3-(2,4-Dibromo­anilino)-2,2-dimethyl-2,3-dihydro­naphtho[1,2-b]furan-4,5-dione: a new substituted aryl­amino nor-β-lapachone derivative

Eufrânio N da Silva, Jr; Carlos A De Simone; Marília O F Goulart; Carlos K Z Andrade; Raphael S F Silva; Antonio V Pinto

doi:10.1107/S1600536808034545

. 2008 Nov 13;64(Pt 12):o2348. doi: 10.1107/S1600536808034545

3-(2,4-Dibromoanilino)-2,2-dimethyl-2,3-dihydronaphtho[1,2-b]furan-4,5-dione: a new substituted arylamino nor-β-lapachone derivative

Eufrânio N da Silva Jr ^a, Carlos A De Simone ^b,^*, Marília O F Goulart ^b, Carlos K Z Andrade ^a, Raphael S F Silva ^c, Antonio V Pinto ^c

PMCID: PMC2959894 PMID: 21581322

Abstract

The title compound, C₂₀H₁₅Br₂NO₃, shows the furan ring to adopt a half-chair conformation and the two ring systems to be approximately perpendicular [dihedral angle = 71.0 (2)°]. In the crystal structure, intermolecular C—H⋯O contacts link the molecules.

Related literature

For general background, see: Hillard et al. (2008 ▶); Pinto et al., (1997 ▶); Dos Santos et al. (2001 ▶); Lima et al. (2004 ▶). For related structures and biological activity, see: da Silva Júnior et al. (2007 ▶, 2008 ▶); Lima et al. (2002 ▶). For the synthesis, see: da Silva Júnior et al. (2007 ▶, 2008 ▶). For geometric analysis, see: Cremer & Pople (1975 ▶).

Experimental

Crystal data

C₂₀H₁₅Br₂NO₃
M _r = 477.15
Triclinic,
a = 8.1430 (3) Å
b = 11.2584 (4) Å
c = 11.4742 (5) Å
α = 112.073 (2)°
β = 95.546 (2)°
γ = 108.696 (2)°
V = 894.70 (6) Å³
Z = 2
Mo Kα radiation
μ = 4.55 mm⁻¹
T = 293 (2) K
0.31 × 0.28 × 0.16 mm

Data collection

Nonius KappaCCD diffractometer
Absorption correction: multi-scan (SADABS; Sheldrick, 1996 ▶) T _min = 0.272, T _max = 0.490
9784 measured reflections
4099 independent reflections
3610 reflections with I > 2σ(I)
R _int = 0.032

Refinement

R[F ² > 2σ(F ²)] = 0.048
wR(F ²) = 0.139
S = 1.09
4070 reflections
235 parameters
H-atom parameters constrained
Δρ_max = 0.59 e Å⁻³
Δρ_min = −1.49 e Å⁻³

Data collection: COLLECT (Nonius, 2000 ▶); cell refinement: SCALEPACK (Otwinowski & Minor, 1997 ▶); data reduction: DENZO (Otwinowski & Minor, 1997 ▶) and SCALEPACK; 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 I, global. DOI: 10.1107/S1600536808034545/tk2311sup1.cif

e-64-o2348-sup1.cif^{(20.8KB, cif)}

Structure factors: contains datablocks I. DOI: 10.1107/S1600536808034545/tk2311Isup2.hkl

e-64-o2348-Isup2.hkl^{(195.4KB, 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
C3—H3⋯O2ⁱ	0.98	2.64	3.347 (6)	129
C1′′—H1A⋯O2ⁱ	0.96	2.67	3.389 (6)	132

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Symmetry code: (i) Inline graphic .

