N-(3,4-Difluoro­phen­yl)-3,4,5-trimethoxy­benzamide

Hyeong Choi; Byung Hee Han; Taewoo Lee; Sung Kwon Kang; Chang Keun Sung

doi:10.1107/S1600536810013796

. 2010 Apr 24;66(Pt 5):o1142. doi: 10.1107/S1600536810013796

N-(3,4-Difluorophenyl)-3,4,5-trimethoxybenzamide

Hyeong Choi ^a, Byung Hee Han ^a, Taewoo Lee ^a, Sung Kwon Kang ^a,^*, Chang Keun Sung ^b

PMCID: PMC2979189 PMID: 21579190

Abstract

In the title amide, C₁₆H₁₅F₂NO₄, the dihedral angle between the benzene rings is 2.33 (15)°. Molecules are linked in the crystal structure by N—H⋯O hydrogen bonding involving N—H and C=O groups of the amide function, leading to a supramolecular chain along [100].

Related literature

For background to the development of potent inhibitory agents of tyrosinase and melanin formation as whitening agents, see: Cabanes et al. (1994 ▶); Dawley & Flurkey (1993 ▶); Ha et al. (2007 ▶); Hong et al. (2008 ▶); Kwak et al. (2010 ▶); Lee et al. (2007 ▶); Nerya et al. (2003 ▶); Park et al. (2010 ▶); Sung & Samyang Genex (2001 ▶); Yi et al. (2009 ▶, 2010 ▶).

Experimental

Crystal data

C₁₆H₁₅F₂NO₄
M _r = 323.29
Monoclinic,
a = 5.0031 (3) Å
b = 8.8986 (5) Å
c = 32.726 (2) Å
β = 93.896 (4)°
V = 1453.59 (15) Å³
Z = 4
Mo Kα radiation
μ = 0.12 mm⁻¹
T = 174 K
0.12 × 0.05 × 0.04 mm

Data collection

Bruker SMART CCD area-detector diffractometer
10828 measured reflections
2634 independent reflections
1522 reflections with I > 2σ(I)
R _int = 0.080

Refinement

R[F ² > 2σ(F ²)] = 0.065
wR(F ²) = 0.185
S = 1.05
2634 reflections
216 parameters
H atoms treated by a mixture of independent and constrained refinement
Δρ_max = 0.32 e Å⁻³
Δρ_min = −0.31 e Å⁻³

Data collection: SMART (Bruker, 2002 ▶); cell refinement: SAINT (Bruker, 2002 ▶); 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, 1997 ▶); software used to prepare material for publication: WinGX (Farrugia, 1999 ▶).

Supplementary Material

Crystal structure: contains datablocks global, I. DOI: 10.1107/S1600536810013796/tk2658sup1.cif

e-66-o1142-sup1.cif^{(15.6KB, cif)}

Structure factors: contains datablocks I. DOI: 10.1107/S1600536810013796/tk2658Isup2.hkl

e-66-o1142-Isup2.hkl^{(126.7KB, hkl)}

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
N15—H15⋯O14ⁱ	0.93 (4)	2.02 (4)	2.872 (4)	152 (3)

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Symmetry code: (i) Inline graphic .

Acknowledgments

We wish to thank the DBIO company for partial support of this work.

supplementary crystallographic information

Comment

Melanin synthesis is principally responsible for skin color and plays a key role in the prevention of UV-induced skin damages. Tyrosinase is the key enzyme (Ha et al., 2007) that converts tyrosine to melanin and its inhibitors are target molecules for developing anti-pigmentation agents. Therefore, treatments using potent inhibitory agents on tyrosinase and melanin formation may be cosmetically useful. Common tyrosinase inhibitors (Dawley & Flurkey, 1993; Nerya et al., 2003) are hydroquinone, ascorbic acid, kojic acid and arbutin (Cabanes et al., 1994). Recently, a number of reports have focused on the development of new agents for the inhibition of tyrosinase. They contain aromatic, methoxy, hydroxyl (Hong et al., 2008; Lee et al., 2007), aldehyde (Yi et al., 2010), amide (Kwak et al., 2010), thiosemicarbazone (Yi et al., 2009) groups in their respective molecule structure. The application of natural products as a melanin synthesis inhibitors has also attracted interest (Park et al., 2010; Sung et al., 2001). However, most of these are not sufficiently potent for practical use owing to their weak individual activities or due to safety concerns. Undoubtedly, significant research and development into novel tyrosinase inhibitors is required to generate molecules with better activities and reduced side-effects. In continuation of our program aimed to develop tyrosinase inhibitors, we have synthesized the title compound, N-(3,4-difluorophenyl)-3,4,5-trimethoxybenzamide, (I), from the reaction of 3,4-difluoroaniline with 3,4,5-trimethoxybenzoyl chloride under ambient condition. Herein, the crystal structure of (I) is described (Fig. 1).

The 3,4,5-trimethoxybenzoic acid moiety (except for the C10 methyl group) and 3,4-difluoroaniline group are essentially planar, with a mean deviations of 0.027 Å and 0.006 Å, respectively, from the corresponding least-squares plane defined by the ten and nine, respectively, constituent atoms. The dihedral angle between the benzene rings is 2.33 (15) °. The presence of intermolecular N15—H15···O14ⁱ (symmetry code: (i) x-1, y, z) hydrogen bonds lead to the formation an 1-D supramolecular chain along the a axis, Table 1.

Experimental

3,4,5-Trimethoxybenzoyl chloride 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 3,4,5-trimethoxybenzoyl chloride (1.078 g, 5 mmol) and 3,4-difluoroaniline (0.5 g, 4 mmol) in THF with TEA (15 ml) as a catalyst. After being stirred for 5 h at 298 K, the mixture was treated with water and extracted with ethyl acetate. The combined extracts were dried over anhydrous magnesium sulfate. Removal of solvent gave a white solid (90%, m.pt. 428 K). Single crystals were obtained by slow evaporation of a methylene chloride and ethyl alcohol solution of (I) held at room temperature.