Single crystal X-ray structure of 2,6-di-tert-butyl-4-(3-(4-chlorophenyl)- 4-methyl-4,5-dihydroisoxazol-5-yl)phenol 1,4-dioxane hemisolvate

Article abstract of DOI:10.1134/S0022476613010368

The title compound (2,6-di-tert-butyl-4-(3-(4-chlorophenyl)-4-methyl-4,5- dihydroisoxazol-5-yl)phenol is synthesized and studied by the single crystal X-ray diffraction method. The structure of the product was confirmed by IR, ¹H and ¹³C NMR spectroscopy. The crystal structure of 1,4-dioxane hemisolvate of the product is solved in the monoclinic space group P2₁/c with a = 17.713(6) A, b = 9.529(3) A, c = 13.972(4) A, β = 94.09(4), V = 2352.3(13) A³, Z = 4, T = 120(2) K.

Full text of DOI:10.1134/S0022476613010368

Journal of Structural Chemistry. Vol. 54, No. 1, pp. 217-222, 2013
Original Russian Text Copyright © 2012 by M. Rimaz, J. Khalafy, M. Badali, K. ꢀlepokura, T. Lis, A. Souldozi, A. Ramazani, S.W. Joo
SINGLE CRYSTAL X-RAY STRUCTURE OF 2,6-DI-
TERT-BUTYL-4-(3-(4-CHLOROPHENYL)-4-
METHYL-4,5-DIHYDROISOXAZOL-5-YL)PHENOL
1,4-DIOXANE HEMISOLVATE
M. Rimaz,1 J. Khalafy,2 M. Badali,2 K. ꢀlepokura,3
©
DOI: 10.1134/S0022476613010368
T. Lis,3 A. Souldozi,4 A. Ramazani,5 and S.W. Joo6
The title compound (2,6-di-tert-butyl-4-(3-(4-chlorophenyl)-4-methyl-4,5-dihydroisoxazol-5-yl)phenol is
synthesized and studied by the single crystal X-ray diffraction method. The structure of the product was
1
confirmed by IR, H and 13C NMR spectroscopy. The crystal structure of 1,4-dioxane hemisolvate of the
product is solved in the monoclinic space group P21/c with a = 17.713(6) Å, b = 9.529(3) Å, c = 13.972(4) Å,
ꢀ = 94.09(4)ꢁ, V = 2352.3(13) Å3, Z = 4, T = 120(2) K.
Keywords: single crystal X-ray structure, quinone methide, isoxazoline, oxime, DDQ.
Isoxazoline moieties represent a class of unique pharmacophores, which are observed in many therapeutic agents
and are versatile intermediates for the synthesis of complex natural products and are found in GPII/IIIa inhibitors [1]. They
are also known to exhibit interesting biological activities in the agricultural field [2] and possess medicinal properties,
including anticancer, antibiotic [3] or antiviral and anti-HIV activities [4]. Quinone methides are interesting compounds and
play an important role in biosynthesis and in the biological activity of many quinonoid antitumor compounds [5]. However,
synthetic methodologies to produce such quinone methides and their applications are limited because in situ generated
o-quinone methides act as heterodynes in Diels-Alder reactions [6]. p-Quinone methides have been proposed as intermediates
in enzyme inhibition [7], insect cuticle chemistry [8], wood lignin chemistry [9], and release mechanisms in photographic
processes [10].
EXPERIMENTAL
Typical experimental procedure. 3-[3,5-Di-tert-4-hydroxyphenyl]-1-(4-chlorophenyl)-2-methyl-propan-1-one
oxime 5: to the mixture of hydroxylamine hydrochloride (1 g) and sodium acetate trihydrate (2 g) in water (1 ml) a solution
of 3-[3,5-di-tert-4-hydroxyphenyl]-1-(4-chlorophenyl)-2-methyl-propan-1-one (0.5 g, 1.3 mmol) in EtOH (5 ml) was added,
and the mixture refluxed for 1 h. After the removal of EtOH, water (5 ml) was added and stirred in an ice bath until oxime
crystallization was complete. The precipitate was filtered and recrystallized from EtOH (96%) to give the product as white
2
1Department of Chemistry, Payame Noor University, Tehran, Iran. Chemistry Department, Urmia University,
3
4
Urmia, Iran. Faculty of Chemistry, University of Wrocꢀaw, Wrocꢀaw, Poland. Department of Chemistry, Urmia Branch,
5
Islamic Azad University, Urmia, Iran. Department of Chemistry, Zanjan Branch, Islamic Azad University, Zanjan, Iran;
aliramazani@gmail.com. 6School of Mechanical Engineering, WCU Nano Research Center, Yeungnan University,
Gyeongsan 712-749, South Korea; swjoo@yu.ac.kr. The text was submitted by the authors in English. Zhurnal Strukturnoi
Khimii, Vol. 53, No. 6, pp. 1175-1180, November-December, 2012. Original article submitted June 28, 2011.
0022-4766/13/5401-0217
217

