2-(5,6-Diphenyl-1,2,4-triazin-3-yl)aniline

Mariusz Mojzych; Zbigniew Karczmarzyk; Andrzej Fruziński

doi:10.1107/S1600536812044194

. 2012 Nov 3;68(Pt 12):o3278. doi: 10.1107/S1600536812044194

2-(5,6-Diphenyl-1,2,4-triazin-3-yl)aniline

Mariusz Mojzych ^a, Zbigniew Karczmarzyk ^a,^*, Andrzej Fruziński ^b

PMCID: PMC3588826 PMID: 23468791

Abstract

The title compound, C₂₁H₁₆N₄, obtained under standard Suzuki cross-coupling conditions, is a model compound in the synthesis and biological activity evaluation of new aza-analogues of sildenafil containing a pyrazolo[4,3-e][1,2,4]triazine system. An N—H⋯N intramolecular hydrogen bond involving the aminobenzene system and the 1,2,4-triazine moiety helps to establish a near coplanar orientation of the rings with a dihedral angle of 12.04 (4)°, which is believed to be necessary for the biological activity of sildenafil analogues. The 1,2,4-triazine ring is slightly distorted from planarity [r.m.s deviation = 0.0299 (11) Å] and forms dihedral angles of 58.60 (4) and 36.35 (3)° with the pendant phenyl rings. The crystal packing features bifurcated N—H⋯(N,N) hydrogen bonds linking screw-axis-related molecules into chains parallel to the [010] direction and π–π interactions, with a centroid–centroid separation of 3.8722 (7) Å and a slippage of 1.412 (3) Å. The crystal studied was a nonmerohedral twin with a ratio of 0.707 (2):0293 (2).

Related literature

For background information on the activity of sildenafil citrate, see: Terrett et al. (1996 ▶); Card et al. (2004 ▶). For the synthesis of the title compound, see: Agarwal et al. (2010 ▶). For a description of the Cambridge Structural Database, see: Allen (2002 ▶); Bruno et al. (2002 ▶).

Experimental

Crystal data

C₂₁H₁₆N₄
M _r = 324.38
Monoclinic,
a = 11.8797 (3) Å
b = 6.0788 (1) Å
c = 23.8710 (5) Å
β = 101.489 (1)°
V = 1689.29 (6) Å³
Z = 4
Cu Kα radiation
μ = 0.61 mm⁻¹
T = 293 K
0.21 × 0.14 × 0.01 mm

Data collection

Bruker APEXII CCD diffractometer
Absorption correction: multi-scan (SADABS; Bruker, 2005 ▶) T _min = 0.906, T _max = 1.000
4591 measured reflections
3173 independent reflections
2837 reflections with I > 2σ(I)

Refinement

R[F ² > 2σ(F ²)] = 0.035
wR(F ²) = 0.103
S = 1.05
4591 reflections
275 parameters
All H-atom parameters refined
Δρ_max = 0.10 e Å⁻³
Δρ_min = −0.13 e Å⁻³

Data collection: APEX2 (Bruker, 2005 ▶); cell refinement: SAINT (Bruker, 2005 ▶); data reduction: SAINT; program(s) used to solve structure: SHELXS97 (Sheldrick, 2008 ▶); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008 ▶); molecular graphics: ORTEP-3 for Windows (Farrugia, 2012 ▶); software used to prepare material for publication: SHELXL97 and WinGX (Farrugia, 2012 ▶).

Supplementary Material

Click here for additional data file.^{(25.3KB, cif)}

Crystal structure: contains datablock(s) global, I. DOI: 10.1107/S1600536812044194/lr2082sup1.cif

e-68-o3278-sup1.cif^{(25.3KB, cif)}

Click here for additional data file.^{(220.4KB, hkl)}

Structure factors: contains datablock(s) I. DOI: 10.1107/S1600536812044194/lr2082Isup2.hkl

e-68-o3278-Isup2.hkl^{(220.4KB, hkl)}

Click here for additional data file.^{(6.4KB, cml)}

Supplementary material file. DOI: 10.1107/S1600536812044194/lr2082Isup3.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
N7—H72⋯N2	0.94 (2)	2.00 (2)	2.7037 (19)	130 (2)
N7—H71⋯N1ⁱ	0.93 (3)	2.26 (3)	3.1779 (19)	169 (2)
N7—H71⋯N2ⁱ	0.93 (3)	2.49 (2)	3.2677 (18)	141.3 (19)

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

Acknowledgments

This research was supported by grant No. NN405 092340 from the National Science Centre, Poland.

