Crystal structure of 3-(3,4,5-tri­meth­oxy­phen­yl)-1,2,3,4-tetra­hydro­cyclo­penta[b]indole-2-carb­oxy­lic acid

Daniara Fernandes; Deborah de Alencar Simoni; Manoel T Rodrigues, Jr; Marilia S Santos; Fernando Coelho

doi:10.1107/S2056989015008786

. 2015 May 13;71(Pt 6):o395–o396. doi: 10.1107/S2056989015008786

Crystal structure of 3-(3,4,5-trimethoxyphenyl)-1,2,3,4-tetrahydrocyclopenta[b]indole-2-carboxylic acid

Daniara Fernandes ^a, Deborah de Alencar Simoni ^b,^*, Manoel T Rodrigues Jr ^a, Marilia S Santos ^a, Fernando Coelho ^a

PMCID: PMC4459319 PMID: 26090185

Abstract

In the title compound, C₂₁H₂₁NO₅, obtained from a Morita–Baylis–Hillman adduct, the hydrogenated five-membered ring adopts a shallow envelope conformation, with the C atom bearing the carboxylic acid substituent deviating by 0.237 (1) Å from the mean plane of the other four atoms (r.m.s. deviation = 0.007 Å). The dihedral angle between the fused ring system (all atoms; r.m.s. deviation = 0.057 Å) and the pendant trimethoxy benzene ring is 66.65 (3)°. The C atoms of the meta-methoxy groups lie close to the plane of the benzene ring [deviations = 0.052 (1) and −0.083 (1) Å], whereas the C atom of the para-methoxy group is significantly displaced [deviation = −1.289 (1) Å]. In the crystal, carboxylic acid inversion dimers generate R ₂ ²(8) loops. The dimers are connected by N—H⋯O hydrogen bonds, forming [011] chains. A C—H⋯O interaction is also observed.

Keywords: crystal strycture, indole skeleton, Morita–Baylis–Hillman adduct, hydrogen bonding

Related literature

For compounds presenting an indole skeleton unit and examples of them, see: Xu et al. (2012 ▸); Humphrey & Kuethe (2006 ▸). For methods of synthesis of indoles, see: Jordan et al. (2011 ▸); Humphrey & Kuethe (2006 ▸). For the use of Morita–Baylis–Hillman adducts as building blocks for organic synthesis, see: Basavaiah & Veeraraghavaiah (2012 ▸); Coelho et al. (2002 ▸).

Experimental

Crystal data

C₂₁H₂₁NO₅
M _r = 367.39
Triclinic,
a = 7.203 (1) Å
b = 9.5844 (12) Å
c = 12.9957 (17) Å
α = 91.939 (5)°
β = 97.198 (6)°
γ = 91.716 (5)°
V = 889.1 (2) Å³
Z = 2
Mo Kα radiation
μ = 0.10 mm⁻¹
T = 100 K
0.34 × 0.17 × 0.13 mm

Data collection

Bruker APEX CCD diffractometer
Absorption correction: multi-scan (SADABS; Bruker, 2010 ▸) T _min = 0.967, T _max = 0.987
100846 measured reflections
7825 independent reflections
6558 reflections with I > 2σ(I)
R _int = 0.031

Refinement

R[F ² > 2σ(F ²)] = 0.038
wR(F ²) = 0.119
S = 0.94
7825 reflections
248 parameters
H-atom parameters constrained
Δρ_max = 0.58 e Å⁻³
Δρ_min = −0.27 e Å⁻³

Data collection: APEX2 (Bruker, 2010 ▸); cell refinement: SAINT (Bruker, 2010 ▸); data reduction: SAINT; program(s) used to solve structure: SHELXS97 (Sheldrick, 2008 ▸); program(s) used to refine structure: SHELXLE (Hübschle et al., 2011 ▸); molecular graphics: Mercury (Macrae et al., 2006 ▸); software used to prepare material for publication: OLEX2 (Dolomanov et al., 2003 ▸) and publCIF (Westrip, 2010 ▸).

Supplementary Material

Crystal structure: contains datablock(s) I, New_Global_Publ_Block. DOI: 10.1107/S2056989015008786/hb7417sup1.cif

e-71-0o395-sup1.cif^{(2.8MB, cif)}

Structure factors: contains datablock(s) I. DOI: 10.1107/S2056989015008786/hb7417Isup2.hkl

e-71-0o395-Isup2.hkl^{(621.3KB, hkl)}

Click here for additional data file.^{(3.3KB, cdx)}

Supporting information file. DOI: 10.1107/S2056989015008786/hb7417Isup3.cdx

Click here for additional data file.^{(7.4KB, cml)}

Supporting information file. DOI: 10.1107/S2056989015008786/hb7417Isup4.cml

Click here for additional data file.^{(1.7MB, tif)}

. DOI: 10.1107/S2056989015008786/hb7417fig1.tif

The molecular structure of the title compound with 50% probability displacement ellipsoids.

