Ethyl 1-acetyl-1H-indole-3-carboxyl­ate

Tasneem Siddiquee; Shahid Islam; Dennis Bennett; Matthias Zeller; Mahmun Hossain

doi:10.1107/S1600536809025379

. 2009 Jul 8;65(Pt 8):o1802–o1803. doi: 10.1107/S1600536809025379

Ethyl 1-acetyl-1H-indole-3-carboxylate

Tasneem Siddiquee ^a,^*, Shahid Islam ^b, Dennis Bennett ^b, Matthias Zeller ^c, Mahmun Hossain ^b

PMCID: PMC2977149 PMID: 21583507

Abstract

The title compound, C₁₃H₁₃NO₃, was synthesized by acetylation of ethyl 1H-indole-3-carboxylate. The aromatic ring system of the molecule is essentially planar, but the saturated ethyl group is also located within this plane and the overall r.m.s. deviation from planarity is only 0.034 Å. Pairs of C—H⋯O interactions connect molecules into chains along the diagonal of the unit cell. Molecules also form weakly connected dimers via π⋯π stacking interactions of the indole rings with centroid–centroid separations of 3.571 (1) Å. C—H⋯π interactions between methylene and methyl groups and the indole and benzene ring complete the directional intermolecular interactions found in the crystal structure.

Related literature

For the biological properties of tryptophan derivatives, see: Ma et al. (2001 ▶); Zhou et al. (2006 ▶); Zhao, Smith et al. (2002 ▶); Zhao, Liao & Cook (2002 ▶). For synthetic procedures towards tryptophan-like compounds, see: Ager & Laneman (2004 ▶); Amir-Heidari et al. (2007 ▶); Carlier et al. (2002 ▶); Hengartner et al. (1979 ▶); Moriya et al. (1980 ▶). For the synthesis of 2-acetamido-3-ethoxy-3-oxopropanoic acid, see: Hellmann et al. (1958 ▶). For NMR data for the title compound, see: Reimann et al. (1990 ▶).

Experimental

Crystal data

C₁₃H₁₃NO₃
M _r = 231.24
Triclinic,
a = 7.519 (1) Å
b = 8.479 (1) Å
c = 10.187 (2) Å
α = 97.38 (1)°
β = 95.78 (2)°
γ = 114.28 (1)°
V = 578.58 (15) Å³
Z = 2
Mo Kα radiation
μ = 0.10 mm⁻¹
T = 296 K
0.51 × 0.41 × 0.20 mm

Data collection

Siemens P4 diffractometer
Absorption correction: multi-scan [XSCANS (Siemens, 1996 ▶) and XPREP (Siemens, 1994 ▶)] T _min = 0.823, T _max = 0.981
2536 measured reflections
2027 independent reflections
1696 reflections with I > 2σ(I)
R _int = 0.019
3 standard reflections every 97 reflections intensity decay: <1%

Refinement

R[F ² > 2σ(F ²)] = 0.042
wR(F ²) = 0.120
S = 1.09
2027 reflections
155 parameters
H-atom parameters constrained
Δρ_max = 0.17 e Å⁻³
Δρ_min = −0.18 e Å⁻³

Data collection: XSCANS (Siemens, 1996 ▶); cell refinement: XSCANS; data reduction: XSCANS; program(s) used to solve structure: XPREP (Siemens 1994 ▶) and SHELXTL (Sheldrick, 2008 ▶); program(s) used to refine structure: SHELXTL; molecular graphics: SHELXTL; software used to prepare material for publication: SHELXTL.

Supplementary Material

Crystal structure: contains datablocks I, global. DOI: 10.1107/S1600536809025379/bh2233sup1.cif

e-65-o1802-sup1.cif^{(16.5KB, cif)}

Structure factors: contains datablocks I. DOI: 10.1107/S1600536809025379/bh2233Isup2.hkl

e-65-o1802-Isup2.hkl^{(99.7KB, 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
C2—H2⋯O3ⁱ	0.93	2.61	3.296 (2)	131
C5—H5⋯O1ⁱⁱ	0.93	2.64	3.273 (2)	125
C12—H12B⋯Cg1ⁱⁱⁱ	0.96	2.95	3.618 (3)	127
C13—H13B⋯Cg2ⁱⁱⁱ	0.96	2.78	3.587 (3)	142

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Symmetry codes: (i) Inline graphic ; (ii) ; (iii) . Cg1 is the centroid of the N1,C1,C6–C8 pyrrole ring and Cg2 is the centroid of the C1–C6 phenyl ring.

