3)	N2—C11—C10	113.8 (2)
C3—C2—C1	135.4 (3)	C12—C11—C10	125.0 (3)
C7—C2—C1	106.4 (3)	C17—C12—C13	117.5 (2)
C4—C3—C2	119.0 (3)	C17—C12—C11	121.0 (2)
C4—C3—H3	120.5	C13—C12—C11	121.5 (2)
C2—C3—H3	120.5	C14—C13—C12	120.6 (3)
C3—C4—C5	121.3 (3)	C14—C13—H13	119.7
C3—C4—H4	119.3	C12—C13—H13	119.7
C5—C4—H4	119.3	C13—C14—C15	121.5 (3)
C6—C5—C4	121.5 (4)	C13—C14—H14	119.2
C6—C5—H5	119.3	C15—C14—H14	119.2
C4—C5—H5	119.3	C16—C15—C14	117.8 (3)
C5—C6—C7	117.2 (3)	C16—C15—C18	121.3 (3)
C5—C6—H6	121.4	C14—C15—C18	120.9 (3)
C7—C6—H6	121.4	C15—C16—C17	121.1 (3)
N1—C7—C6	129.4 (3)	C15—C16—H16	119.4
N1—C7—C2	107.8 (3)	C17—C16—H16	119.4
C6—C7—C2	122.8 (3)	C12—C17—C16	121.5 (3)
N1—C8—C1	110.9 (3)	C12—C17—H17	119.3
N1—C8—H8	124.6	C16—C17—H17	119.3
C1—C8—H8	124.6	C15—C18—H18A	109.5
O1—C9—C1	109.6 (2)	C15—C18—H18B	109.5
O1—C9—C10	102.3 (2)	H18A—C18—H18B	109.5
C1—C9—C10	119.4 (2)	C15—C18—H18C	109.5
O1—C9—H9	108.3	H18A—C18—H18C	109.5
C1—C9—H9	108.3	H18B—C18—H18C	109.5
C9—O1—N2—C11	−14.5 (3)	C2—C1—C9—O1	−66.9 (4)
C8—C1—C2—C3	−179.3 (3)	C8—C1—C9—C10	−128.9 (3)
C9—C1—C2—C3	1.1 (6)	C2—C1—C9—C10	50.6 (4)
C8—C1—C2—C7	0.3 (3)	O1—C9—C10—C11	−22.9 (3)
C9—C1—C2—C7	−179.3 (3)	C1—C9—C10—C11	−144.1 (3)
C7—C2—C3—C4	0.3 (4)	O1—N2—C11—C12	179.2 (2)
C1—C2—C3—C4	179.8 (3)	O1—N2—C11—C10	−2.0 (3)
C2—C3—C4—C5	−0.2 (5)	C9—C10—C11—N2	16.5 (3)
C3—C4—C5—C6	0.0 (6)	C9—C10—C11—C12	−164.8 (2)
C4—C5—C6—C7	0.2 (5)	N2—C11—C12—C17	164.8 (3)
C8—N1—C7—C6	179.7 (3)	C10—C11—C12—C17	−13.8 (4)
C8—N1—C7—C2	0.4 (4)	N2—C11—C12—C13	−15.8 (4)
C5—C6—C7—N1	−179.3 (3)	C10—C11—C12—C13	165.5 (3)
C5—C6—C7—C2	−0.1 (5)	C17—C12—C13—C14	1.0 (4)
C3—C2—C7—N1	179.2 (3)	C11—C12—C13—C14	−178.4 (3)
C1—C2—C7—N1	−0.4 (3)	C12—C13—C14—C15	0.4 (4)
C3—C2—C7—C6	−0.1 (4)	C13—C14—C15—C16	−1.9 (4)
C1—C2—C7—C6	−179.8 (3)	C13—C14—C15—C18	178.0 (3)
C7—N1—C8—C1	−0.2 (4)	C14—C15—C16—C17	2.0 (4)
C2—C1—C8—N1	0.0 (4)	C18—C15—C16—C17	−177.9 (3)
C9—C1—C8—N1	179.6 (3)	C13—C12—C17—C16	−0.9 (4)
N2—O1—C9—C1	151.5 (2)	C11—C12—C17—C16	178.5 (3)
N2—O1—C9—C10	23.8 (3)	C15—C16—C17—C12	−0.6 (5)
C8—C1—C9—O1	113.6 (3)

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
N1—H1A···O1^i	0.82 (4)	2.13 (4)	2.937 (4)	170 (5)

Symmetry code: (i) x−1/2, −y−1/2, −z+1.