supplementary crystallographic information

Comment

Nowadays, sildenafil citrate (Viagra) is the first orally effective phosphodiesterase type 5 (PDE5) inhibitor available for the treatment of common and important medical problem e.g. male erectile dysfunction (MED) (Terrett et al., 1996). The earlier work on crystal structures of the catalytic domains of PDEs with different inhibitors have revealed two common features of inhibitor binding to PDEs: a planar ring structure of the inhibitor and hydrogen bond iteractions with an invariant glutamine residue (Card et al., 2004). With this in mind we have planned a new series of sildenafil analogues with pyrazolo[4,3-e][1,2,4]triazine system in which triazine ring nitrogen N1 plays a role of C=O group present in pyrimidinone moiety of sildenafil and ethylamino group in the position 2' of phenyl ring allowed to form intramolecular hydrogen bond between aminophenyl ring and pyrazolotriazine ring system. To clearly define the possibility and the place of intramolecular hydrogen bond formation in the new sildenafil analogues the synthesis and the crystal structure determination of an appropriate model 2-(5,6-diphenyl-1,2,4-triazin-3-yl)aniline, (I), were undertaken.

A search of the Cambridge Structural Database (CSD version 5.33, November 2011; Allen, 2002; Bruno et al., 2002) did not reveal any crystal structures containing the 3-(2-aminophenyl)-1,2,4-triazine structural unit. The structure of the molecule (I) is shown in Fig. 1. One can see that the 3-aminophenyl-1,2,4-triazine system exists in the crystal in the conformation with the torsion angle N2–C3–C31–C32 of -6.86 (17)°. This conformation is forced by the strong N7–H72···N2 intramolecular hydrogen bond (Table 1). The conformation of the 5- and 6-phenyl substituents of the 1,2,4-triazine system in relation to the triazine ring described by the torsion angles N4–C5–C51–C52 of -120.48 (13)° and N1–C6–C61–C62 of 35.44 (15)°, respectively, is forced by the steric effect of these bulky groups in adjacent positions of the heterocyclic system. This strong steric interaction causing the appearance of the strains in the triazine ring results in the distortion of its planarity with the displacements of the triazine atoms from the best plane within 0.0299 (11) Å.

In the crystal structure, the screw-related molecules are linked into chains along the [010] direction by bifurcated N7–H71···N1 and N7–H71···N2 intermolecular hydrogen bonds (Fig. 2) and the methine groups C53—H53 of the inversion-related molecules interact with π-electron system of the aminophenyl ring via C—H···π interaction (Table 1). Moreover, nearly coplanar mutual position of the triazine and aminophenyl rings is stabilized by the π–π interaction of these rings in the crystal structure. The π-electron systems of the pairs of triazine and aminophenyl rings belonging to the translation-related molecules overlap each other, with centroid-to-centroid separation of 3.8722 (7) Å between the triazine ring at (x, y, z) and aminophenyl ring at (x, -1 + y, z) and aminophenyl ring at (x, y, z) and triazine ring at (x, 1 + y, z). The π–π distances are 3.2886 (4) and 3.6055 (6) Å, respectively, the angle between overlapping planes is 12.13 (6)° and the slippage is 1.412 (3) Å.

In conclusion, the X-ray investigations of molecule (I) confirmed the assumed possibility of forming the N7–H···N2 intramolecular hydrogen bond stabilizing its cis conformation in the crystalline state, analogous to active conformation of sildenafil molecule.

Experimental

The title compound, (I), was obtained using standard Suzuki cross-coupling conditions (Agarwal et al., 2010), in the reaction of 3-bromo- and 3-chloro-5,6-diphenyl-1,2,4-triazine with 2-aminophenylboronic acid. To a solution of 3-halogeno-5,6-diphenyl-1,2,4-triazine (0.2 mmol) and 2-aminophenylboronic acid (0.22 mmol) in dioxane/water mixture (4:1) (2.5 ml) solution of K₂CO₃ (0.6 mmol) in 1 ml of water and Pd(PPh₃)₄ were added. The reaction mixture was stirred at 70°C for 12 h. After that time the solution was diluted with H₂O (1.5 ml), and then the product was extracted three times with CH₂Cl₂ (3x2mL). The combined organic layer was dried over Na₂SO₄ and the solvent was removed in vacuo. The crude product was then subjected to column chromatography using CH₂Cl₂:hexane (4:1) as eluent. mp 161°C. Crystals suitable for X-ray diffraction analysis were grown by slow evaporation of an ethanol solution.