5-Meth­oxy-2-[(5-meth­oxy-1H-indol-1-yl)carbon­yl]-1H-indole

Mohamed I Attia; Nasser R El-Brollosy; Ali A El-Emam; Seik Weng Ng; Edward R T Tiekink

doi:10.1107/S1600536812020399

. 2012 May 19;68(Pt 6):o1775. doi: 10.1107/S1600536812020399

5-Methoxy-2-[(5-methoxy-1H-indol-1-yl)carbonyl]-1H-indole

Mohamed I Attia ^a,^‡, Nasser R El-Brollosy ^a, Ali A El-Emam ^a, Seik Weng Ng ^b,^c, Edward R T Tiekink ^b,^*

PMCID: PMC3379355 PMID: 22719553

Abstract

The asymmetric unit of the title compound, C₁₉H₁₆N₂O₃, comprises three independent molecules (A, B and C). The inversion-related molecule of A is virtually superimposable upon the other two molecules. In each molecule, there is a twist in the link between the approximately syn carbonyl and amine groups [the N—C—C—O torsion angles range from 19.73 (19) to −21.2 (2)°]. Each molecule has a bent shape quantified in terms of the dihedral angle between the indole and indole fused-ring systems [range = 45.69 (5)–47.91 (5)°]. In the crystal, the A and B molecules form dimeric aggregates via ten-membered {⋯HNC₂O}₂ synthons, while the C molecules self-associate similarly but about a centre of inversion.

Related literature

For background to melatonin and melatonin preparations, see: Barrenetxe et al. (2004 ▶); Williamson et al. (1998 ▶). For background to melatonin receptor ligands, see: Bedini et al. (2006 ▶); Attia et al. (2008 ▶). For a related structure, see: Attia et al. (2012 ▶). graphic file with name e-68-o1775-scheme1.jpg

Experimental

Crystal data

C₁₉H₁₆N₂O₃
M _r = 320.34
Triclinic,
a = 11.3153 (4) Å
b = 12.1183 (5) Å
c = 17.1300 (6) Å
α = 76.251 (3)°
β = 79.747 (3)°
γ = 88.913 (3)°
V = 2244.50 (15) Å³
Z = 6
Cu Kα radiation
μ = 0.80 mm⁻¹
T = 100 K
0.30 × 0.20 × 0.02 mm

Data collection

Agilent SuperNova Dual diffractometer with an Atlas detector
Absorption correction: multi-scan (CrysAlis PRO; Agilent, 2011 ▶) T _min = 0.367, T _max = 1.000
17372 measured reflections
9182 independent reflections
7534 reflections with I > 2σ(I)
R _int = 0.029

Refinement

R[F ² > 2σ(F ²)] = 0.043
wR(F ²) = 0.121
S = 1.02
9182 reflections
661 parameters
H atoms treated by a mixture of independent and constrained refinement
Δρ_max = 0.28 e Å⁻³
Δρ_min = −0.30 e Å⁻³

Data collection: CrysAlis PRO (Agilent, 2011 ▶); cell refinement: CrysAlis PRO; data reduction: CrysAlis PRO; program(s) used to solve structure: SHELXS97 (Sheldrick, 2008 ▶); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008 ▶); molecular graphics: ORTEP-3 (Farrugia, 1997 ▶), Qmol (Gans & Shalloway, 2001 ▶) and DIAMOND (Brandenburg, 2006 ▶); software used to prepare material for publication: publCIF (Westrip, 2010 ▶).

Supplementary Material

Crystal structure: contains datablock(s) global, I. DOI: 10.1107/S1600536812020399/su2424sup1.cif

e-68-o1775-sup1.cif^{(39.3KB, cif)}

Structure factors: contains datablock(s) I. DOI: 10.1107/S1600536812020399/su2424Isup2.hkl

e-68-o1775-Isup2.hkl^{(449KB, hkl)}

Supplementary material file. DOI: 10.1107/S1600536812020399/su2424Isup3.cml

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
N1—H1n⋯O5	0.91 (2)	1.98 (2)	2.8536 (16)	159 (2)
N3—H3n⋯O2	0.91 (2)	1.97 (2)	2.8384 (16)	159.0 (19)
N5—H5n⋯O8ⁱ	0.90 (2)	2.00 (2)	2.8796 (15)	163.9 (19)

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Symmetry code: (i) Inline graphic .