Click here for additional data file.^{(2.1MB, tif)}

. DOI: 10.1107/S2056989015008786/hb7417fig2.tif

Crystal packing of the title compound, showing hydrogen-bonding interactions.

CCDC reference: 1063387

Additional supporting information: crystallographic information; 3D view; checkCIF report

Table 1. Hydrogen-bond geometry (, ).

DHA	DH	HA	D A	DHA
O4H4O3ⁱ	0.84	1.84	2.6748(8)	176
N1H1O1ⁱⁱ	0.88	2.20	2.9041(8)	136
C12H12BO2ⁱⁱⁱ	0.98	2.62	3.3905(11)	137

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Symmetry codes: (i) Inline graphic ; (ii) ; (iii) .

Acknowledgments

The authors acknowledge the Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP 2013/07600-3 and 09/51602-5) for financial support and the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) for a research fellowship. MTRJr and MSS thank CNPq and Fapesp for fellowships.

supplementary crystallographic information

S1. Introduction

Indole skeleton is an aromatic heterocycle possessing a benzene ring fused to a pyrrole ring which exhibits a wide range of biological and pharmacological activities. Compounds presenting this moiety have been successfully synthesized and used in medicinal chemistry (Xu et al., 2012). In spite of the number of developed methods for the preparation of indoles (Xu et al., 2012; Humphrey and Kuethe, 2006), our interest to use Morita–Baylis–Hillman adducts as building blocks for organic synthesis resulted in a successful stereoselective strategy to obtain compounds of this class.

S2. Experimental

S2.1. Synthesis and crystallization

\ The synthesis of 3-(3,4,5-trimethoxyphenyl)-1,2,3,4-tetrahydrocyclopenta[b]indole-2-\ carboxylic acid started with a mixture of 1 mmol of (±)-methyl 2-[hydroxy(3,4,5-trimethoxyphenyl)-methyl]acrylate (the Morita–Baylis–Hillman adduct), 1.2 mmol of indole and 1 mmol of 2-iodoxybenzoic acid, in acetonitrile (5 mL). This mixture was kept under reflux to give 1,3-dicarbonyl compound, which was further reduced by sodium tetrahydroborate, resulting in the corresponding β-hydroxy-carbonyl.

This was then treated with trifluoromethanesulfonic acid and submitted to basic hydrolysis. The cyclopenta[b]indole, obtained with excellent diastereoselectivity (>99:1) and overall yield of 70%, was purified by flash chromatography (hexane/ethyl acetate (60:40)). 3-(3,4,5-trimethoxyphenyl)-1,2,3,4-tetrahydrocyclopenta[b]indole-2-\ carboxylic acid was dissolved in 10:1 (v/v) chloroform/methanol mixture and kept in the freezer to allow slowly formation of irregular colorless single crystals.

S2.2. Refinement

The positions of hydrogen atoms bound to carbon atoms were idealized and calculated by riding model, with C—H bond lengths of 0.95, 0.98 and 0.99 Å for phenyl, methyl and methylene, respectively. The isotropic displacement parameters values (Uiso(H)) were fixed at 1.5Ueq(C) for methyl H atoms and 1.2Ueq(C) for all other attached H atoms.

S3. Results and discussion

The molecules of the title compound present a trimethoxyphenyl ring bonded to a system of three rings, in which an indole skeleton unit is fused to a five-membered ring possessing a carboxylic unit (Fig. 1). It crystallized in P1 space group and has a conformational structure determined by intra and intermolecular nonclassical (C—H—O) and intermolecular (O—H—O and N—H—O) bonding (Table 1, Fig. 2).

All of the rings in the structure are almost planar, with r.m.s. of 0.010, 0.066, 0.006 and 0.006 Å for trimethoxyphenyl, five-membered, pyrrole and benzene rings, respectively. The three rings fused system is essentially planar (r.m.s. deviation of 0.057 Å) and make a plane-plane angle of 113.35° with the trimethoxyphenyl ring.

With respect to the pyrrole ring, the benzene ring and the five-membered ring make dihedral angles C14—C13—N1—C5 = 176.67 (7)° and C3—C4—C16—C17 = -175.72 (8)°, respectively. The dihedral angle between the five-membered ring and its trimethoxyphenyl substituent (C5—C6—C7—C8) is -164.79 (16)°, while that between the five-membered ring and the carboxylic unit (C16—C17—C18—O4) is -56.30 (8)°, which is consistent with the expected trans relative configuration of this isomer.