1
needles (0.4 g, 81%), m.p. 97-98°C. H NMR (CDCl3, 300 MHz): δ 1.16 (d, 3H in one isomer, J = 7.2 Hz), 1.33 (d, 3H in
other isomer, J = 6.9 Hz), 1.39 (s, 18H in one isomer), 1.42 (s, 18H in other isomer), 2.50-3.00 (m, 2H in both isomers), 3.39-
3.62 (m, 1H in both isomers), 5.06 (s, 1H, D2O exchangeable), 5.10 (s, 1H, D2O exchangeable), 6.90 (s, 2H in one isomer),
6.92 (s, 2H in other isomer), 7.06 (d, 2H in one isomer, J = 8.1 Hz), 7.12 (d, 2H in other isomer, J = 7.8 Hz), 7.23 (d, 2H in
one isomer, J = 8.1 Hz), 7.35 (d, 2H in other isomer, J = 7.8 Hz), 8.21 (bs, 1H in one isomer, D2O exchangeable), 8.37 (bs,
13
1H in other isomer, D2O exchangeable). C NMR (CDCl3, 75.5 MHz): 17.03, 18.30. 30.29, 30.34, 34.19, 34.24, 36.80,
39.19, 40.81, 41.84, 47.86, 125.37, 125.58, 127.24, 127.43, 127.55, 128.05, 128.16, 128.32, 128.80, 129.11, 130.24, 130.58,
–1
134.43, 135.13, 135.68, 152.07, 161.66, 162.95. IR (KBr, cm ): 3627, 3228, 3005, 2965, 2915, 2874, 1593, 1488, 1432,
1392, 1232, 1148, 1º94, 996, 933, 832, 821, 769.
2,6-Di-tert-butyl-4-(3-(4-chlorophenyl)-4-methyl-4,5-dihydroisoxazol-5-yl)phenol 7: to a solution of 3-[3,5-di-tert-
4-hydroxyphenyl]-1-(4-chlorophenyl)-2-methyl-propan-1-one oxime 5 (0.401 g, 1 mmol) in dry DCM (10 ml), DDQ (0.25 g,
1.1 mmol) was added and the mixture stirred at room temperature for 5 min. The contents were filtered using Celite as filter
aid, then the filtrate was washed with water (3×20 ml) and dried over Na2SO4. The removal of the solvent gave a yellow solid
1
that was recrystallized from hexane to give the title compound as white needles (0.24 g, 60%), m.p. 201-202°C. H NMR
(CDCl3, 300 MHz): δ 1.43 (d, 3H, 7.2 Hz), 1.45 (s, 18H), 3.70 (quin, 1H, J = 6.9 Hz), 5.21 (d, 1H, J = 6.6 Hz), 5.26 (s, 1H,
13
D2O exchangeable), 7.15 (s, 2H), 7.40 (d, 2H, J = 8.4 Hz), 7.64 (d, 2H, J = 8.1 Hz). C NMR (CDCl3, 75.5 MHz): 17.94,
–1
30.19, 34.38, 50.02, 91.31, 122.63, 127.68, 128.24, 129.06, 130.78, 135.74, 136.25, 153.95, 159.51. IR (KBr, cm ): 3632,
3010, 2968, 2915, 2871, 1587, 1494, 1456, 1436, 1401, 1367, 1213, 1160, 1096, 918, 899, 878, 843, 831, 650.
Single crystals of 7 were prepared from a mixture of n-hexane/dioxane (10:1) at 46°C during two weeks using the
branch tube method [11]. The colorless crystals were filtered off, washed with a cold mixture of n-hexane/dioxane (20:1,
10 ml), and dried in vacuum over P4O10.
X-Ray crystal structure determination of 7⋅0.5(C4H8O2). The crystallographic measurement was performed on a
κ-geometry automated four-circle Xcalibur PX diffractometer with graphite-monochromatized MoKα radiation. The data for
the crystal were collected at 120(2) K using the Oxford-Cryosystems cooler. A summary of conditions for the data collection
and the structure refinement parameters are given in Table 1. The data were corrected for Lorentz and polarization effects.
Data collection, cell refinement, and data reduction and analysis were carried out with the Xcalibur PX software (Oxford
Diffractiod Ltd.): CrysAlis CCD and CrysAlis RED respectively [12]. The structure was solved by direct methods with the
SHELXS-97 program [13] and refined by a full-matrix least-squares technique with SHELXL-97 [13] and anisotropic
thermal parameters for non-H atoms. All H atoms were found in difference Fourier maps and refined isotropically. In the
final refinement cycles, the H atoms were treated as riding atoms in geometrically optimized positions, with C–H = 0.95-
1.00 Å and O–H = 0.84 Å, and with Uiso(H) = 1.2Ueq(C) for CH and CH2, or 1.5Ueq(C,O) for CH3 and OH. Figures were
made with the XP program [14]. Puckering parameters were calculated using the PLATON program [15]. CCDC-827546
contains the supplementary crystallographic data for 7⋅0.5(C4H8O2). These data can be obtained free of charge via
http://www.ccdc.cam.ac.uk/data_request/cif.
RESULTS AND DISCUSSION
The conventional method of the preparation of isoxazolines involves a 1,3-dipolare cycloaddition of nitrile oxide to
alkenes [16]. Herein, we report the random synthesis of isoxazoline derivative 7 from 3-[3,5-di-tert-butyl-4-hydroxyphenyl]-
1-(4-chlorophenyl)-2-methyl-propan-1-one oxime 5 by novel C–O bond formation via in situ generated p-quinone methide
(Scheme 1). 2,6-Disubstitution imparts increased stability to quinone methide [17], so the subsequent cyclization would
require an internal nucleophile (cyclization terminator). To the best of our knowledge, there are no reports in the literature on
the formation of isoxazoline derivative 7. Treatment of 3-[3,5-di-tert-butyl-4-hydroxyphenyl]-1-(4-chlorophenyl)-2-methyl-
propan-1-one oxime 5 with DDQ. 2,6-di-tert-butyl-4-methoxymethylphenol 2 is required to generate quinone methide, which
218

