5-[(4-Fluoro­anilino)meth­yl]-6-methyl-N-(4-methyl­phen­yl)-2-phenyl­pyrimidin-4-amine

Jerzy Cieplik; Marcin Stolarczyk; Iwona Bryndal; Tadeusz Lis

doi:10.1107/S160053681203783X

. 2012 Sep 12;68(Pt 10):o2922. doi: 10.1107/S160053681203783X

5-[(4-Fluoroanilino)methyl]-6-methyl-N-(4-methylphenyl)-2-phenylpyrimidin-4-amine

Jerzy Cieplik ^a, Marcin Stolarczyk ^a, Iwona Bryndal ^b,^c,^*, Tadeusz Lis ^b

PMCID: PMC3470299 PMID: 23125712

Abstract

In the title compound, C₂₅H₂₃FN₄, the pyrimidine ring makes dihedral angles of 11.3 (2), 24.5 (2) and 70.1 (2)° with the phenyl and two benzene rings, and the molecular conformation is stabilized by an intramolecular N—H⋯N hydrogen bond with an S(6) ring motif. In the crystal, a pair of weak C—H⋯F hydrogen bonds link two molecules into an inversion dimer with an R ₂ ²(16) motif. In the dimer, there is also an intermolecular π–π stacking interaction [centroid–centroid distance = 3.708 (4) Å] between the fluorinated benzene rings. The dimers are further linked by a C—H⋯π interaction, so forming a column along the c axis.

Related literature

For the antibacterial activity of 6-methyl-2-phenyl-5-substituted pyrimidine derivatives, see: Cieplik et al. (2003 ▶, 2008 ▶); Cieplik, Stolarczyk et al. (2011 ▶). For related structures, see: Cieplik et al. (2006 ▶, 2012 ▶); Cieplik, Pluta et al. (2011 ▶).

Experimental

Crystal data

C₂₅H₂₃FN₄
M _r = 398.47
Triclinic,
a = 8.306 (4) Å
b = 10.070 (4) Å
c = 12.234 (5) Å
α = 88.78 (4)°
β = 89.12 (4)°
γ = 82.75 (5)°
V = 1014.8 (8) Å³
Z = 2
Mo Kα radiation
μ = 0.09 mm⁻¹
T = 85 K
0.36 × 0.18 × 0.14 mm

Data collection

Oxford Xcalibur PX diffractometer with Onyx CCD
17245 measured reflections
8461 independent reflections
4334 reflections with I > 2σ(I)
R _int = 0.033

Refinement

R[F ² > 2σ(F ²)] = 0.049
wR(F ²) = 0.093
S = 1.00
8461 reflections
279 parameters
H atoms treated by a mixture of independent and constrained refinement
Δρ_max = 0.38 e Å⁻³
Δρ_min = −0.31 e Å⁻³

Data collection: CrysAlis CCD (Oxford Diffraction, 2007 ▶); cell refinement: CrysAlis CCD; data reduction: CrysAlis RED (Oxford Diffraction, 2007 ▶); program(s) used to solve structure: SHELXS97 (Sheldrick, 2008 ▶); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008 ▶); molecular graphics: XP in SHELXTL (Sheldrick, 2008 ▶); software used to prepare material for publication: SHELXL97.

Supplementary Material

Crystal structure: contains datablock(s) I, global. DOI: 10.1107/S160053681203783X/is5187sup1.cif

e-68-o2922-sup1.cif^{(30.1KB, cif)}

Structure factors: contains datablock(s) I. DOI: 10.1107/S160053681203783X/is5187Isup2.hkl

e-68-o2922-Isup2.hkl^{(413.8KB, hkl)}

Supplementary material file. DOI: 10.1107/S160053681203783X/is5187Isup3.cml

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

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

Cg1 is the centroid of the N1/C2/N3/C4–C6 ring.