Acknowledgments

The financial support of the Deanship of Scientific Research and the Research Center of the College of Pharmacy, King Saud University is greatly appreciated. We also thank the Ministry of Higher Education (Malaysia) for funding structural studies through the High-Impact Research scheme (UM.C/HIR/MOHE/SC/12).

supplementary crystallographic information

Comment

Melatonin (N-acetyl-5-methoxytryptamine, MLT) is primarily produced by the pineal gland in the brain with a marked circadian rhythm normally peaking in the dark to regulate sleep patterns (Barrenetxe et al., 2004). It has been reported that commercial melatonin preparations contain N-{2-[1-({3-[2-(acetylamino)ethyl]-5-methoxy-1H-indol-2-yl}-methyl)-5-methoxy-1H-indol-3-yl]ethyl}acetamide (1) as a contaminant (Williamson et al., 1998). The title compound, namely (5-methoxy-1H-indol-1-yl)(5-methoxy-1H-indol-2-yl)methanone (I), can be elaborated to give compound 1, in four steps. The synthesis of compound 1 on a preparative scale is required for the development of an analytical method for the determination of MLT in the presence of this contaminant in commercial MLT preparations. Herein, the crystal and molecular structure of the title compound (I) is described in continuation of on-going studies of melatonin receptor ligands (Bedini et al., 2006; Attia et al., 2008; Attia et al., 2012).

Three crystallographically independent molecules comprises the asymmetric unit of the title compound (I), Fig. 1. In each molecule there is a twist in the link between the carbonyl and amine groups but, each of these is approximately syn with the N1—C9—C10—O2, N3—C28—C29—O5 and N5—C47—C48—O8 torsion angles being 19.73 (19), -20.34 (19) and -21.2 (2)°, respectively. Each molecule has a bent shape quantified in terms of the dihedral angle between the indole and indonyl fused ring systems. For the N1-containing molecule this angle is 45.69 (5)° which compares to 45.86 (5) and 47.91 (5)° in the other two molecules. If the inversion-related N1-containing molecule is overlapped with the N2- and N3-containing molecules, it can be seen that all three molecules are virtually superimposable, as shown in Fig. 2. The major differences are apparent in the relative orientations of the terminal methoxy groups of the indonyl rings. In the N1- and N-3 containing molecules, the methyl group is orientated in almost the opposite direction to that seen in the N2-containing molecule. Further, in the N3-containing molecule, the methoxy group is slightly twisted out of the plane of the benzene ring to which it is connected. This is quantified in the values of the C16—C17—O3—C19, C35—C36—O6—C37 and C54—C55—O9—C57 torsion angles of -179.18 (14), 0.06 (2) and 168.68 (13)°, respectively.

In the crystal, the N1- and N2-containing molecules associate via N—H···O(carbonyl) hydrogen bonds to form dimeric aggregates via 10-membered {···HNC₂O}₂ synthons, Fig. 3. The N3-containing molecules self-associate similarly but about a centre of inversion. Molecules assemble into a three-dimensional architecture viaπ—π interactions with the closest of these occurring between five-membered (N2,C11–C14) and six-membered C32–C37 rings [inter-centroid distance = 3.5307 (9) Å for symmetry operation (i) = -x+1, -y+1, -z+1].

Experimental

A mixture of (5-methoxy-2,3-dihydro-1H-indol-1-yl)(5-methoxy-1H-indol-2-yl)- methanone (0.20 g, 0.62 mmol) and 2,3-dichloro-5,6-dicyanobenzoquinone (0.19 g, 0.68 mmol) in ethyl acetate (30 ml) was heated at reflux temperature for 18 h. The reaction mixture was evaporated under reduced pressure and the residue was purified by silica gel chromatography (chloroform/methanol/ammonia, 10:1:0.1) to furnish 0.19 g (96%) of (5-methoxy-1H-indol-1-yl)(5-methoxy-1H-indol-2-yl)methanone as a light-red powder which was recrystallized from ethanol to give colourless crystals of the title compound (I); M.pt: 451–452 K.