1-(4-Methoxy­phen­yl)-3-phenyl-1H-pyrazol-5-amine

Isuru R Kumarasinghe; Victor J Hruby; Gary S Nichol

doi:10.1107/S1600536809015463

. 2009 Apr 30;65(Pt 5):o1170. doi: 10.1107/S1600536809015463

1-(4-Methoxyphenyl)-3-phenyl-1H-pyrazol-5-amine

Isuru R Kumarasinghe ^a, Victor J Hruby ^a, Gary S Nichol ^a,^*

PMCID: PMC2977835 PMID: 21583972

Abstract

The synthesis of the title compound, C₁₆H₁₅N₃O, is regiospecific and single-crystal X-ray diffraction provides the only means of unambiguous structural analysis, with the benzene ring bonded to the imine C atom. The phenyl ring and the essentially planar (r.m.s. deviation 0.0354 Å) methoxybenzene group are rotated by 29.41 (5) and 37.01 (5)°, respectively, from the central pyrazole ring. An intermolecular N—H⋯N hydrogen bond links symmetry-related molecules into a C(5) chain, which runs parallel to the b axis.

Related literature

For background to this study, see: Gavrin et al. (2007 ▶); Joshi et al. (1979 ▶); Michaux & Charlier (2004 ▶); Ossipov et al. (2004 ▶); Raffa (2001 ▶).

Experimental

Crystal data

C₁₆H₁₅N₃O
M _r = 265.31
Orthorhombic,
a = 14.9638 (6) Å
b = 6.3639 (2) Å
c = 28.2466 (12) Å
V = 2689.87 (18) Å³
Z = 8
Mo Kα radiation
μ = 0.09 mm⁻¹
T = 296 K
0.35 × 0.35 × 0.05 mm

Data collection

Bruker Kappa APEXII diffractometer
Absorption correction: none
11632 measured reflections
3019 independent reflections
2256 reflections with I > 2σ(I)
R _int = 0.031

Refinement

R[F ² > 2σ(F ²)] = 0.044
wR(F ²) = 0.111
S = 1.02
3019 reflections
190 parameters
H atoms treated by a mixture of independent and constrained refinement
Δρ_max = 0.20 e Å⁻³
Δρ_min = −0.15 e Å⁻³

Data collection: APEX2 (Bruker, 2007 ▶); cell refinement: SAINT (Bruker, 2007 ▶); data reduction: SAINT; program(s) used to solve structure: SHELXTL (Sheldrick, 2008 ▶); program(s) used to refine structure: SHELXTL; molecular graphics: ORTEP-3 for Windows (Farrugia, 1997 ▶) and Mercury (Macrae et al., 2008 ▶); software used to prepare material for publication: SHELXTL and local programs.

Supplementary Material

Crystal structure: contains datablocks I, global. DOI: 10.1107/S1600536809015463/lh2810sup1.cif

e-65-o1170-sup1.cif^{(18.1KB, cif)}

Structure factors: contains datablocks I. DOI: 10.1107/S1600536809015463/lh2810Isup2.hkl

e-65-o1170-Isup2.hkl^{(148.3KB, hkl)}

Additional supplementary materials: crystallographic information; 3D view; checkCIF report

Enhanced figure: interactive version of Fig. 1

Table 1. Hydrogen-bond geometry (Å, °).

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A
N3—H3NA⋯N2ⁱ	0.89 (2)	2.37 (2)	3.228 (2)	162.5 (16)

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Symmetry code: (i) Inline graphic .

Acknowledgments

This work was supported by the United States Public Health Service, National Institute on Drug Abuse grants DA06284 and DA13449. We thank Professor Bob Downs, Department of Geosciences, University of Arizona, for the data collection.

supplementary crystallographic information

Comment

It has been pharmacologically shown that co-administration of opioids with cyclooxygenase (COX) inhibitors is synergistic and reduces development of drug tolerance (Raffa, 2001; Ossipov et al., 2004). The creation of bifunctional molecules having both COX2 inhibitory activity and Opioid mu agonist activity is a promising approach to retain better analgesic properties. We are investigating plausible COX2 pharmacophores that can be obtained for bifunctional design using known organic reactions. Based on the evidence so far (Joshi et al.,1979; Gavrin et al., 2007) we probed whether the reaction between hydrazine derivatives and benzoylacetonitrile will usefully yield pyrazoles as a product substituted with 1,5-vicinal diaryls, which is an important structural feature for COX2 inhibitory activity (Michaux & Charlier, 2004). We observed that the reaction between benzoylacetonitrile with 2-(4-methoxyphenyl)hydraziniumchloride is regiospecific which means it provides solely 1-(4-methoxyphenyl)-3-phenyl-1H-pyrazol-5-amine, (I), which is undesired for our purpose. Furthermore it cannot be correctly identified with one-dimensional nuclear Overhauser effect or two-dimensional heteronuclear multiple bond correlation spectroscopic methods, leaving single-crystal X-ray diffraction as the only possible means of unambiguous identification of the compound.

The molecular structure of (I) is shown in Figure 1. Two regioisomers were possible and here the structure is unambiguous with the phenyl ring (C11-C16) bonded to the imine carbon atom C1. Molecular dimensions are unexceptional. The methoxybenzyl group is essentially planar (r.m.s. deviation of a mean plane fitted through C4 to C10 and O is 0.0354 Å) and is rotated by 37.01 (5)° from the central pyrazole ring. The phenyl ring (C11-C16) is rotated by 29.41 (5)° from the central pyrazole ring. A lone N–H···N hydrogen bond links the molecules into a C(5) chain which runs parallel to the b axis(Figure 2).

Experimental

Benzoylacetonitrile (1.45 g, 10 mmol) in 50 ml of absolute ethanol was treated with 2-(4-methoxyphenyl) hydraziniumchloride (1.75 g, 10 mmol) under reflux for 1 day. The solvent was then removed by rotary evaporation and the residue was extracted with a 1:1 mix of dichloromethane and H₂O. The organic layer was separated and dried with anhydrous MgSO₄, filtered and then the solvent removed by rotary evaporation to leave a vrown residue. This was washed with hexane and recrystallized from dichloromethane. C₁₆H₁₅N₃O, (I), yield = 90%. TOF MS EI m/z 264.9839. ¹H NMR (CDCl₃)δ 3.85 (s, 3H), 5.95 (s, 1H), 7.0 (d,2H), 7.25 (m,1H), 7.4 (t,2H) 7.5(d,2H), 7.8 (d,2H) ¹³CNMR (CDCl₃) δ 55.50, 87.59, 114.61, 125. 522, 126.049, 127.626, 128.391, 131.463,133.551, 145.740, 151.043, 158.971