Acknowledgments

This work received partial support from CNPq, CAPES, FAPEAL, FAPERJ, IM-INOFAR, CTPETRO and FINEP.

supplementary crystallographic information

Comment

The search for substances with pharmacological activity has grown exponentially in recent years and quinones play a major role as bioreductive drugs, reactive oxygen species (ROS) enhancers, and redox catalysts (Hillard et al., 2008). Substances such as lapachol (I), (Pinto et al., 1997; dos Santos et al., 2001; Lima et al., 2004), β-lapachone (II) (Hillard et al., 2008) and nor-β-lapachone (III) (da Silva Júnior et al., 2007), Scheme 1, are prototypes that can be used as starting points for the synthesis of new bioactive molecules. In this context, different compounds with anti-cancer activity (da Silva Júnior et al., 2007), trypanocides (da Silva Júnior et al., 2008), molluscicides (Lima et al., 2002) among others, were synthesized. The introduction of arylamino groups in the furan ring of III retained/enhanced the anticancer activity against six cancer cell lines with IC₅₀ values below 1µg/ml (da Silva Júnior et al., 2007), as well as intensified trypanocidal activity (da Silva Júnior et al., 2008), demonstrating clearly that the arylamino group is important for pharmacological activity. In this paper, we report the molecular and crystal structure of (IV) that was easily obtained as described in the literature (da Silva Júnior et al., 2007; 2008).

The atoms of the naphthoquinonic ring of (IV), Fig. 1, are co-planar and the greatest deviation from their least-squares plane is exhibited by atom C5 [0.069 (4) Å]. The O1 atom lies in the mean least-square plane of the naphthoquinonic ring with a deviation of 0.051 (3) Å while atoms O2 and O3 are -0.129 (3) and 0.212 (4)Å out of that plane, respectively. The furane ring adopts a half chair conformation and the calculated puckering parameters are: q₂ = 0.229 (4) Å and φ = -12 8.04 (1)° (Cremer & Pople, 1975). The dihedral angle between planes passing through atoms C1'-C6' of the aromatic ring and the naphthoquinonic ring is 71.0 (2) °. In the crystal packing, molecules interact through two intermolecular C—H···O contacts, Table 1.

Experimental

To a chloroform (25mL) solution of the nor-lapachol (2-hydroxy-3-(2-methylprop-1-enyl)naphthalene-1,4-dione, 228 mg, 1 mmol), bromine (2 mL, 38 mmol) was added. The bromo intermediate, 3-bromo-2,2-dimethyl-2,3-dihydro-naphtho[1,2-b]furan-4,5-dione, precipitated immediately as an orange solid. Over this mixture, an excess of 2,4-dibromobenzenamine was added and the mixture was left under agitation overnight. After the addition of water (50 ml), the organic phase was separated and washed with 10% HCl (3 x 50 ml), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The arylaminoderivative,3-(2',4'-dibromophenylamine)-2H,3H-2,2- dimethylnaphtho[1,2 - b]furan-4,5-dione species, was purified by column chromatography over silica-gel, using as eluent a gradient mixture of hexane/ethyl acetate (9/1 to 7/3) with increasing polarity and obtained as a red solid (330 mg, 0.70 mmol, 70% yield). ¹H NMR (300 MHz, CDCl₃) δ: 8.14 (1H, dd, J = 6.7, 1.3 Hz), 7.76–7.63 (3H, m), 7.56 (1H, d, J = 2.0 Hz), 7.30 (1H, dd, J = 8.8, 2.0 Hz), 6.53 (1H, d, J = 8.8 Hz), 4.83 (1H, d, J = 7.5 Hz), 4.48 (NH, d,J = 7.5 Hz), 1.66 (3H, s), 1.54 (3H, s). ¹³C NMR (75 MHz, CDCl₃) δ: 180.6 (C=O), 175.0 (C=O), 169.7 (C_q), 143.0 (C_q), 134.6 (CH), 132.6 (CH),131.1 (CH), 131.0 (C_q), 129.5 (CH), 127.1 (C_q), 125.1 (CH), 114.4 (C_q),112.6(CH), 110.2 (C_q), 108.9 (C_q), 96.0 (C_q), 134.5(CH), 61.2 (CH), 27.5 (CH₃), 21.6 (CH₃).