TABLE 1. Crystal Data and Structure Refinement Details for 7⋅0.5(C4H8O2)
Crystalized from
Empirical formula
Mr
n-Hexane/CHCl3
C24H30ClNO2⋅0.5(C4H8O2)
443.99
Scan type
ω and ϕ
MoKα, 0.71073
–27 ≤ h ≤ 28
–13 ≤ k ≤ 12
–22 ≤ l ≤ 22
25074
Radiation type, λ, Å
Index ranges
Crystal color, habit
Crystal dimensions, mm
Temperature, K
Crystal system
Space group
Colorless, parallelepiped
0.22×0.17×0.09
120(2)
Measured reflections
Independent reflections
Reflections with I > 2σ(I )
Rint
Monoclinic
P21/c
9409
5036
Z
4
0.051
4.18–35.00
0.98
θ range, deg
Completeness to θ = 25.0°
Refinement on
Unit cell parameters:
F 2
a, Å
17.713(6)
9.529(3)
Data, restraints, parameters
R (F02 > 2σ(F02))
9409, 0, 288
b, Å
R1 = 0.046
c, Å
13.972(4)
94.09(4)
2352.3(13)
1.254
wR2 = 0.072
R1 = 0.106
wR2 = 0.077
1.001
R (all data)
β, deg
3
V, Å
–3
COOF = S
dx (calc), g⋅cm
–1
μ, mm
0.19
Weighting parameter a/b
–3
Δρ(max; min), e⋅Å
0.0190/0.0
0.38; –0.33
F(000), e
952
2
[w(F 2 − F 2 ) 2 ] / [w(F 2 ) 2 ];
2
R1 = ∑||F0| – |Fc||/∑||F0|;
weighting scheme: w = 1/[σ2(F0 ) + (aP) + b],
wR2 =
∑
∑
0
c
0
where P = (F 2 + 2 c )/3.
2
F
0
Scheme 1. Synthesis of 2,6-di-tert-butyl-4-(3-(4-chlorophenyl)-4-methyl-4,5-dihydroisoxazol-5-yl)phenol 7
allows a subsequent nucleophilic attack to give 3-[3,5-di-tert-butyl-4-hydroxyphenyl]-1-(4-chlorophenyl)-2-methyl-propan-1-
one 4 (Scheme 1). 2,6-Di-tert-butyl-4-methoxymethylphenol 2 was prepared from the KOH catalyzed condensation of
formaldehyde with 2,6-di-tert-butylphenol 1 in methanol [18]. 2,6-Di-tert-butyl-4-methoxymethylphenol 2 was treated with
219

