3-(1,3-Di­phenyl­propan-2-yl)-4-methyl-6-phenyl­isoxazolo[3,4-d]pyridazin-7(6H)-one

Charles F Campana; Joseph Mirzaei; Chris Koerner; Christina Gates; Nicholas R Natale

doi:10.1107/S160053681302802X

. 2013 Oct 23;69(Pt 11):o1680–o1681. doi: 10.1107/S160053681302802X

3-(1,3-Diphenylpropan-2-yl)-4-methyl-6-phenylisoxazolo[3,4-d]pyridazin-7(6H)-one

Charles F Campana ^a, Joseph Mirzaei ^b, Chris Koerner ^b, Christina Gates ^b, Nicholas R Natale ^b,^*

PMCID: PMC3884336 PMID: 24454112

Abstract

In the title compound, C₂₇H₂₃N₃O₂, the geminal benzyl groups branching out from the methine adjacent to the isoxazole group are both syn-oriented to the methyl group of the pyridazinone moiety, as reflected by C—C distances of 3.812 (2) and 4.369 (2) Å between the methyl carbon and the nearest ring carbon of each benzyl group. This kind of conformation is retained in CDCl₃ solution, as evidenced by distinct phenyl-shielding effects on the ¹H NMR signals of the methyl H atoms. The isoxazolo[3,4-d]pyridazin ring system is virtually planar (r.m.s. deviation from planarity = 0.031 Å), but the N-bonded phenyl group is inclined to the former by an ring–ring angle of 55.05 (3)°. In the crystal, the T-shaped molecules are arranged in an interlocked fashion, forming rod-like assemblies along [10-1]. The molecules are held together by unremarkable weak C—H⋯N, C—H⋯O and C—H⋯π interactions (C—O,N,C > 3.4 A), while significant π–π-stacking interactions are absent.

Related literature

For chemistry of isoxazolo[3,4-d]pyridazinone preparation, see: Renzi & Dal Piaz (1965 ▶). For deprotonation with sodium alkoxides, see: Dal Piaz et al. (1975 ▶); Chimichi et al. (1986 ▶). For the rearrangement of the isoxazolo[3,4-d]pyridazinone ring system to pyrazole, see: Dal Piaz et al. (1985 ▶). For isoxazole lateral metalation, see: Natale & Niou (1984 ▶); Natale et al. (1985 ▶); Niou & Natale (1986 ▶); Schlicksupp & Natale (1987 ▶). For recent applications of lateral metalation and electrophilic quenching of isoxazoles to targets of biological interest, see: Nakamura et al. (2010 ▶); Hulubei et al. (2012 ▶). For a review of the lateral metalation and electrophilic quenching of isoxazoles, see: Natale & Mirzaei (1993 ▶). graphic file with name e-69-o1680-scheme1.jpg

Experimental

Crystal data

C₂₇H₂₃N₃O₂
M _r = 421.48
Triclinic,
a = 7.5163 (4) Å
b = 9.6774 (5) Å
c = 15.9053 (8) Å
α = 86.798 (1)°
β = 83.512 (1)°
γ = 69.385 (1)°
V = 1075.75 (10) Å³
Z = 2
Cu Kα radiation
μ = 0.66 mm⁻¹
T = 100 K
0.40 × 0.22 × 0.19 mm

Data collection

Bruker D8 Venture PHOTON 100 CMOS diffractometer
Absorption correction: numerical (SADABS; Bruker, 2012 ▶) T _min = 0.80, T _max = 0.89
12012 measured reflections
3714 independent reflections
3597 reflections with I > 2σ(I)
R _int = 0.017

Refinement

R[F ² > 2σ(F ²)] = 0.032
wR(F ²) = 0.078
S = 1.03
3714 reflections
313 parameters
86 restraints
Only H-atom displacement parameters refined
Δρ_max = 0.22 e Å⁻³
Δρ_min = −0.14 e Å⁻³

Data collection: SMART (Bruker, 2012 ▶); cell refinement: SAINT (Bruker, 2012 ▶); data reduction: SAINT; program(s) used to solve structure: SHELXS97 (Sheldrick, 2008 ▶); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008 ▶); molecular graphics: Mercury (Macrae et al., 2008 ▶); software used to prepare material for publication: publCIF (Westrip, 2010 ▶).

