N-(3,4-Difluorophenyl)-N′-(2,5-dimethoxyphenyl)urea

In the title compound, C15H14F2N2O3, the dihedral angle between the benzene rings is 64.5 (1)°. One F atom is disordered over two meta positions, with occupancy factors of 0.72 and 0.28. In the crystal, molecules are linked by N—H⋯O hydrogen bonds involving two N—H and one C=O groups of the urea central fragment, leading to a supramolecular chain along [011].

In the title compound, C 15 H 14 F 2 N 2 O 3 , the dihedral angle between the benzene rings is 64.5 (1) . One F atom is disordered over two meta positions, with occupancy factors of 0.72 and 0.28. In the crystal, molecules are linked by N-HÁ Á ÁO hydrogen bonds involving two N-H and one C O groups of the urea central fragment, leading to a supramolecular chain along [011].

Comment
Melanin is the pigment responsible for the color of human skin and it is formed through a series of oxidative reaction in the presence of key enzyme tyrosinase (Ha et al., 2007) that converts tyrosine into melanin. It is secreted by melanocyte cells distributed in the basal layer of the dermis. Its role is to protect the skin from ultraviolet (UV) damage by absorbing the ultraviolet sunlight and removing reactive oxygen species. Therefore these inhibitors are target molecules for developing anti-pigmentation agents. Common tyrosinase inhibitors (Dawley & Flurkey, 1993;Nerya et al., 2003) are hydroquinone, ascorbic acid, kojic acid and arbutin (Cabanes et al., 1994). Recently, numerous reports have focused on the inhibition of tyrosinase. They are containing aromatic, methoxy, hydroxyl (Hong et al., 2008;Lee et al., 2007), aldehyde (Yi et al., 2010), amide (Kwak et al., 2010;Choi et al., 2010), thiosemicarbazone (Yi et al., 2009), thiazole (Germanas et al., 2007), thiourea (Criton & Le Mellay-Hamon, 2008) groups in their structures, and act as a specific functional group to make the skin white by inhibiting the production of melanin. However, most of them are not potent enough to put into practical use due to their weak individual activities, poor skin penetration, and low stability of formulations, as well as toxicity or safety concerns. Consequently, there is still need to search and develop novel tyrosinase inhibitors with better activities together with lower side effects. To complement the inadequacy of current whitening agent above mentioned and maximize the effect of inhabitation of melanin creation, we have synthesized the title compound, (I), from the reaction of 3,4-difluoroaniline with 2,5-dimethoxyphenyl isocyanate, under ambient conditions. Herein, the crystal sturucture of (I) is described (Fig. 1).
The 3,4-difluoroaniline group and 2,5-dimethoxyphenyl moiety are essentially planar, with a mean deviations of 0.007 Å and 0.016 Å, respectively, from the corresponding least-squares planes defined by each nine constituent atoms. The dihedral angle between the benzene rings is 64.5 (1) °. The presence of intermolecular N-H···O hydrogen bonds lead to the formation a supramolecular chain along [011].
Experimental 2,5-Dimethoxyphenyl isocyanate and 3,4-difluoroaniline were purchased from Sigma Chemical Co. Solvents used for synthesis were redistilled before use. All other chemicals and solvents were of analytical grade and used without further purification. The title compound was prepared from the reaction of 3,4-difluoroaniline (0.28 ml, 3 mmol) and 2,5-dimethoxyphenyl isocyanate (0.5 g, 3 mmol) in acetonitrile (6 ml). The mixture was refluxed for 8 h at 353 K, and then treated with water and extracted with methylene chloride (2 × 50 mL). The combined extracts were dried over anhydrous magnesium sulfate.
Removal of solvent gave a white solid (90%, m.p. 454 K). Single crystals were obtained by slow evaporation of a methylene chloride solution at room temperature.

Refinement
The amide H atoms were located in a difference map and refined freely. The remaining H atoms were positioned geometrically and refined using a riding model with C-H = 0.93-0.96 Å, and with U iso (H) = 1.2U eq (C) for aromatic and 1.5U eq (C) for methyl H atoms. Atom F7 is disordered over two positions and the two split atoms are designated by having the suffix A supplementary materials sup-2 after the atom number. The final occupancy factors are F7 0.72 and F7A 0.28. The measured diffraction fraction is relatively low of 95.5% due to a tiny single-crystal for data collection. This single-crystal was the largest one we could produce as described in the experimental section. Fig. 1. Molecular structure of (l), showing the atom-numbering scheme and 50% probability ellipsoids. 119.0 (3) C15-C14-C13 120.1 (4) C3-C2-H2 120.5 C14-C15-C16 120.0 (4)