Fig. 1. Molecular structure of compound 7 along with 1,4-dioxane co-
crystallizing in a 7⋅0.5(C4H8O2) crystal, showing the X-ray atom
numbering scheme and intermolecular O/C–H⋯O hydrogen bonds
(dashed lines). Displacement ellipsoids represent the 50% probability
level. Symmetry code: (i) –x, –y+1, –z+1.
Fig. 2. Arrangement of the ribbons of 7 (running down the b axis) and 1,4-dioxane molecules in the crystal
lattice of 7⋅0.5(C4H8O2). O/C–H⋯O/N/π contacts are shown with dashed lines. Symmetry codes are given in
Table 3.
KOH followed by the addition of p-chloropropiophenone 3 to afford 3-[3,5-di-tert-butyl-4-hydroxyphenyl]-1-(4-
chlorophenyl)-2-methyl-propan-1-one 4 in good yield [19]. Ketone 4 was condensed with hydroxylamine [20] in EtOH to
give 3-[3,5-di-tert-butyl-4-hydroxyphenyl]-1-(4-chlorophenyl)-2-methyl-propan-1-one oxime 5, which was obtained as two Z
1
and E isomers in a 60:40 ratio. The formation of oxime 5 in two different ratios was confirmed with its H NMR spectrum by
the appearance of two signals for each proton of oxime 5. Finally, oxime 5 was treated with DDQ in dry DCM and stirred at
room temperature affording 2,6-di-tert-butyl-4-(3-(4-chlorophenyl)-4-methyl-4,5-dihydroisoxazol-5-yl)phenol 7 as a white
solid in 60% yield (Scheme 1) [20]. The cyclization was indicated by the absence of the OH proton of oximes as broad
1
1
13
singlets at δ 8.37 and 8.21 in the H NMR spectrum. Product 7 was characterized by H and C NMR and IR analysis.
The structure of substituted isoxazoline 7 was elucidated the by X-ray single crystal determination (Fig. 1).
Crystal structure of 7⋅0.5(C4H8O2). The centrosymmetric space group shows that the crystal contains racemic
compound 7. The RR isomer is shown in Fig. 1. Compound 7 crystallizes with 1,4-dioxane molecules (1/0.5) lying on the
inversion centre.
In the molecule of compound 7, the central 4,5-dihydroisoxazole ring is puckered in an envelope (E) manner on the
C(15) atom, as confirmed by the pseudorotation parameters [21] P = 234.4(2)° and τm = 18.9(1)° (reference C(17)–C(16)
220

