Methyl 2-[(2-{2-[(2-acetamidophenyl)ethynyl]benzamido} phenyl)ethynyl]benzoate

Abstract

The title compound was prepared by inducing amide bond formation between methyl 2-[(2-aminophenyl)ethynyl]benzoate and 2-[(2-acetamidophenyl)ethynyl]benzoic acid in the presence of dichlorotriphenylphosphorane. The structure of the synthesized compound was determined on the basis of its ¹H-nuclear magnetic resonance (NMR), ¹³C-NMR, and mass spectral data. Furthermore, the compound’s crystal structure is also reported.

Introduction

The de novo design of oligomers that form well-defined three-dimensional conformations is of extraordinary importance in the fields of biotechnology, nanotechnology, and medicinal chemistry. Such conformationally ordered molecules are called foldamers [1], and amide, urea, arene, and acetylene units are often utilized as templates for constructing such foldamers [2,3,4,5,6,7,8,9,10]. In this note, we report the synthesis of the hybrid foldamer methyl 2-[(2-{2-[(2-acetamidophenyl)ethynyl]benzamido}phenyl)ethynyl]benzoate (3), which possesses both amide and acetylene units. Its dominant conformation in the crystalline state was also analyzed by X-ray crystallographic analysis.

During the synthesis of the molecule, the coupling of methyl 2-[(2-aminophenyl)ethynyl]benzoate (1) [11] and 2-[(2-acetamidophenyl)ethynyl]benzoic acid (2) [12] was induced with dichlorotriphenylphosphorane in CHCl₃ to give the target molecule 3 in a 95% yield. The structure of 3 was subsequently determined on the basis of its ¹H-nuclear magnetic resonance (NMR), ¹³C-NMR, and mass spectral data.

The three-dimensional structure of 3 was determined by X-ray crystallographic analysis [13,14]. Single crystals of 3 were obtained via the slow evaporation of tetrahydrofuran. The X-ray crystallographic structure of 3 was solved with a C_c spacer group, resulting in left- and right-handed folded structures containing 1.5 residues per turn (Figure 1). In the crystal structure of 3, two hydrogen bonds were observed between H-N(1) and C(1)=O(1) [N(1)···O(1) = 3.15 Å; N-H···O 165.9°] and between H-N(2) and C(2)=O(2) [N(2)···O(2) = 3.10 Å; N-H···O 159.9°]. The new folding molecule described in this study is expected to be useful for designing foldamer scaffolds.

Experimental Section

General Information

The molecule’s ¹H and ¹³C-NMR spectra were recorded on a Varian AS 400 spectrometer (Agilent, Santa Clara, CA, USA) after being dissolved in CDCl₃, and tetramethylsilane was used as an internal standard. The molecule’s coupling constants (J) are reported in Hz and refer to the apparent peak multiplicities (s = singlet, d = doublet, t = triplet, m = multiplet, br s= broad singlet). The molecule’s melting point was determined using a Yanako MP-13 (Yanako, Kyoto, Japan). High resolution mass spectra were recorded on a SHIMADZU LCMS-IT-TOF spectrometer (SHIMADZU, Kyoto, Japan). The data collection for the X-ray diffraction analysis was performed on Rigaku RAXIS-RAPID and Bruker AXS SMART APEX imaging plate diffractometers (Bruker, Yokohama, Japan) using graphite-monochromated MoKα radiation.

Synthesis of Methyl 2-[(2-{2-[(2-acetamidophenyl)ethynyl]benzamido}phenyl)ethynyl]benzoate (3)

Dichlorotriphenylphosphorane (1.0 g, 3.0 mmol) and 2-[(2-aminophenyl)ethynyl]benzoate (1) (376.9 mg 1.5 mmol) were added to a solution of 2-[(2-acetamidophenyl)ethynyl]benzoic acid (2) (279.3 mg, 1.0 mmol) in chloroform (5.0 mL). The reaction mixture was stirred for 3 h at 70 °C under an argon atmosphere. Chloroform (50 mL) was added to the solution, which was then washed with water (30 mL × 2) and brine (10 mL), before being dried over Na₂SO₄. The solvent was removed in vacuo, and the resultant product was purified by chromatography on silica gel (30% AcOEt in hexane) to give 3 (486 mg, 95%) as a colorless crystal.

Mp: 161–163 °C

¹H-NMR (CDCl₃, 400 MHz) δ 9.73 (br s, 1H), 8.81 (br s, 1H), 8.48-8.51 (m, 2H), 7.98 (d, 2H, J = 8.0 Hz), 7.85 (d, 1H, J = 7.2 Hz), 7.67 (d, 1H, J = 6.8 Hz), 7.57 (t, 2H, J = 7.6 Hz), 7.47–7.53 (m, 2H), 7.35–7.43 (m, 3H), 7.31 (t, 1H, J = 8.4 Hz), 7.15 (t, 1H, J = 7.6 Hz), 6.97 (t, 1H, J = 7.6 Hz), 3.34 (s, 3H), 2.29 (s, 3H).

¹³C-NMR (CDCl₃, 400 MHz) δ 24.6, 51.9, 89.8, 90.4, 93.9, 95.1, 111.5, 113.1, 119.6, 120.6, 122.2, 122.7, 123.8, 123.9, 127.9, 128.2, 129.0, 129.7, 129.9, 130.1, 130.5, 130.6, 131.6, 132.1, 132.3, 133.0, 133.7, 137.6, 140.2, 140.7, 165.4, 167.3, 170.1.

HRMS (ESI-TOF): [M + Na]⁺ calcd for C₃₃H₂₄N₂NaO₄ 535.1628; found 535.1634.