Supplementary Material

Crystal structure: contains datablock(s) global, I. DOI: 10.1107/S160053681302802X/qk2060sup1.cif

e-69-o1680-sup1.cif^{(29.9KB, cif)}

Structure factors: contains datablock(s) I. DOI: 10.1107/S160053681302802X/qk2060Isup2.hkl

e-69-o1680-Isup2.hkl^{(182.1KB, hkl)}

Click here for additional data file.^{(8.4KB, cml)}

Supplementary material file. DOI: 10.1107/S160053681302802X/qk2060Isup3.cml

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
C26—H26⋯O1ⁱ	0.95	2.61	3.4159 (13)	143
C24—H24⋯N1ⁱⁱ	0.95	2.73	3.5407 (15)	143
C11—H11⋯C18ⁱⁱⁱ	0.95	2.78	3.6182 (15)	148

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Symmetry codes: (i) Inline graphic ; (ii) ; (iii) .

Acknowledgments

NRN, JM, CG and CK thank the National Institutes of Health for grants NINDS P20RR015583 Center for Structural and Functional Neuroscience (CSFN) and P20 RR017670 Center for Environmental Health Sciences (CEHS), We also thank NINDS P30 (NN and JM), and the University of Montana Grant Program (NN).

supplementary crystallographic information

1. Comment

The title compound (Fig. 1) was prepared by lateral metalation with lithium hexamethyldisilazide and electrophilic quenching with benzyl bromide (Natale & Mirzaei, 1993), under thermodynamic conditions (Niou & Natale, 1986; Schlicksupp & Natale, 1987), during which a facile second deprotonation and quenching leads to double incorporation (Natale et al., 1985, Natale & Niou, 1984). Mono-alkylation and recovered starting material account for sufficient material balance to rule out substantial rearrangement under these conditions. The present study unambiguously establishes the regiochemistry of double alkylation. Previous reports on analogous deprotonation with sodium alkoxides (Dal Piaz, et al., 1975; Chimichi, et al., 1986), reported rearrangement to pyrazoles with longer reaction times (Dal Piaz et al., 1985). The lateral metalation and electrophilic quenching of isoxazoles continues to lead to candidates with promising biological activity (Nakamura, et al., 2010; Hulubei et al., 2012) and is the subject of active investigation, to be reported in due course. The conformation observed in the solid state (Fig. 1) would be expected to result in magnetic anisotropy if maintained in solution, and this is indeed observed, as the ¹H NMR resonance of the C(4) methyl is observed at δ 2.55 in the starting material, δ 2.21 in the monoalkylated product, and δ 1.86 in the title compound. Further chemistry and pharmacology studies based upon this reaction are underway and will be reported in due course.

2. Experimental

Starting material, 3-methyl-4-methyl-6-phenylisoxazolo[3,4-d]pyridazin-7(6H)-one (Fig. 2) was prepared according to Renzi and Dal Piaz (1965). To starting material (88 mg, 0.36 mmol) was added freshly distilled tetrahydrofuran (THF, 25 ml), under an argon atmosphere. The temperature was lowered to 195 K, and a solution of lithium hexamethyldisilazide (1 ml, 1.0M in THF, Aldrich, 28% excess) was added dropwise over five minutes. After stirring for 1 h, benzyl bromide was added via syringe (0.1 ml, 0.84 mmol, 14% excess). The reaction was allowed to come to room temperature with stirring overnight, after which time the solvent was removed in vacuo by rotary evaporator, and the residue chromatographed on an 80 x 35 cm silica gel column. Gradient chromatogrpahy was performed beginning with chloroform-hexane (1:1), and the gradient slowly increased in polarity to ethyl acetate (EtOAc)-hexane-chloroform (1:2:1). The product 3-(1,3-diphenylpropan-2-yl)-4-methyl-6-phenylisoxazolo[3,4-d]pyridazin-7(6H)-one was obtained from the column fraction with R_f 0.6 (SiO2, EtOAc-hexane-chloroform 2:1:1) as a solid (57.1 mg, 38% yield), and was recrystallized by slow evaporation from EtOAc/hexanes to which a small amount of heptane had been added. The resulting crystals were used in the single crystal X-ray study. A clear light yellow prism-like specimen was selected for the X-ray data collection with a Bruker D8 Venture PHOTON 100 CMOS system equipped with a Cu K_α INCOATEC micro-focus source (λ = 1.54178 Å).