TABLE 2. Selected Interatomic Distances (Å), Valence (deg.) and Torsion Angles (deg) of 7⋅0.5(C4H8O2)
Bond lengths
Cl(1)–C(22)
O(1)–C(1)
O(2)–N(1)
O(2)–C(15)
1.7487(12)
1.3803(13)
1.4170(12)
1.4648(14)
N(1)–C(17)
C(4)–C(15)
C(16)–C(17)
C(17)–C(19)
1.2853(14)
1.5093(15)
1.5109(15)
1.4798(15)
Valence angles
N(1)–O(2)–C(15)
C(17)–N(1)–O(2)
O(2)–C(15)–C(4)
O(2)–C(15)–C(16)
108.53(8)
109.16(9)
108.90(9)
104.73(8)
C(4)–C(15)–C(16)
C(17)–C(16)–C(18)
C(17)–C(16)–C(15)
C(18)–C(16)–C(15)
118.22(9)
116.70(9)
99.80(9)
111.24(9)
Torsion angles
C(15)–O(2)–N(1)–C(17)
C(1)–C(6)–C(7)–C(8)
11.75(11)
174.60(11)
–176.62(10)
–145.80(9)
–18.44(10)
68.01(13)
C(4)–C(15)–C(16)–C(18)
O(2)–N(1)–C(17)–C(19)
O(2)–N(1)–C(17)–C(16)
C(18)–C(16)–C(17)–N(1)
C(15)–C(16)–C(17)–N(1)
C(18)–C(16)–C(17)–C(19)
C(15)–C(16)–C(17)–C(19)
N(1)–C(17)–C(19)–C(20)
C(16)–C(17)–C(19)–C(20)
–97.74(12)
176.59(9)
0.39(12)
C(1)–C(2)–C(11)–C(12)
N(1)–O(2)–C(15)–C(4)
N(1)–O(2)–C(15)–C(16)
C(3)–C(4)–C(15)–O(2)
C(3)–C(4)–C(15)–C(16)
O(2)–C(15)–C(16)–C(17)
C(4)–C(15)–C(16)–C(17)
O(2)–C(15)–C(16)–C(18)
–131.29(11)
–11.39(12)
52.84(15)
172.73(10)
16.51(16)
–167.79(10)
–51.25(15)
17.04(10)
138.46(10)
140.84(9)
TABLE 3. Geometry of Proposed Hydrogen Bonds and Close Contacts for 7⋅0.5(C4H8O2)
D–H⋯A
D–H, Å
H⋯A, Å
D⋯A, Å
D–H⋯A, deg
Offset, Å
O(1)–H(1)⋯O(3)
C(10)–H(10C)⋯O(3)
C(13)–H(13B)⋯O(1)
C(14)–H(14B)⋯O(1)
0.84
0.98
0.98
0.98
1.00
0.95
0.95
2.16
2.43
2.39
2.25
2.58
2.41
2.81
2.800(2)
3.309(2)
3.014(2)
2.905(2)
3.360(2)
3.327(2)
3.570(2)
133
149
121
123
135
162
137
—
—
—
—
ii
C(16)–H(16)⋯N(1)
—
ii
C(24)–H(24)⋯O(2)
—
ii
C(23)–H(23)⋯Cg(1)
0.41
Symmetry codes: (ii) –x+1, y+1/2, –z+1/2; Cg(1) is the centroid of the C(1) ∼ C(6) ring.
bond), as well as by the Cremer and Pople [22] puckering parameters q2 = 0.181(1) Å and ϕ2 = 142.6(4)°. The chlorophenyl
ring is in the equatorial position, while the remaining substituents (at C(15) and C(16) atoms) are in bisectional positions
(being in relative trans configuration). The chlorophenyl ring is almost coplanar with the 4,5-dihydroisoxazole reference
plane (defined by O(2), N(1), C(17), C(16) atoms), as reflected in the value of the N(1)–C(17)–C(19)–C(20) torsion angle
(Table 2). In contrast, the ring of another aromatic substituent is almost perpendicular to the dihydroisoxazole reference
plane, as indicated by an angle of 87.6(1)° between the two planes: C(1) ∼ C(6) and O(2) ∼ C(16).
The crystal packing in 7⋅0.5(C4H8O2) is determined mainly by C–H⋯O and C–H⋯N interactions resulting in the
arrangement of the molecules of 7 into ribbons running down the b axis, as shown in Fig. 2 (Table 3). Additional stabilization
of the ribbon is provided by weak C–H⋯π contacts formed between the aromatic rings. The adjacent ribbons interact with
each other mainly through 1,4-dioxane molecules acting as the acceptors of two O–H⋯O and two C–H⋯O bonds from two
different ribbons each (Fig. 2).
221

In conclusion, we have demonstrated a novel quinone methide mediated synthesis of new fully substitued
isoxazoline 7 from treatment of substituted propan-1-one oxime 5 with DDQ in DCM. The simple procedure at room
temperature of this chemical process provides a very straightforward route to construct various fully substituted isoxazolines.
This work is supported by the Grant 2011-0014246 of the National Research Fundation of Korea.
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