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A
N4—H4⋯N5	0.869 (11)	2.294 (11)	2.9820 (18)	136.2 (9)
C57—H571⋯F5ⁱ	0.99	2.54	3.440 (2)	151
C57—H572⋯Cg1ⁱⁱ	0.99	2.60	3.467 (7)	147

Open in a new tab

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

supplementary crystallographic information

Comment

The pyrimidine core attracts attention as natural products and pharmacologically active compounds. In our ongoing research on an immunomodulating agent, we have synthesized some of 6-methyl-2-phenyl-5-substituted pyrimidine derivatives and their antibacterial and antifungal activities have been reported (Cieplik et al., 2003, 2008; Cieplik, Stolarczyk et al., 2011). As part of our study, we previously characterized structures of polymorphic forms of N-(4-chlorophenyl)-5-[(4-chlorophenyl)aminomethyl]-6-methyl-2-phenylpyrimidin-4-amine (Cieplik et al., 2006) and N-(2-fluorophenyl)-5-[(4-alloxyphenyl)aminomethyl]-6-methyl-2-phenylpyrimidin-4-amines (Cieplik, Pluta et al., 2011; Cieplik et al., 2012). In the continuation of our search for more potent antibacterial agent, the title compound, 5-[(4-fluoroanilino)methyl]-6-methyl-2-N-(4-methylphenyl)-phenylpyrimidin-4-amine, was also prepared.

The title compound crystallizes in P1 space group, with one molecule in the asymmetric unit (Fig. 1). There is an intramolecular N—H···N hydrogen bond between N4—H4 and N5, which closes a six-membered ring (Table 1). The N4···N5 distance [2.982 (2) Å] is longer than its conterparts in other similar compound (Cieplik, Pluta et al., 2011; Cieplik, Stolarczyk et al., 2011), compared with 2.940 (3) Å for the polymorphic form of N-(4-chlorophenyl)-5-[(4-chlorophenyl)aminomethyl]-6-methyl-2-phenylpyrimidin-4-amine (denoted as Ia, Cieplik et al., 2006). The conformation of the title molecule is best defined by dihedral angles formed between the pyrimidine ring and the planes of the phenyl ring attached to atom C2 and two other aryl rings of the (4-methylphenyl)amino and the (4-fluorophenyl)aminomethyl groups attached, respectively, to atoms C4 and C5 of the pyrimidine ring. These dihedral angles are 11.3 (2), 24.5 (2) and 70.1 (2)°, respectively.

The N—H···N hydrogen bonds involving the amine atom N5 as a donor are commonly observed in previously described structures (Cieplik et al., 2006, 2012; Cieplik, Pluta et al., 2011). However, in the structure of the title compound, atom H5 is not involved in any interactions. The crystal structure of the title compound is stabilized by weak C—H···F, C—H···π and π–π stacking interactions. The molecules are linked by a C—H···F interaction involving atom C57 as a donor and atom F5 (-x, -y + 1, -z + 2) as an acceptor. This results in the formation of an inversion dimer with an R²₂(16) ring motif. Between aryl rings of (4-fluorophenyl)aminomethyl groups of molecules forming the dimer there is also an aromatic π–π stacking interaction. The distance between the centroids of C51–C56 ring at (x, y, z) and (-x, -y + 1, -z + 2) is 3.708 (4) Å, and the interplanar spacing and the centroid offset are 3.429 (4) Å and 1.41 Å, respectively. Additionally, the C57—H572 group acts as a donor of C—H···π(arene) interaction to the pyrimidine N1/C2/N3/C4–C6 ring (-x, -y + 1, -z + 1). The combination of C—H···F and C—H···π interactions generates a column running along the [001] direction (Fig. 2).

Experimental

The title compound was obtained by adopting the procedure described previously by Cieplik et al. (2003). 4 g (0.0125 mmol) of 5-(chloromethyl)-6-methyl-N-(4-methylphenyl)-2-phenylpyrimidin-4-amine was dissolved in 50 ml of chloroform, and 2 g of 4-fluoroaniline was added. The reaction mixture was refluxed for 4 h with vigorous stirring, then was cooled and poured into 100 ml of water. The aqueous solution was extracted three times with chloroform (50 ml). The combined chloroform phases were dried over MgSO₄, filtered and concentrated under vacuum. The oily residue was purified by column chromatography on silica gel (200–400 mesh) using CHCl₃ as the eluent and by crystallization from methanol to give single crystals (yield: 3.74 g, 76.0%, m.p. 423–425 K).