N-(3,4-Difluorophenyl)-2-(3,4-dimethoxyphenyl)acetamide

In the title amide, C16H15F2NO3, the dihedral angle between the benzene rings is 53.7 (1)°. Molecules are linked in the crystal structure by an intermolecular N—H⋯O hydrogen bond involving N—H and C=O functionalities of the amide group. A one-dimensional network is thus formed along the [001] direction. No significant interchain contacts are observed.


S1. Comment
Tyrosinase is the key enzyme (Ha et al., 2007) that converts tyrosine to melanin, and its inhibitors are the target molecules to develop and research anti-pigmentation agents for application to skin. The melanin formation is also accelerated by exposure under sunlight, especially U.V. (Ha et al., 2007;Yan et al., 2007). Therefore, treatments using potent inhibitory agents on tyrosinase and melanin formation may be cosmetically useful. Most of the whitening agents (Maeda et al., 1991;Dawley et al., 1993;Nerya et al., 2003) contain hydroxyl (Hong et al., 2008;Lee et al., 2007), aromatic, alkene, carbonyl, and ether groups in their structure, and act as a specific functional group to make the skin white by inhibiting the production of melanin.
During our work on developing potent whiting agents, in order to prevent the inadequacies of current whitening agents (poor skin penetration and toxicity) and maximize the inhibitory effects of melanin creation, we synthesized the title compound, (I), via a general chemical reaction, and studied its X-ray crystal structure.
The 3,4-dimethoxyphenyl moiety and 3,4-difluoroaniline group are essentially planar, with a mean deviation of 0.005 and 0.006 Å, respectively, from the corresponding least-squares planes. The dihedral angle between the benzene rings is 53.7 (1)°. The intermolecular N7-H7···O9 i (symmetry code: (i) x, -y + 3/2, z -1/2) hydrogen bond (involving the H atom of the amine and O atom of carbonyl) allows to form an extensive one-dimensional network along the c-axis, which stabilizes the crystal structure.

S2. Experimental
3,4-Difluoroaniline and 3,4-dimethoxy phenyl acetyl chloride were purchased from Sigma Chemicals Co. Solvents used for organic synthesis were distilled 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 (1 mmol) and 3,4dimethoxy phenyl acetyl chloride (1.2 mmol) by simple substitution (nucleophilic addition-elimination on carbonyl C atom) in THF. Removal of solvent gave a white solid. The solid was purified by column chromatography on silica gel (2:1 hexane/ethyl acetate) to give the title compound (92% yield). Colourless crystals (m.p. 393 K) were obtained by slow evaporation of an ethyl acetate solution at 298 K.

S3. Refinement
Although diffraction data were collected using optimized parameters, a poor quality pattern resulted, which is reflected in the high final residuals. Atom H7 of the NH group was located in a differnce map and refined freely. Other H atoms were positioned geometrically and refined using a riding model, with C-H = 0.93-0.97 Å, and with U iso (H) = 1.2U eq (carrier C) for aromatic and CH 2 groups, and 1.5U eq (carrier C) for methyl H atoms.  The molecular structure of the title compound, showing the atom-numbering scheme and 30% probability ellipsoids.