Ethyl 3,3,3-trifluoro-2-hy­droxy-2-(5-meth­oxy-1H-indol-3-yl)propionate

Zukhra Kadirova; Samat Tolipov; Oleg Fedorovskiy; Ibragimov Bakhtiyar; Nusrat Parpiev

doi:10.1107/S1600536811021489

. 2011 Jun 11;67(Pt 7):o1619. doi: 10.1107/S1600536811021489

Ethyl 3,3,3-trifluoro-2-hydroxy-2-(5-methoxy-1H-indol-3-yl)propionate

Zukhra Kadirova ^a,^*, Samat Tolipov ^b, Oleg Fedorovskiy ^c, Ibragimov Bakhtiyar ^b, Nusrat Parpiev ^d

PMCID: PMC3152102 PMID: 21837025

Abstract

In the title compound, C₁₄H₁₄F₃NO₄, the 3,3,3-trifluoropyruvate fragment has a syn configuration and is noncoplanar with the indole plane [dihedral angle = 84.87 (5)°]. In the crystal, molecules form inversion-related dimers via pairs of intermolecular O—H⋯O hydrogen bonds. These dimers are connected by intermolecular N—H⋯O=C(CF₃) hydrogen bonds to form a two-dimensional network structure.

Related literature

For background on the synthesis and activity of trifluoropyruvates of indole, see: Nakamura et al. (2008 ▶); Abid et al. (2008 ▶). For the crystal structures of related compounds, see: Choudhury et al. (2004 ▶); Abid et al. (2008 ▶).

Experimental

Crystal data

C₁₄H₁₄F₃NO₄
M _r = 317.26
Monoclinic,
a = 9.6277 (4) Å
b = 15.9760 (6) Å
c = 9.9738 (4) Å
β = 109.314 (5)°
V = 1447.75 (10) Å³
Z = 4
Cu Kα radiation
μ = 1.15 mm⁻¹
T = 293 K
0.55 × 0.45 × 0.40 mm

Data collection

Oxford Diffraction Xcalibur Ruby CCD diffractometer
Absorption correction: multi-scan (CrysAlis PRO; Oxford Diffraction, 2009 ▶) T _min = 0.782, T _max = 1.000
5738 measured reflections
2911 independent reflections
2319 reflections with I > 2σ(I)
R _int = 0.018

Refinement

R[F ² > 2σ(F ²)] = 0.040
wR(F ²) = 0.116
S = 1.06
2911 reflections
234 parameters
H atoms treated by a mixture of independent and constrained refinement
Δρ_max = 0.20 e Å⁻³
Δρ_min = −0.14 e Å⁻³

Data collection: CrysAlis PRO (Oxford Diffraction, 2009 ▶); 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 for Windows (Farrugia, 1997 ▶); software used to prepare material for publication: publCIF (Westrip, 2010 ▶).

Supplementary Material

Crystal structure: contains datablock(s) I, global. DOI: 10.1107/S1600536811021489/pk2322sup1.cif

e-67-o1619-sup1.cif^{(19.5KB, cif)}

Structure factors: contains datablock(s) I. DOI: 10.1107/S1600536811021489/pk2322Isup2.hkl

e-67-o1619-Isup2.hkl^{(142.9KB, hkl)}

Supplementary material file. DOI: 10.1107/S1600536811021489/pk2322Isup3.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—H1A⋯O2ⁱ	0.86 (2)	2.11 (2)	2.9166 (18)	156.8 (18)
O2—H2B⋯O3ⁱⁱ	0.80 (2)	2.03 (2)	2.7798 (17)	156 (2)

Open in a new tab

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

Acknowledgments

This work was supported by the Grant of Fundamental Research of the Center of Science and Technology, Republic of Uzbekistan (grant No. F3-142).

supplementary crystallographic information

Comment

3,3,3-Trifluoropyruvates have been used as efficient fluorinated building blocks in the synthesis of some biologically active trifluoromethylated compounds owing to the unique properties of the trifluoromethyl group, such as high electronegativity, electron density, steric hindrance and its hydrophobic character. The incorporation of a tertiary α-trifluoromethyl alcohol stereocenter (CF₃C*(OH)R₁R₂) into heterocycles could provide novel drug candidates with unusual biological activities as a result of the presence of the chiral tertiary α-trifluoromethyl alcohol functionality (Nakamura et al. 2008, Abid et al., 2008).

In this study we synthesized the 3,3,3-trifluoropyruvate derivative of indole, which is an analogue of indole alkaloids. The molecular structure is shown in Fig. 1.

The compound crystallizes as a racemate and the carboxy- and hydroxy- groups are syn to each other (torsion angle O2—C9—C10—O3 = 8.1 (2)°. The 3,3,3-trifluoropyruvate fragment is non-coplanar to the plane of the indole [torsion angles C8—C7—C9—C10, C6—C7—C9—C10, C6—C7—C9—O2, C8—C7—C9—O2 are 107.3 (2)°, -69.7 (2)°, 50.0 (2)°, and -133.0 (2)°, respectively)]. The methoxy-, hydroxy- and trifluoromethyl groups deviate from the indole plane by 0.061 (2), 0.854 (1) and 0.165 (2) Å, respectively. The bond distances C—C and C—N in the indole group are in the range 1.369–1.435 Å and 1.358–1.379 Å, respectively. Due to the concurrent influence of electron-withdrawing groups in the 3,3,3-trifluoropyruvate fragment, the EtO(O)C—C(O)CF₃ bond is elongated slightly to 1.554 (2) Å.

The fluorine does not readily accept hydrogen bonds and hence behaves differently from chlorine and bromine, but a signifcant number of compounds pack via weak interactions involving organic fluorine (Choudhury et al., 2004) and generate different packing motifs via F···F, C—H···F and C—F···π interactions. In the presence of a strong acceptor such as C=O, the C—H···O interaction takes priority over C—H···F. The molecules form inversion-related dimers via pairs of intermolecular O—H···O hydrogen bonds. These dimers are connected by intermolecular N—H···O═C(CF₃) hydrogen bonds to form a two-dimensional network structure.

Experimental

A solution of 0.170 g (0.001 mol) of ethyl 3,3,3-trifluoropyruvate in 10 ml of ether was added to a solution of 0.147 g (0.001 mol) of 5-methoxyindole in 10 ml ether, and stirred at room temperature for 24 h. The reaction was monitored by TLC. The reaction mixture was then evaporated under reduced pressure and the residue was purified by chromatography on silica gel (chloroform/ethylacetate=9:1); yield: 0.150 g (47%). The compound was crystallized from ethanolic solution by slow evaporation, giving colorless prism crystals suitable for X-ray diffraction analysis. ¹H NMR (300 MHz, dmso-d6): δ 1.11 (3H, t, CH₃); 4.22 (2H, q, CH₂, J_CH3—CH2 7,2 Hz); 3.72 (3H, s, O—CH₃), 6.78 (1H, d, aromatic, J_6–5 = 6.9 Hz), 7.17 (1H, s, aromatic), 7.32 (1H, d, aromatic), 7.37 (2H, s. br., OH, CH), 11.58 (1H, s. br., NH); ¹⁹F NMR (dmso-d6): 3.01 (s, CF₃); MS (m/z 317).