Acknowledgments

TAS acknowledges the College of Arts and Science at TSU for release time.

supplementary crystallographic information

Comment

Indole substituted at 3-position leads to variety of compounds that are precursors to biologically active important alkaloids. One of the most important compounds of this type is tryptophan, which possesses anticancerous, antimalarial, antiamoebic, and antihypertensive activities (Ma et al., 2001; Zhou et al., 2006; Zhao, Smith et al. 2002; Zhao, Liao, & Cook, 2002). α,β-Dehydroaminoacid esters (e.g.1, Fig. 1) are precursors to synthesizing tryptophan derivatives, which upon hydrogenation yield optically active tryptophan and its analogues (Ager & Laneman, 2004).

α,β-Dehydroamino acid esters were also synthesized using Erlenmeyer condensation (Amir-Heidari et al., 2007), Schmidt olefinations (Carlier et al., 2002), condensation of indole aldehyde with acetylamino malonic acid ester (Hengartner et al., 1979), and Knoevenagel-type condensation (Moriya et al. 1980). One such effort to synthesize hydroxyl dehydrotryptophan (3) from indoleester (1) using mono acid malonic ester (2) and aceticanhydride-pyridine mixture (Fig. 1) proved to be unsuccessful. The reaction resulted in 1H-indole-3-carboxylic acid-N-acetylethyl ester (4) instead. We rationalize that it is the electron withdrawing effect of the ester group which increases the acidity of the molecule. Consequently, in presence of a base, like pyridine, deprotonation and introduction of an acylium ion may occur. In this article we report the crystal structure of this compound.

The structure of the title compound is shown in Figure 2. The aromatic ring system of the molecule is essentially planar, but also the saturated ethyl group is located within this plane and the overall r.m.s. deviation from planarity is only 0.034 Å. Pairs of C—H···O interactions connect molecules into chains along the diagonal of the unit cell (Fig. 3). Molecules form weakly connected dimers viaπ···π stacking interactions of the indole rings with centroid to centroid distances of 3.571 (1) Å [symmetry operator for the second indole ring: (iii) 1 - x, 2 - y, 2 - z]. C—H···π interactions between methylene and methyl groups and the indole and benzene ring complete the range of intermolecular interactions [C12—H12B···Cg1ⁱⁱⁱ = 2.95 Å, X—H···Cg1ⁱⁱⁱ = 127°, X···Cg1ⁱⁱⁱ = 3.618 (3) Å; C13—H13B···Cg2ⁱⁱⁱ = 2.78 Å, X—H···Cg2ⁱⁱⁱ = 142°, X···Cg2ⁱⁱⁱ = 3.587 (3) Å; Cg1 and Cg2 are the centroids of the indole and the benzene rings, respectively].

Experimental

2-Acetamido-3-ethoxy-3-oxopropanoic acid (one of the starting materials) was prepared from acetylamino malonic acid diethylester following the process developed by Hellmann et al. (1958). The title compound was prepared as follows: to a mixture of 0.37 g (1.97 mmol) of the indole ester ethyl 1H-indole-3-carboxylate, 1.1 g (5.9 mmol) of 2-acetamido-3-ethoxy-3-oxopropanoic acid, and 4.54 ml of pyridine was added at 288 K (15 °C) over 15 minutes 1.6 ml of acetic anhydride. The reaction mixture turned yellow and was stirred at 333 K (60 °C) for 3 h. An additional 0.18 g (0.9 mmol) of ethyl acetamido malonate was added and stirring was continued for 22 h. Ice (10 ml) was added, and the mixture was stirred for 2 h and then diluted with 20 ml of water. The resulting solution was extracted with EtOAc (2 × 20 ml), the combined organic layer was dried with anhydrous Na₂SO₄ and the solvent was removed under reduced pressure. 0.4 g (99%) of 1H-indole-3-carboxylicacid-N-acetyl ethyl ester was isolated. ¹HNMR CDCl₃δ (p.p.m.): 8.70–8.50 (m,1H and 2H), 7.60–7.30 (m, 2H), 4.45 (q, J = 7 Hz, OCH₂CH₃), 2.70 (s, COCH₃), 1.45 (t, J = 7 Hz, OCH₂CH₃). The NMR data agree with those reported previously (Reimann et al., 1990). Crystals suitable for X-ray structural analysis were obtained by recrystallization form ethanol in a refrigerator.